Autoinhibited and allosterically activated by 3,5-cyclic adenosine monophosphate (cAMP). An extensive conformational rearrangement relieves this autoinhibition by means of a substrate-mimicking lid that covers the protein-substrate binding surface.
Catalyzes specifically the acetylation of the epsilon-amino group of a highly conserved lysine residue in acetyl-CoA synthetase (ACS). This acetylation results in the inactivation of ACS activity and could be important for mycobacteria to adjust to environmental changes.
Binds 1 dipyrromethane group covalently.
Tetrapolymerization of the monopyrrole PBG into the hydroxymethylbilane pre-uroporphyrinogen in several discrete steps.
The porphobilinogen subunits are added to the dipyrromethane group.
Involved in the biosynthesis of the arabinogalactan (AG) region of the mycolylarabinogalactan-peptidoglycan (mAGP) complex, an essential component of the mycobacterial cell wall. Catalyzes the addition of an arabinofuranosyl (Araf) residue from the sugar donor decaprenyl-phospho-arabinose (DPA) on the C-3 of an alpha-(1->5)-linked Araf from the arabinan backbone of AG.
Expression requires SigE (PubMed:11489128, PubMed:25899163). Induced by carbonyl cyanide m-chlorophenyl hydrazone (CCCP) (PubMed:25899163). Induced in response to thioridazine (THZ) (PubMed:20386700).
Inactivation of the gene increases M.tuberculosis susceptibility to the intramacrophage environment (PubMed:25899163, PubMed:20688819). Deletion mutant shows a significantly reduced ability to arrest the acidification of the phagosome (PubMed:20688819).
Key stress-response regulator that plays an important role in multiple regulatory networks in response to different stress conditions (PubMed:20688819, PubMed:25899163). Involved in preservation of envelope integrity and tolerance to surface stress (PubMed:25899163). Essential for macrophage infection and facilitates intracellular growth of M.tuberculosis (PubMed:25899163, PubMed:20688819). Controls the expression of several protease and chaperone systems, including clpP1, clpP2, clpC1, ptrB, Rv1043c, acr2, clpB, Rv3269 and the clgR-pspA-rv2743c-rv2742c region (PubMed:20688819, PubMed:25899163, PubMed:23560081). Also plays an essential role in RecA/LexA-independent DNA repair mechanism by inducing expression of DNA repair genes in response to DNA damage (PubMed:21771781).
Contains an N-terminal HTH arsR-type DNA-binding domain and a C-terminal rhodanese-like domain.
Knockout mutant is hypersensitive to bedaquiline (PubMed:27573104). Deletion of the gene does not affect sensitivity to capreomycin, pretomanid and rifampicin (PubMed:27573104).
Part of a regulatory network that coordinates tolerance to the antitubercular drug bedaquiline.
Belongs to the glycosyl hydrolase 65 family.
Belongs to the ATP-dependent AMP-binding enzyme family.
Catalyzes the activation of long-chain fatty acids as acyl-adenylates (acyl-AMP), which are then transferred to the multifunctional polyketide synthase (PKS) type III for further chain extension (Probable). Involved in the biosynthesis of sulfolipid 1 (SL-1) (PubMed:17389997, PubMed:17768256).
Disruption of fadD23 increases binding affinity to human macrophage-like cell THP-1 and shows a lack of sulfolipid 1 production as compared to wild-type.
Belongs to the enoyl-CoA hydratase/isomerase family.
Highly up-regulated during the early stages of invasion of the human blood-brain barrier.
Belongs to the acyl-CoA dehydrogenase family.
Heterotetramer composed of 2 IpdE1 subunits and 2 IpdE2 subunits.
Involved in cholesterol degradation. Catalyzes the dehydrogenation of 5OH-HIP-CoA to 5OH-HIPE-CoA (PubMed:32101684). Can also use octanoyl-CoA and dihydroferuloyl-CoA, with lower efficiency. Cannot use 3-oxo-4-pregnene-20-carboxyl-CoA (3-OPC-CoA) (PubMed:32101684).
Based on a mutagenesis study of the catalytic fragment (residues 1-394), the (p)ppGpp phosphohydrolase domain seems to encompass approximately the first 203 residues, while the (p)ppGpp synthase domain seems to be found between residues 87 and 394.
Cells lacking this gene fail to synthesize ppGpp in response to starvation.
In eubacteria ppGpp (guanosine 3'-diphosphate 5'-diphosphate) is a mediator of the stringent response that coordinates a variety of cellular activities in response to changes in nutritional abundance. This enzyme catalyzes both the formation of pppGpp, which is then hydrolyzed to form ppGpp, as well as the hydrolysis of ppGpp. RelA is probably a key factor in the pathogenesis of M.tuberculosis as it regulates the intracellular concentrations of (p)ppGpp.
Transferase activity occurs when RelA binds to a complex containing uncharged tRNA, ribosomes, and mRNA (RelA activating complex or RAC). The addition of charged tRNA to this complex has the opposite effect, inhibiting transferase activity and activating hydrolysis activity.
Phosphorylated by PknJ. Dephosphorylated by PstP.
Mutants show a severe growth defect in the presence of copper. Deletion causes a drastic virulence defect in guinea pigs, mostly due to a much lower bacterial burden in the lungs.
Pore-forming protein, which is involved in efflux of copper across the outer membrane. Essential for copper resistance and maintenance of a low intracellular copper concentration. Required for virulence.
A member of the dormancy regulon. Induced in response to reduced oxygen tension (hypoxia), low levels of nitric oxide (NO) and carbon monoxide (CO). It is hoped that this regulon will give insight into the latent, or dormant phase of infection.
Induced by albendazole and thiabendazole, which inhibit the GTPase activity of FtsZ and probably septum formation.
Was identified as a high-confidence drug target.
Actively produced during the active phase of tuberculosis.
Belongs to the WXG100 family. ESAT-6 subfamily.
Elicits strong humoral responses. Induces significant lymphocyte proliferation and up-regulates the induction of TNF-alpha and IL-6 in tuberculosis patients.
Forms a tight 1:1 complex with EsxU (PubMed:20085764, PubMed:29559126). Complex formation results in induction of alpha-helical conformation and stability against chemical denaturation (PubMed:29559126).
Induces apoptosis of host cells via activation of NF-kappa-B.
Catalyzes the oxidative sulfurization of hercynine (N-alpha,N-alpha,N-alpha-trimethyl-L-histidine) into hercynyl-gamma-L-glutamyl-L-cysteine sulfoxide, a step in the biosynthesis pathway of ergothioneine. Ergothioneine is an antioxidant that protects mycobacteria from oxidative stress.
Belongs to the isocitrate lyase/PEP mutase superfamily. Isocitrate lyase family.
Together with AceAa, they could catalyze the formation of succinate and glyoxylate from isocitrate.
Binds 1 [4Fe-4S] cluster per subunit. The cluster is coordinated with 3 cysteines and an exchangeable S-adenosyl-L-methionine.
Catalyzes the synthesis of the hydroxymethylpyrimidine phosphate (HMP-P) moiety of thiamine from aminoimidazole ribotide (AIR) in a radical S-adenosyl-L-methionine (SAM)-dependent reaction.
Binds to DNA and alters its conformation. May be involved in regulation of gene expression, nucleoid organization and DNA protection.
Binds 1 heme group per monomer (PubMed:15135056, PubMed:17600145, PubMed:18980385). Half-life of Fe(2+) DosT is over 60 hours in air (PubMed:17600145).
Cells lacking this gene show no changes in gene induction following hypoxia, or exposure to NO or CO (PubMed:18474359). Another publication shows a slightly reduced response to CO (PubMed:18400743). Cells lacking both this gene and DevS (DosS) have no response to hypoxia, or exposure to NO or CO showing both proteins are required for the hypoxic, NO and CO responses (PubMed:15033981). 30% decreased induction of the DevR (DosR) regulon during anaerobic growth, 50% decreased induction of the DevR regulon upon exposure to NO during aerobic growth (PubMed:19487478).
Expressed during aerobic growth, it is not further induced in hypoxia, or by nitric oxide (NO) or carbon monoxide (CO) treatment (PubMed:15135056, PubMed:19487478). Expression is not changed in a devR deletion mutant; i.e. it is not part of the dormancy regulon (PubMed:19487478).
Interacts with the two-component regulatory system DevR/DevS (DosR/DosS) involved in onset of the dormancy response. Required for full induction of the DevR (DosR) regulon; required during early adaptation to anaerobiosis, to start induction of the DevR regulon (PubMed:19487478). May act as a direct hypoxia/oxygen sensor (PubMed:17609369, PubMed:17600145, PubMed:28977726). O(2) acts as a switch, with the Fe(2+)-O(2)-bound protein inactive in autophosphorylation (PubMed:17600145). Autophosphorylates under anaerobic but not aerobic conditions, binding of NO or CO has no effect on autophosphorylation (PubMed:17600145). Binds a number of gases; O(2), NO, CO (PubMed:17609369, PubMed:17600145). May be a secondary sensor for CO (PubMed:18400743). Donates a phosphate group to transcriptional regulator DevR (DosR) (PubMed:15135056, PubMed:15033981, PubMed:28977726).
Mg(2+). Both Mn(2+) and Ca(2+) can substitute Mg(2+) ion in the autophosphorylation reaction but not for phosphate transfer to DevR (DosR) (PubMed:15135056). In another study Mn(2+) and Ca(2+) substitute poorly for autophosphorylation (PubMed:17600145). In another study Mg(2+) or Mn(2+) are required for transfer, but Ca(2+) does not substitute as well (PubMed:28977726).
The isolated ATP-binding domain (residues 451-573) crystallized as an asymmetric, domain-swapped dimer without ATP (PubMed:23486471).
Belongs to the glyceraldehyde-3-phosphate dehydrogenase family.
Catalyzes the oxidative phosphorylation of glyceraldehyde 3-phosphate (G3P) to 1,3-bisphosphoglycerate (BPG) using the cofactor NAD. The first reaction step involves the formation of a hemiacetal intermediate between G3P and a cysteine residue, and this hemiacetal intermediate is then oxidized to a thioester, with concomitant reduction of NAD to NADH. The reduced NADH is then exchanged with the second NAD, and the thioester is attacked by a nucleophilic inorganic phosphate to produce BPG.
Belongs to the spermidine/spermine synthase family.
Catalyzes the irreversible transfer of a propylamine group from the amino donor S-adenosylmethioninamine (decarboxy-AdoMet) to putrescine (1,4-diaminobutane) to yield spermidine.
Belongs to the short-chain dehydrogenases/reductases (SDR) family.
A2-type phospholipase, which is probably involved in the degradation of macrophage membrane (PubMed:20103719). Hydrolyzes dipalmitoylphosphatidylcholine (PubMed:20103719). Also shows moderate esterase activity and hydrolyzes the p-nitrophenol-linked aliphatic ester pNP-butyrate (C4) (PubMed:19225166, PubMed:20103719). Does not exhibit cutinase activity (PubMed:19225166).
Circulating B cells able to spontaneously generate specific antibodies directed against Culp4 are detected during active tuberculosis and in some latent-tuberculosis cases.
Inhibited by high concentrations of paraoxon (PubMed:19225166). Inhibited by tetrahydrolipstatin (THL), a specific lipase inhibitor (PubMed:20103719).
Belongs to the FPP/GGPP synthase family.
Catalyzes the condensation of isopentenyl pyrophosphate (IPP) with (2E,6E)-farnesyl diphosphate (E,E-FPP) to yield geranylgeranyl diphosphate (GGPP).
Contains two aspartate-rich DDxxD motifs, designated as FARM (the first aspartate-rich motif) and SARM (the second aspartate-rich motif).
Belongs to the PINc/VapC protein family.
Toxic component of a type II toxin-antitoxin (TA) system. An RNase. The cognate antitoxin is VapB13 (By similarity).
Belongs to the thiolase-like superfamily. Beta-ketoacyl-ACP synthases family.
Deletion of the gene results in loss of acid-fast staining, which is a simple and rapid diagnostic test for detecting M.tuberculosis (PubMed:17360388, PubMed:22516756). The region between the inner and outer membranes of the mutant, which is composed mainly of cell wall anchored mycolic acids, shows a significant decrease in electron density as compared to the wild type. It suggests that altered mycolic acids patterns in the mutant may have affected the packing of the lipid rich layer of the M.tuberculosis cell envelope, resulting in a reduced electron density of this layer and loss of acid-fastness in light microscopical observation (PubMed:22516756). Mutants synthesize mycolic acids that are 2-6 carbons shorter than wild type and show a significant reduction in the abundance of keto-mycolates (PubMed:12950920, PubMed:17360388). Deletion of the gene affects mycolic acid trans-cyclopropanation, alters the colony morphology and abolishes classic serpentine growth (PubMed:17360388). Mutants exhibit strikingly altered cell wall permeability, leading to a marked increase in susceptibility to lipophilic antibiotics and the host antimicrobial molecules defensin and lysozyme (PubMed:12950920). Deletion mutant can persist in infected immunocompetent mice for up to 600 days without causing disease or mortality (PubMed:17360388).
Identified as a drug target (PubMed:10747933, PubMed:12950920). Inhibited by isoniazid (INH), thiolactomycin (TLM) and related analogs (PubMed:10747933, PubMed:12464486).
Part of the mycobacterial fatty acid elongation system FAS-II, which is involved in mycolic acid biosynthesis. Catalyzes the elongation of long chain acyl-ACP substrates by the addition of two carbons from malonyl-ACP to an acyl acceptor (PubMed:11600501, PubMed:12464486, PubMed:16873379). Involved in extension of the mycolate chains to full lengths and produces longer chain multiunsaturated hydrocarbons averaging 54 carbons in length (PubMed:12464486). Essential for resistance to macrophage antimicrobial activity (PubMed:12950920).
Phosphorylated on Thr-313 and Thr-315 (PubMed:24809459). Phosphorylated in vitro by several Ser/Thr protein kinases (STPKs) (PubMed:16873379).
Phosphorylation decreases the condensing activity of KasB and leads to the production of shorter mycolic acids, which is associated to dramatic phenotype changes, such as loss of acid-fastness, increase of cell wall permeability, severe attenuation in infected mice and defect in macrophage colonization.
Belongs to the FAD-dependent oxidoreductase 2 family. FRD/SDH subfamily.
Part of an enzyme complex containing four subunits: a flavoprotein (FrdA), an iron-sulfur protein (FrdB), and two hydrophobic anchor proteins (FrdC and FrdD).
A histidine residue in the pterin-binding domain interferes with substrate binding, and seems to be responsible for abolishing dihydropteroate synthase activity.
Has very low affinity for the DHPS substrate 6-hydroxymethyl-7,8-dihydropterin-pyrophosphate, but can bind the inhibitor dapsone. Seems to lack dihydropteroate synthase activity, and does probably not function in folate metabolism.
Antitoxin component of a type II toxin-antitoxin (TA) system. Upon expression in M.smegmatis neutralizes the effect of cognate toxin VapC46.
Belongs to the phD/YefM antitoxin family.
An ATPase (shown for residues 80-506) (PubMed:26396239). Part of the ESX-5 specialized secretion system, which is responsible for the secretion of EsxN and a number of PE_PGRS and PPE proteins, including PPE41.
Part of the ESX-5 / type VII secretion system (T7SS), which is composed of cytosolic and membrane components. The ESX-5 membrane complex is composed of EccB5, EccC5, EccD5 and EccE5.
Part of the eccB5-eccC5 operon, which is essential for in vitro growth.
Belongs to the binding-protein-dependent transport system permease family.
Belongs to the complex I 30 kDa subunit family.
NDH-1 is composed of 14 different subunits. Subunits NuoB, C, D, E, F, and G constitute the peripheral sector of the complex.
NDH-1 shuttles electrons from NADH, via FMN and iron-sulfur (Fe-S) centers, to quinones in the respiratory chain. The immediate electron acceptor for the enzyme in this species is believed to be a menaquinone. Couples the redox reaction to proton translocation (for every two electrons transferred, four hydrogen ions are translocated across the cytoplasmic membrane), and thus conserves the redox energy in a proton gradient.
Catalyzes the Claisen rearrangement of chorismate to prephenate. May play some role in the pathogenicity.
In the presence of high concentrations of tyrosine, phenylalanine, and tryptophan, the enzyme is completely protected from proteolytic degradation.
Tyrosine, phenylalanine, and tryptophan moderately enhance chorismate mutase activity at low concentrations, but allosterically inhibit the enzyme at higher concentrations.
Binds to the upstream region of Rv1714 and probably modulates the expression of the downstream gene(s).
Participates actively in the response to hyperosmotic and heat shock by preventing the aggregation of stress-denatured proteins, in association with DnaK and GrpE. It is the nucleotide exchange factor for DnaK and may function as a thermosensor. Unfolded proteins bind initially to DnaJ; upon interaction with the DnaJ-bound protein, DnaK hydrolyzes its bound ATP, resulting in the formation of a stable complex. GrpE releases ADP from DnaK; ATP binding to DnaK triggers the release of the substrate protein, thus completing the reaction cycle. Several rounds of ATP-dependent interactions between DnaJ, DnaK and GrpE are required for fully efficient folding.
Belongs to the CoA-transferase III family.
Involved in regulation of glutamate metabolism. Acts as a phosphorylation-dependent molecular switch that modulates the activities of Kgd, Gdh and GltB.
Monomer. Binds via its FHA domain to Kgd, Gdh, GltB, PknB, and the N-terminal region of PknG.
Phosphorylated on Thr-22 by PknB. Phosphorylated on Thr-21 by PknG. Phosphorylation at either Thr-21 or Thr-22 prevents binding to target enzymes. Phosphorylation at these two threonines is mutually exclusive in vitro. Could also be phosphorylated by PknD, PknE and PknF.
Phosphorylation triggers an intra-molecular protein closure, which blocks the FHA binding site and interaction with target enzymes, and switches off the regulatory function of GarA.
Belongs to the class-V pyridoxal-phosphate-dependent aminotransferase family.
Cells lacking this gene display impaired growth.
Lacks the conserved Lysine residue that is involved in covalent pyridoxal phosphate binding in other members of the family.
Presumably involved in the processing and regular turnover of intracellular proteins. Catalyzes the removal of unsubstituted N-terminal amino acids from various peptides (By similarity).
Belongs to the methyltransferase superfamily. RsmH family.
Specifically methylates the N4 position of cytidine in position 1402 (C1402) of 16S rRNA.
Belongs to the long-chain O-acyltransferase family.
Constitutively expressed at a low level, it is not further induced by hypoxia or nitric oxide exposure.
Upon expression in E.coli functions very weakly as a triacylglycerol synthase, making triacylglycerol (TG) from diolein and long-chain fatty acyl-CoA. Has no wax synthase activity.
Exhibits S-adenosyl-L-methionine-dependent methyltransferase activity.
Belongs to the sigma-70 factor family. ECF subfamily.
Extracytoplasmic function (ECF) sigma factors are held in an inactive form by an anti-sigma factor until released by regulated intramembrane proteolysis (RIP). RIP occurs when an extracytoplasmic signal triggers a concerted proteolytic cascade to transmit information and elicit cellular responses. The membrane-spanning anti-sigma factor is first cut extracytoplasmically (site-1 protease, S1P), then within the membrane itself (site-2 protease, S2P, Rip1), while cytoplasmic proteases finish degrading the regulatory protein, liberating SigK (Probable).
Interacts transiently with the RNA polymerase catalytic core formed by RpoA, RpoB, RpoC and RpoZ (2 alpha, 1 beta, 1 beta' and 1 omega subunit) to form the RNA polymerase holoenzyme that can initiate transcription. Interacts (via sigma-70 factor domain 4) with anti-sigma-K factor RskA.
Sigma factors are initiation factors that promote the attachment of RNA polymerase to specific initiation sites and are then released. Extracytoplasmic function (ECF) sigma factors are held in an inactive form by an anti-sigma factor until released by regulated intramembrane proteolysis. Sigma-K controls genes such as mpt70 and mpt83.
The sigma-70 factor domain-2 mediates sequence-specific interaction with the -10 element in promoter DNA, and plays an important role in melting the double-stranded DNA and the formation of the transcription bubble. The sigma-70 factor domain-2 mediates interaction with the RNA polymerase subunits RpoB and RpoC (By similarity).
The sigma-70 factor domain-4 contains a helix-turn-helix (H-T-H) motif that mediates interaction with the -35 element in promoter DNA. The domain also mediates interaction with the RNA polymerase subunit RpoA. Interactions between sigma-70 factor domain-4 and anti-sigma factors prevents interaction of sigma factors with the RNA polymerase catalytic core (By similarity).
Cleaves peptides in various proteins in a process that requires ATP hydrolysis. Has a chymotrypsin-like activity. Plays a major role in the degradation of misfolded proteins (By similarity). Degrades anti-sigma-D factor RsdA when present in a complex with ClpP1 and ClpX. Degrades anti-sigma-E factor RseA in the presence of ClpC1. Does not seem to act on anti-sigma-L factor RslA.
Fourteen ClpP subunits assemble into 2 heptameric rings which stack back to back to give a disk-like structure with a central cavity, resembling the structure of eukaryotic proteasomes (By similarity). Forms a complex with ClpP1 and ClpX.
Belongs to the P-Pant transferase superfamily.
Inhibited by the amidino-urea compound 1-[(2,6-diethylphenyl)-3-N-ethylcarbamimodoyl]urea (compound 8918). It acts by binding to the phosphopantetheine pocket in the active site. Inhibition by compound 8918 kills M.tuberculosis.
Required for the replication and survival of Mycobacterium during the acute and chronic phases of infection in mice.
Transfers the 4'-phosphopantetheine moiety from coenzyme A to a Ser of acyl-carrier-protein (PubMed:9831524, PubMed:16709676, PubMed:25785780, PubMed:28203522). Involved in post-translational modification of various type-I polyketide synthases required for the formation of both mycolic acids and lipid virulence factors (PubMed:16709676). Acts on Pks13, Mas, PpsA, PpsB, PpsC and PpsD (PubMed:16709676, PubMed:28203522). Also acts on AcpM, the meromycolate extension acyl carrier protein (PubMed:25785780). In addition, is involved in the activation of the acyl carrier protein MbtL and the nonribosomal peptides synthases MbtB and MbtE, which are involved in the biosynthesis of the siderophore mycobactin (PubMed:9831524, PubMed:28203522).
May function as a glyoxylase involved in the methylglyoxal detoxification pathway (PubMed:20975714). Induces maturation of dendritic cells in a TLR2-dependent manner, causing increased expression of cell-surface molecules (CD80, CD86, MHC class I and II) and pro-inflammatory cytokines (TNF-alpha, IL-6, IL-1 beta and IL-12p70). Acts via both the NF-kappa-B and MAPK signaling pathways. Induces Th1-polarized immune responses (PubMed:22415304).
Monomer in solution (PubMed:21761124). Interacts with human TLR2 (PubMed:22415304).
Overexpression confers resistance to pyrimidine-imidazoles (PIs) compounds.
Belongs to the acetyltransferase family.
Could possibly oxidize fatty acids using specific components.
Belongs to the phosphohexose mutase family.
Belongs to the FAD-dependent glycerol-3-phosphate dehydrogenase family.
Belongs to the sulfatase-modifying factor family.
Cells are viable and do not display growth defects. They however show reduced sulfatase activity.
Oxidase that catalyzes the conversion of cysteine to 3-oxoalanine on target proteins. 3-oxoalanine modification, which is also named formylglycine (fGly), occurs in the maturation of arylsulfatases and some alkaline phosphatases that use the hydrated form of 3-oxoalanine as a catalytic nucleophile.
The catalytic copper is required to activate oxygen and catalyze oxidative C-H activation.
Belongs to the DmpD/TodF/XylF esterase family.
Ref.2 (CAA41963) sequence was wrongly assigned to be a thymidylate synthase.
Antitoxin component of a type II toxin-antitoxin (TA) system. Upon expression in M.smegmatis neutralizes the effect of cognate toxin VapC28.
Belongs to the class-V pyridoxal-phosphate-dependent aminotransferase family. Csd subfamily.
Catalyzes the removal of elemental sulfur and selenium atoms from L-cysteine, L-cystine, L-selenocysteine, and L-selenocystine to produce L-alanine.
Belongs to the mycobacterial PPE family.
Homodimer (PubMed:17433643). Interacts with PE35. PE35/PPE68 complex interacts with human TLR2 (PubMed:24467650). Interacts in vitro with EspG1, EccA1 and EsxB (PubMed:17433643).
Inactivation does not abolish EsxA secretion, EsxA-specific immunogenicity and enhanced virulence.
PPE68 is recognized by antigen-specific T-cell lines from HLA-heterogeneous subjects. Peptide P9 is an immunodominant and HLA-DR promiscuous peptide of PPE68 (amino acids 121-145), and may be exploited as a peptide-based vaccine candidate against tuberculosis and other mycobacterial diseases.
Plays a major role in RD1-associated pathogenesis, and may contribute to the establishment and maintenance of M.tuberculosis infection. Together with PE35, stimulates the secretion of IL-10 and MCP-1 from human macrophages, via the interaction with human Toll-like receptor 2 (TLR2) (PubMed:24467650). Stimulates high levels of gamma interferon secretion in peripheral blood mononuclear cells isolated from tuberculosis patients, as well as from healthy tuberculin purified protein derivative-positive donors. Does not interfere with the secretion and immunogenicity of EsxA (ESAT-6) and EsxB (CFP-10) (PubMed:14573626, PubMed:15039340).
5-fold by phosphate starvation, part of the pstS3-pstC2-pstA1 operon.
Belongs to the binding-protein-dependent transport system permease family. CysTW subfamily.
Part of the ABC transporter complex PstSACB involved in phosphate import; probably responsible for the translocation of the substrate across the membrane.
The complex is composed of two ATP-binding proteins (PstB), two transmembrane proteins (PstC and PstA) and a solute-binding protein (PstS).
Binds 4 Mg(2+) or Mn(2+) ions per subunit.
Composed of two chains; the small (or glutamine) chain promotes the hydrolysis of glutamine to ammonia, which is used by the large (or ammonia) chain to synthesize carbamoyl phosphate.
Belongs to the transposase mutator family.
Required for the transposition of the insertion element.
Forms a heterodimer with PPE41. The dimer forms a 1:1:1 heterotrimeric complex with EspG5 (PubMed:16690741, PubMed:25155747, PubMed:25275011). Interacts with PPE51 (PubMed:32139546).
The PE25/PPE41 dimer induces both a strong humoral and cellular immune response. PE25 protein alone induces low response (PubMed:18974870). The dimer induces necrosis, but not apoptosis, in mouse macrophage cells (PubMed:25379378). It also induces activation and maturation of mouse dendritic cells and drives Th2-biased immune responses (PubMed:26318856).
Belongs to the class-II aminoacyl-tRNA synthetase family. ProS type 1 subfamily.
Catalyzes the attachment of proline to tRNA(Pro) in a two-step reaction: proline is first activated by ATP to form Pro-AMP and then transferred to the acceptor end of tRNA(Pro). As ProRS can inadvertently accommodate and process non-cognate amino acids such as alanine and cysteine, to avoid such errors it has two additional distinct editing activities against alanine. One activity is designated as 'pretransfer' editing and involves the tRNA(Pro)-independent hydrolysis of activated Ala-AMP. The other activity is designated 'posttransfer' editing and involves deacylation of mischarged Ala-tRNA(Pro). The misacylated Cys-tRNA(Pro) is not edited by ProRS.
Consists of three domains: the N-terminal catalytic domain, the editing domain and the C-terminal anticodon-binding domain.
Constitutively expressed during growth in culture.
Hydrolyzes N(G),N(G)-dimethyl-L-arginine (ADMA) and N(G)-monomethyl-L-arginine (MMA).
Disruption abolishes EsxA and EsxB secretion, but not their expression (PubMed:14557547, PubMed:14557536). It results in a lack of antigen specific immunogenicity and leads to attenuated virulence (PubMed:16368961). Mutants exhibit defects in bacterial growth during the acute phase of a mouse infection (PubMed:14557536). No growth in the human macrophage-like cell line THP-1, no cytotoxicity (PubMed:14756778).
EsxB binding to the second FtsK domain of EccCb1 causes multimerization; a subsequent unknown step relieves the allosteric inhibition of linker 2 on FtsK domain 1 (in EccCa1 subunit), activating the ATPase activity (PubMed:25865481).
In ESX-1 cluster, the FtsK/SpoIIIE-like protein is split in two genes.
Part of the ESX-1 / type VII secretion system (T7SS), which is composed of cytosolic and membrane components. The ESX-1 membrane complex is composed of EccB1, EccCa1, EccCb1, EccD1 and EccE1 (PubMed:14557536, PubMed:16368961, PubMed:19876390). Interacts with EccCa1, EspK and the C-terminus of EsxB (PubMed:14557536, PubMed:16973880, PubMed:17676952). Residues 1-261 interact with EsxB and an artificial EsxB-EsxA heterodimer (PubMed:19854905).
Part of the ESX-1 specialized secretion system, which delivers several virulence factors to host cells during infection, including the key virulence factors EsxA (ESAT-6) and EsxB (CFP-10) (PubMed:14557547, PubMed:14557536, PubMed:16368961, PubMed:16973880). EccCb1 may link the cytosolic components of the system with the membrane components (PubMed:16973880).
The C-terminus (residues 252-747) interacts with EsxB, the whole protein is required for interaction with EccCa1 (PubMed:14557536).
Interacts with multiple cell division proteins such as FtsZ, PbpB (PBP3, FtsI), FtsQ, PBPA and CwsA.
Involved in cell division. Plays an important role in septal peptidoglycan synthesis and cell shape morphogenesis. May facilitate the recruitment of the peptidoglycan synthesis machinery to poles and septal zones and coordinate peptidoglycan synthesis at these sites.
Antitoxin component of a type II toxin-antitoxin (TA) system. Upon expression in M.smegmatis neutralizes the effect of cognate toxin VapC35.
Belongs to the ABC transporter superfamily.
Belongs to the SIMIBI class G3E GTPase family. ZNG1 subfamily.
Zinc chaperone that directly transfers zinc cofactor to target proteins, thereby activating them. Zinc is transferred from the CXCC motif in the GTPase domain to the zinc binding site in target proteins in a process requiring GTP hydrolysis.
Specifically induced by a broad range of inhibitors of cell wall biosynthesis, including antibiotics that inhibit the synthesis of peptidoglycan (ampicillin), arabinogalactam (ethambutol), mycolic acids (isoniazid, ethionamide) and fatty acids (5-chloropyrazinamide). Down-regulated by the nucleoid-associated protein Lsr2.
Belongs to the LytR/CpsA/Psr (LCP) family.
Contains two rhodanese domains with different primary structures but with near identical secondary structure conformations suggesting a common evolutionary origin. Only the C-terminal rhodanese domain contains the catalytic cysteine residue (By similarity).
May be a sulfotransferase involved in the formation of thiosulfate.
Belongs to the DNA repair enzymes AP/ExoA family.
Probably binds two magnesium or manganese ions per subunit.
Part of the ESX-2 / type VII secretion system (T7SS), which is composed of cytosolic and membrane components.
Belongs to the geranylgeranyl reductase family.
Catalyzes the reduction of a single double bond in the isoprenoid tail of menaquinone (MK-9) in M.tuberculosis, likely the beta-isoprene unit, forming the predominant form of menaquinone found in mycobacteria, MK-9(II-H2). Is required for M.tuberculosis survival in host macrophages.
Cells lacking this gene show complete abolition of the synthesis of MK-9(II-H2) accompanied by accumulation of MK-9. They have similar growth rates than wild-type in both aerated and hypoxic culture conditions. However, despite having similar levels of adhesion and infection at the earliest time point, the survival of mutant bacilli in the macrophages is dramatically reduced.
Constitutively expressed at a low level, not induced by salicylate.
A possible member of the dormancy regulon. Induced in response to reduced oxygen tension (hypoxia) and low levels of nitric oxide (NO). It is hoped that this regulon will give insight into the latent, or dormant phase of infection.
Catalyzes the terminal and only committed step in triacylglycerol synthesis by using diacylglycerol and fatty acyl CoA as substrates. Required for storage lipid synthesis.
Upon expression in E.coli functions weakly as a triacylglycerol synthase, making triacylglycerol (TG) from diolein and long-chain fatty acyl-CoA. Has no wax synthase activity to produce wax esters.
Belongs to the class I-like SAM-binding methyltransferase superfamily. MenG/UbiE family.
Methyltransferase required for the conversion of demethylmenaquinol (DMKH2) to menaquinol (MKH2).
Has acyl-CoA dehydrogenase activity on a number of substrates. N-octanoyl-CoA is the best tested, but n-lauroyl-CoA, n-palmitoyl-CoA and isovaleryl-CoA were also used.
Belongs to the cytochrome ubiquinol oxidase subunit 2 family.
Part of the binding-protein-dependent transport system for phosphate; probably responsible for the translocation of the substrate across the membrane.
Transcription slightly induced by phosphate starvation, part of the pstB3-pstS2-pstC1-pstA2 operon (PubMed:20933472).
Cleaves peptides in various proteins in a process that requires ATP hydrolysis. Has a chymotrypsin-like activity. Plays a major role in the degradation of misfolded proteins (By similarity). Degrades anti-sigma-D factor (rsdA) when present in a complex with ClpP2 and ClpX. Does not seem to act on anti-sigma-L factor (rslA).
Fourteen ClpP subunits assemble into 2 heptameric rings which stack back to back to give a disk-like structure with a central cavity, resembling the structure of eukaryotic proteasomes. Forms a complex with ClpP2 and ClpX.
Pupylation of this protein has been demonstrated, however it is unknown if it is the product of this gene, of the identical gene Rv0814c (AC P0CG95), or of both of them.
Pupylation of this protein has been demonstrated, however it is unknown if it is the product of this gene, of the identical gene Rv3118 (AC P0CG96), or of both of them.
Belongs to the cytochrome ubiquinol oxidase subunit 1 family.
Belongs to the mycobacterial PE family. PGRS subfamily.
Contains a tightly bound zinc ion. The presence of this ion is unexpected, and two His residues from the hexahistidine tag on the expression vector contribute to the zinc binding site.
Contains an aspartic proteinase-like domain in the C-terminal region. However, the enzyme is inactive. A comparison of the structure with pepsins showed significant differences in the critical substrate binding residues and in the flap tyrosine conformation that could contribute to the lack of proteolytic activity of PE_PGRS16.
Expression is induced in macrophages and infected mice (PubMed:16672626). Highly up-regulated during the early stages of invasion of the human blood-brain barrier (PubMed:16586367).
Expression of this gene in M.smegmatis leads to increased levels of NO and IL-12 and poor survival of recombinant strains in macrophages.
Tetramer of two alpha and two beta chains.
The beta subunit is responsible for the synthesis of L-tryptophan from indole and L-serine.
Belongs to the inositol monophosphatase superfamily.
Catalyzes the dephosphorylation of histidinol-phosphate to histidinol, the direct precursor of histidine.
Strains lacking this gene appear to be not viable, even in the presence of high levels of exogenous inositol.
When comparing gene expression levels of the four IMPase family genes in exponential cultures of M.tuberculosis, the level of cysQ is the highest, almost equal to sigA; impA and impC are expressed at approximately 40% of this level, while suhB is lowest, at 12% of the cysQ level.
Binds 1 [4Fe-4S] cluster per subunit. Contains 1 [2Fe-2S] cluster after reconstitution of overexpressed protein from E.coli. Following nitrosylation of the [4Fe-4S] cluster binds 1 [4Fe-8(NO)] cluster per subunit.
By sublethal doses of antibiotics such as erythromycin, streptomycin and tetracycline as well as the fatty acids palmitic and oleic acid (in clinical strain 1254). By the antibiotic erythromycin. Positively regulates its own expression (in strain H37Rv).
Decreased resistance to macrolides, a lincosamide, and an aminoglycoside antibiotic.
The Fe-S cluster can be nitrosylated by nitric oxide (NO).
The apo- but not holo-form probably binds DNA (By similarity). Acts as a transcriptional regulator. Probably redox-responsive. Upon overproduction at least 10 other genes are up-regulated, among them are Rv1258c, Rv1988, Rv2301, Rv2416c, Rv2725c and whiB7 itself. Probably redox-responsive. The apo-form has been shown to act as a protein disulfide reductase.
Upon Fe-S cluster removal intramolecular disulfide bonds are formed.
4-fold by phosphate starvation, part of the pstS3-pstC2-pstA1 operon.
Dicyclohexylcarbodiimide (DCDD) binding to the active glutamate residue inhibits ATPase in vitro.
F(1)F(0) ATP synthase produces ATP from ADP in the presence of a proton or sodium gradient. F-type ATPases consist of two structural domains, F(1) containing the extramembraneous catalytic core and F(0) containing the membrane proton channel, linked together by a central stalk and a peripheral stalk. During catalysis, ATP synthesis in the catalytic domain of F(1) is coupled via a rotary mechanism of the central stalk subunits to proton translocation.
F-type ATPases have 2 components, F(1) - the catalytic core - and F(0) - the membrane proton channel. F(1) has five subunits: alpha(3), beta(3), gamma(1), delta(1), epsilon(1). F(0) has three main subunits: a(1), b(2) and c(10-14). The alpha and beta chains form an alternating ring which encloses part of the gamma chain. F(1) is attached to F(0) by a central stalk formed by the gamma and epsilon chains, while a peripheral stalk is formed by the delta and b chains.
Key component of the F(0) channel; it plays a direct role in translocation across the membrane. A homomeric c-ring of between 10-14 subunits forms the central stalk rotor element with the F(1) delta and epsilon subunits.
Belongs to the beta sliding clamp family.
Confers DNA tethering and processivity to DNA polymerases and other proteins. Acts as a clamp, forming a ring around DNA (a reaction catalyzed by the clamp-loading complex) which diffuses in an ATP-independent manner freely and bidirectionally along dsDNA. Initially characterized for its ability to contact the catalytic subunit of DNA polymerase III (Pol III), a complex, multichain enzyme responsible for most of the replicative synthesis in bacteria; Pol III exhibits 3'-5' exonuclease proofreading activity. The beta chain is required for initiation of replication as well as for processivity of DNA replication (By similarity). Binds ds- and ssDNA (PubMed:22545130). Binds the antibiotic griselimycin and its derivatives with high affinity (1.0 x 10(-10) to 2.0 x 10(-10) M sec(-1)) (PubMed:26045430). Binding occurs in a hydrophobic cleft between domains 2 and 3, which have been shown to be responsible for binding DNA polymerases and other DNA-modifying proteins (PubMed:26045430).
Forms a ring-shaped head-to-tail homodimer (PubMed:21219854, PubMed:22545130, PubMed:26045430) around DNA which binds and tethers DNA polymerases and other proteins to the DNA (PubMed:21219854, PubMed:22545130). The DNA replisome complex has a single clamp-loading complex (3 tau and 1 each of delta, delta', psi and chi subunits) which binds 3 Pol III cores (1 core on the leading strand and 2 on the lagging strand) each with a beta sliding clamp dimer (By similarity). Additional proteins in the replisome are other copies of gamma, psi and chi, Ssb, DNA helicase and RNA primase (By similarity). Interacts with the tau/gamma subunit (dnaX) (PubMed:22545130).
Strains that are resistant to griselimycin occur at a very low frequency and are associated with amplification of a 10.3 kb chromosomal segment containing this gene as well as the ori site, suggesting antibiotic resistance may be due to overexpression of the wild-type protein (PubMed:26045430).
Belongs to the major facilitator superfamily.
Antitoxin component of a type II toxin-antitoxin (TA) system. Upon expression in M.smegmatis neutralizes the effect of cognate toxin VapC26.
Forms a complex with cognate antitoxin MazE2.
Toxic component of a type II toxin-antitoxin (TA) system. Upon expression in E.coli partially inhibits cell growth after one cell generation (PubMed:16611633). Its cognate antitoxin is MazE2. Probably an endoribonuclease (By similarity).
Belongs to the acetaldehyde dehydrogenase family.
Involved in cholesterol degradation. Catalyzes the conversion of propanal to propanoyl-CoA, using NAD(+) and coenzyme A. Has a broad substrate specificity, and can also use acetaldehyde, butyrlaldehyde, isobutyrlaldehyde and pentaldehyde as substrates.
Monomer. Forms an heterotetramer composed of two aldolase (HsaF) and two dehydrogenase (HsaG) subunits.
Unlike HsaF, HsaG is active both in the presence and absence of its partner enzyme.
Belongs to the anaerobic coproporphyrinogen-III oxidase family. HemW subfamily.
Might carry two S-adenosyl-L-methionine binding sites with only one binding to the iron-sulfur cluster.
Probably acts as a heme chaperone, transferring heme to an unknown acceptor. Binds one molecule of heme per monomer, possibly covalently (By similarity). Binds 1 [4Fe-4S] cluster. The cluster is coordinated with 3 cysteines and an exchangeable S-adenosyl-L-methionine (By similarity).
Could be a prospective candidate for the development of subunit vaccine against tuberculosis.
Expression is high during exponential phase. Induced during hypoxic conditions. Induced in the lung and in spleen tissues of mice during the early and chronic stages of infection.
Plays significant roles in mycobacterial persistence during infection and modulates host immune response.
The immunization of mice with recombinant PE3 protein stimulates the secretion of TNF, IL-6 and IL-2 cytokines and generates strong protective immunity against challenge with live mycobacteria.
Toxic component of a type II toxin-antitoxin (TA) system. Probably exerts its toxic effect by binding to mRNA, inhibiting translation. Binds to, recognizes and cleaves ssRNA at ACGC and AC(A/U)GC sequences, usually between the G and C; cleavage is not very efficient, nor is cleavage required to inhibit protein synthesis. Upon expression in situ, in M.smegmatis or E.coli inhibits cell growth and colony formation; in at least E.coli also causes increased levels of cellular RNA. Its toxic effect is neutralized by coexpression with cognate antitoxin VapB4.
Belongs to the methyltransferase superfamily. RsmI family.
Catalyzes the 2'-O-methylation of the ribose of cytidine 1402 (C1402) in 16S rRNA.
Up-regulated 34-fold 7 days after infection of human macrophages.
Belongs to the purine/pyrimidine phosphoribosyltransferase family.
Competitively inhibited by acyclic nucleoside phosphonates (ANPs) with Ki values as low as 0.69 uM. Prodrugs of these compounds arrest the growth of a virulent strain of M.tuberculosis with MIC50 values as low as 4.5 uM and possess low cytotoxicity in mammalian cells (PubMed:25915781). Inhibited by pyrrolidine nucleoside bisphosphonates, which are also able to arrest the growth of virulent M.tuberculosis not only in its replicating phase but also in its latent phase, and to arrest the growth of M.tuberculosis in infected macrophages while having low cytotoxicity in mammalian cells (PubMed:30265958).
Homodimer and homotetramer in equilibrium. The presence or absence of divalent metal ions, as well as phosphate, can affect the oligomerization state of the enzyme. Likely functions as a tetramer (rather than a dimer) in its biological environment, which is the most active form. The dimeric structure is also active though ~50% of that of the tetramer.
Is a target for anti-TB drug development.
Purine salvage pathway enzyme that catalyzes the transfer of the ribosyl-5-phosphate group from 5-phospho-alpha-D-ribose 1-diphosphate (PRPP) to the N9 position of the 6-oxopurines hypoxanthine and guanine to form the corresponding ribonucleotides IMP (inosine 5'-monophosphate) and GMP (guanosine 5'-monophosphate), with the release of PPi (PubMed:19362594, PubMed:25915781). Thus, specifically recycles hypoxanthine and guanine imported from the external medium, and converts them to IMP and GMP, respectively. Cannot use xanthine as substrate (PubMed:19362594).
Heterotetramer with 2 subunits each of MbcT and MbcA; the tetramers further assemble into trimers with 3-fold symmetry. The antitoxin acts by blocking acces to the toxin active site.
Induced by hypoxia (PubMed:18231589). Expression induced in both active and resting C57BL/6 mouse macrophages (PubMed:20628579). Induced in persister cells (PubMed:21673191). Induced by streptomycin treatment and by starvation (PubMed:28724903). Induced by starvation stress; probably part of the mbcT-mbcA operon (PubMed:30792174).
Molecules that disrupt the MbcT-MbcA complex could be candidates for anti-tuberculosis therapy.
Not essential, it can be deleted (PubMed:28096490). Deletion of the mbcT-mbcA operon has no visible phenotype (PubMed:30792174).
Toxic component of a type II toxin-antitoxin (TA) system. Neutralized by cognate antitoxin MbcA (PubMed:30315706, PubMed:30792174). Degrades NAD(+) by phosphorolysis. Expression in the absence of its cognate antitoxin MbcA causes dramatic reduction of intracellular NAD(+) levels and is deleterious to cell growth, causing cell death. In a SCID mouse infection model, mice infected with bacteria overexpressing this protein survive longer. Overexpression of this protein in a mouse infection model at 21 days leads to bacterial death, and shows a synergistic 100-fold increase in mouse survival when combined with isoniazid treatment (PubMed:30792174).
Required for maturation of 30S ribosomal subunits.
Belongs to the glycosyltransferase 2 family.
Interacts with Rv3789. Is thus probably part of an AG biosynthetic complex.
Involved in the biosynthesis of the arabinogalactan (AG) region of the mycolylarabinogalactan-peptidoglycan (mAGP) complex, an essential component of the mycobacterial cell wall. Catalyzes the transfer of the first two galactofuranosyl (Galf) units from UDP-galactofuranose (UDP-Galf) onto the rhamnosyl-GlcNAc-diphospho-decaprenol (Rha-GlcNAc-PP-C50) acceptor, yielding galactofuranosyl-galactofuranosyl-rhamnosyl-GlcNAc-diphospho-decaprenol (Galf-Galf-Rha-GlcNAc-PP-C50). Thus, GlfT1 is the initiator of galactan synthesis, while GlfT2 continues with the subsequent polymerization events.
Toxic component of a type II toxin-antitoxin (TA) system. An RNase. The cognate antitoxin is VapB9 (By similarity).
In the C-terminal section; belongs to the ferredoxin--NADP reductase family.
Belongs to the cytochrome c oxidase subunit 3 family.
Belongs to the resistance-nodulation-cell division (RND) (TC 2.A.6) family. MmpL subfamily.
Deletion of the gene does not affect the biosynthesis of all three types of mycolic acid.
Shows trans-enoyl-CoA hydratase/3-hydroxyacyl-CoA dehydratase activity (PubMed:19136596, PubMed:20511508). Displays a broad chain length specificity, with a predilection for the C8 to C12 substrates (PubMed:20511508).
Belongs to the methyltransferase superfamily.
Belongs to the ATP phosphoribosyltransferase family. Long subfamily.
Catalyzes the condensation of ATP and 5-phosphoribose 1-diphosphate to form N'-(5'-phosphoribosyl)-ATP (PR-ATP). Has a crucial role in the pathway because the rate of histidine biosynthesis seems to be controlled primarily by regulation of HisG enzymatic activity.
Equilibrium between an active dimeric form, an inactive hexameric form and higher aggregates. Interconversion between the various forms is largely reversible and is influenced by the natural substrates and inhibitors of the enzyme.
Feedback inhibited by histidine. Also inhibited by AMP.
Belongs to the RNA polymerase subunit omega family.
Promotes RNA polymerase assembly. Latches the N- and C-terminal regions of the beta' subunit thereby facilitating its interaction with the beta and alpha subunits.
The RNAP catalytic core consists of 2 alpha, 1 beta, 1 beta' and 1 omega subunit. When a sigma factor is associated with the core the holoenzyme is formed, which can initiate transcription.
Important for the siderophore-mediated iron-acquisition function of ESX-3.
PE5-PPE4 double mutant exhibits a severe iron phenotype but secretes EsxG and EsxH normally. Mildly attenuated in vivo.
Belongs to the complex I subunit 6 family.
NDH-1 shuttles electrons from NADH, via FMN and iron-sulfur (Fe-S) centers, to quinones in the respiratory chain. Couples the redox reaction to proton translocation (for every two electrons transferred, four hydrogen ions are translocated across the cytoplasmic membrane), and thus conserves the redox energy in a proton gradient.
Belongs to the aldehyde dehydrogenase family.
Catalyzes the NADP(+)-dependent oxidation of succinate semialdehyde to succinate. It is believed to be the main source of succinate semialdehyde dehydrogenase activity in Mycobacterium. NAD(+) can substitute for NADP(+), but enzymatic activity is three times reduced.
Belongs to the short-chain fatty acyl-CoA assimilation regulator (ScfR) family.
Belongs to the DNA polymerase type-Y family.
Poorly processive, error-prone DNA polymerase involved in untargeted mutagenesis. Copies undamaged DNA at stalled replication forks, which arise in vivo from mismatched or misaligned primer ends. These misaligned primers can be extended by PolIV. Exhibits no 3'-5' exonuclease (proofreading) activity. May be involved in translesional synthesis, in conjunction with the beta clamp from PolIII (By similarity).
Anchors the catalytic components of the fumarate reductase complex to the cell membrane, binds quinones.
Candidate for development of a vaccine for the control of tuberculosis.
Probably plays a key role in regulating innate and adaptive immune responses through human Toll-like receptor 2 (TLR2). Interacts with TLR2, leading to the subsequent activation of the mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NF-kappa-B) signaling pathways. Stimulates macrophage activation by augmenting pro-inflammatory cytokine production (TNF-alpha, IL-6 and IL-12p40) and the expression of cell surface molecules (CD80, CD86, MHC class I and II). Also participates in adaptive immunity by directing Th1-polarised immune responses.
This protein serves as an immunogenic antigen, inducing gamma-interferon responses in whole-blood cultures from M.tuberculosis-exposed adults in Uganda, The Gambia and South Africa, indicating this might be a good vaccine candidate.
Deletion mutant does not synthesize SMK and shows a hypervirulent phenotype in the mouse model of infection (PubMed:27933784). Loss of the gene does not affect levels of menaquinone-9 (MK-9), an essential component in the electron-transport chain in M.tuberculosis (PubMed:27933784).
Involved in the biosynthesis of sulfomenaquinone (SMK, initially named S881 on the basis of its mass), which is localized in the outer envelope of M.tuberculosis and negatively regulates its virulence (PubMed:27933784). Catalyzes the hydroxylation of beta-dihydromenaquinone-9, leading to the formation of omega-hydroxy-beta-dihydromenaquinone-9 (PubMed:27933784).
Mutants with simultaneous deletion of PPE25/PE18/PPE26/PPE27/PE19 genes have a slight growth defect at 100 mM phosphate in defined media, and at 30 mM phosphate, growth is severely impaired. Knockdown of PE32 or PPE65 in PPE25/PE18/PPE26/PPE27/PE19 deletion mutants result in a severely impaired growth in phosphate-limiting media.
Belongs to the peptidase M24A family. Methionine aminopeptidase type 1 subfamily.
Binds 2 divalent metal cations per subunit. Has a high-affinity and a low affinity metal-binding site. The true nature of the physiological cofactor is under debate. The enzyme is active with cobalt, zinc, manganese or divalent iron ions. Most likely, methionine aminopeptidases function as mononuclear Fe(2+)-metalloproteases under physiological conditions, and the catalytically relevant metal-binding site has been assigned to the histidine-containing high-affinity site.
Inhibited by various metalloform-selective inhibitors.
Removes the N-terminal methionine from nascent proteins. The N-terminal methionine is often cleaved when the second residue in the primary sequence is small and uncharged (Met-Ala-, Cys, Gly, Pro, Ser, Thr, or Val). Requires deformylation of the N(alpha)-formylated initiator methionine before it can be hydrolyzed.
Elicits a strong B-cell humoral response among different clinical categories of both adult and child tuberculosis patients. Could be used in the serodiagnosis of tuberculosis.
Expression of this gene in M.smegmatis leads to enhanced survival within U937 human macrophages in vitro, with increased host cell death and a marked higher secretion of tumor necrosis factor-alpha.
Induces maturation and activation of human dendritic cells (DCs), via TLR2-dependent activation of ERK1/2, p38 MAPK, and NF-kappa-B signaling pathways, and enhances the ability of DCs to stimulate CD4(+) T cells. By activating DCs, could potentially contribute to the initiation of innate immune responses during tuberculosis infection and hence regulate the clinical course of tuberculosis.
A possible member of the dormancy regulon. Induced in response to reduced oxygen tension (hypoxia). It is hoped that this regulon will give insight into the latent, or dormant phase of infection.
Belongs to the SLC26A/SulP transporter (TC 2.A.53) family.
Expression in E.coli induces sulfate uptake during early- to mid-log phase growth. Uptake is maximal at pH 6.0, is sulfate-specific, requires E.coli CysA and the transmembrane segment but not the STAS domain of the protein.
Belongs to the metallo-dependent hydrolases superfamily. NagA family.
Binds 1 divalent metal cation per subunit.
A member of the dormancy regulon. Induced in response to reduced oxygen tension (hypoxia) (at protein level), low levels of nitric oxide (NO) and carbon monoxide (CO). It is hoped that this regulon will give insight into the latent, or dormant phase of infection.
Belongs to the universal stress protein A family.
No visible phenotype under normal or hypoxic and normoxic stationary phase growth, nor in mouse- or human-derived macrophage cell lines.
Probably involved in aminoglycosides resistance and virulence. Overexpression increases resistance to the aminoglycosides amikacin (AK) and kanamycin (KM).
A nucleoid-associated protein (NAP) that probably plays a role in chromosome compactation. Binds DNA non-specifically, with greater affinity for supercoiled than linear DNA, binds well to nicked DNA, gapped and cruciform DNA. Has a preference for A:T rich DNA (PubMed:20824060, PubMed:10645441). Required for activation of the mtbB operon. Binds the mtbB promoter in the presence of iron, binding is seen with as little as 25 uM Fe(2+) and increases with increasing Fe(2+) (PubMed:24610707). RNase E and HupB jointly contribute to cellular adaptation to changing growth conditions and survival during antibiotic treatment and in the host (PubMed:35521527). Plays a role in stress survival (PubMed:36071978). Stimulates supercoiling relaxation by topoisomerase 1 (Top1, topA) (By similarity).
Belongs to the bacterial histone-like protein family. Long actinobacterial subfamily.
Binds Fe(3+) but not Fe(2+). Has ferroxidase activity, converts Fe(2+) into Fe(3+) and in the presence of H(2)O(2) prevents the generation of hydroxyl radicals (the Fenton reaction). Protects DNA from damage in the presence of FeSO(4) and H(2)O(2). May function in iron storage (PubMed:21698192). Involved in iron uptake by bacteria (either Fe(3+) or extracellular carboxymycobactin); antibodies against HupB block uptake of both. Following uptake iron is mostly found in the iron siderophores carboxymycobactin (CMb, extracellular) or mycobactin (Mb, lipophilic). Facilitates transfer of iron from CMb to Mb when liposomes plus a cell wall lysate are incubated with CMb. Binds iron, ferri-CMb and ferri-Mb; has 10-fold higher affinity for ferri-Mb. Suggested to transfer iron from CBm to Mb at the cell membrane (PubMed:33609202).
Increased expression under iron limitation (at protein level) (PubMed:17028216, PubMed:24610707). Expressed at all growth phases in rich and minial medium; more protein in mid- to late-log and stationary phases (at protein level). Increased expression under oxidative stress or growth on isoniazid (INH), decreased expression under nitrosative or acidic stress, or growth on rifampicin (at protein level) (PubMed:36071978).
May play a role in cell wall assembly (PubMed:17873049) (Probable). In vitro at low levels enhances formation of TMM and TDM by antigen 85 proteins (fbpA, fbpB, fbpC), at higher levels inhibits TMM and TDM formation (PubMed:17873049) (Probable).
Oligomerizes (By similarity). Interacts with topoisomerase 1 (topA) (By similarity). Interacts with Eis (By similarity). Interacts with antigen 85 proteins (fbpA, fbpB, fbpC) (PubMed:17873049) (Probable).
Probably acetylated by Eis in vivo (By similarity). In vitro acetylated by Eis (strain H37Rv and H37Ra) on many more residues than those identified in vivo (PubMed:29345920). Deacetylated in vitro by NAD-dependent protein deacylase (Rv1151c) (PubMed:29345920).
Probably succinylated by Rv0802c and desuccinylated by NAD-dependent protein deacylase (Rv1151c).
Pronounced lag-phase during growth; the lag is greater in low iron conditions (0.02 ug Fe/ml). 3 to 5-fold decreases in expression of iron siderophores mycobactin and carboxymycobactin in low iron media. Altered expression of a number of genes, including decreased expression of some involved in iron homeostasis (PubMed:24610707). Bacteria do not take up iron either as Fe(3+) or as carboxymycobactin (PubMed:33609202). Bacteria do not survive in mouse macrophages (PubMed:24610707, PubMed:29170282). Does not form biofilm (PubMed:29170282). Much slower growth in rich medium, greatly increased sensitivity to all stresses, death at low pH, oxidative and nitrosative stress, greatly decreased uptake by and survival in human macrophages, increased sensitivity to INH and rifampicin, greatly increased sensitivity to 0.05% SDS, enhanced permeability of the cell membrane due to decreased expression of polyketide synthases including ppsA, ppsC, and ppsE, downregulates DrrA efflux pump expression (PubMed:36071978).
Required for biofilm formation; trimethylation by recombinant human SUV39H1 (a histone methyltransferase) inhibits biofilm formation (PubMed:29170282). Induces lymphoproliferation, particularly in health tuberculin reactors, and is immunogenic (PubMed:10645441). Maybe involved in pathogenesis of inflammatory bowel disease (IBD) in patients with ulcerative colitis and Crohn disease (CD). Bound by anti-neutrophil cytoplasmic antibodies (pANCA), which are a hallmark of IBD. The binding is due to pANCA directed against H1-3 cross-reacting with DBH epitopes. In CD, target of a strong IgA response (PubMed:10569769).
The highly basic C-terminus confers greater specificity in DNA binding to all tested dsDNA (PubMed:20824060). Residues 1-102 stimulate Top1 and physically interact with it (By similarity).
The revised start codon for the 216-residue version of this protein is GTT.
Trimethylated on Lys-140 by human SUV39H1; trimethylation inhibits mycobacterial growth. SUV39H1 probably also trimethylates another residue (PubMed:29170282).
In nitrogen-limiting conditions, when the ratio of Gln to 2-ketoglutarate decreases, P-II is uridylylated to P-II-UMP. P-II-UMP allows the deadenylation of glutamine synthetase (GS), thus activating the enzyme. Conversely, in nitrogen excess P-II is deuridylated and promotes the adenylation of GS. P-II indirectly controls the transcription of the GS gene (glnA). P-II prevents NR-II-catalyzed conversion of NR-I to NR-I-phosphate, the transcriptional activator of glnA. When P-II is uridylylated to P-II-UMP, these events are reversed (By similarity).
Putative antitoxin component of a possible type II toxin-antitoxin (TA) system. The cognate toxin is VapC10.
Catalyzes the production of L-lysyl-tRNA(Lys)transfer and the transfer of a lysyl group from L-lysyl-tRNA(Lys) to membrane-bound phosphatidylglycerol (PG), which produces lysylphosphatidylglycerol (LPG), one of the components of the bacterial membrane with a positive net charge. LPG synthesis contributes to the resistance to cationic antimicrobial peptides (CAMPs) and likely protects M.tuberculosis against the CAMPs produced by competiting microorganisms (bacteriocins). In fact, the modification of anionic phosphatidylglycerol with positively charged L-lysine results in repulsion of the peptides.
In the C-terminal section; belongs to the class-II aminoacyl-tRNA synthetase family.
In the N-terminal section; belongs to the LPG synthetase family.
There are two lysyl-tRNA ligases in M.tuberculosis.
Antitoxin component of a type II toxin-antitoxin (TA) system. Upon expression in M.smegmatis neutralizes the effect of cognate toxin VapC43.
Belongs to the adenylyl cyclase class-3 family.
Toxic component of a type II toxin-antitoxin (TA) system. An RNase (By similarity). Upon expression in M.smegmatis inhibits colony formation. Its toxic effect is neutralized by coexpression with cognate antitoxin VapB32.
Belongs to the bacterial solute-binding protein 5 family.
Binding of effector molecule SA, or its structural analog PAS, to the binding pocket of Rv2887 induces conformational change in its DNA binding domain, preventing binding to the promoter region of htm, triggering the expression of this SAM-dependent methyltransferase.
Conformational changes take place in the N-terminal and the winged-HTH (wHTH) domain on ligand or DNA binding. SA and PAS stabilize a conformation of Rv2887 incompatible with DNA binding. Rotation of the N-terminal plays a key role in the dimerization.
Mutation of the gene leads to derepression and increased expression of htm (PubMed:27432954). Inactivation of the gene confers resistance to the imidazo[1,2-a]pyridine-4-carbonitrile-based agent MP-III-71, an effective antimycobacterial compound that shows no cross-resistance to existing antituberculosis drugs (PubMed:26303802).
Represses expression of the HQNO methyltransferase htm gene (Rv0560c) by binding to its promoter region (PubMed:26303802, PubMed:27432954, PubMed:28743871). Also represses the expression of at least five other genes, including the methyltransferase Rv0558 (PubMed:26303802). Binds salicylate (SA), para-aminosalicylic acid (PAS) and gemfibrozil (PubMed:28743871).
Binds 2 magnesium or manganese ions per subunit.
Component of a biotin-dependent acyl-CoA carboxylase complex. This subunit catalyzes the ATP-dependent carboxylation of the biotin carried by the biotin carboxyl carrier (BCC) domain, resulting in the formation of carboxyl biotin (PubMed:25695631). When associated with the beta1 subunit AccD1, is involved in branched amino-acid catabolism with methylcrotonyl coenzyme A as the substrate (PubMed:25695631).
The biotin-dependent acyl-CoA carboxylase complex is composed of AccA1, which contains the biotin carboxylase (BC) and biotin carboxyl carrier protein (BCCP) domains, and AccD1, which contains the carboxyl transferase (CT) domain (PubMed:25695631). The AccA1/AccD1 complex forms a dodecamer (PubMed:25695631).
Antitoxin component of a type II toxin-antitoxin (TA) system. Upon expression in E.coli and M.smegmatis neutralizes the effect of cognate toxin MazF9.
Forms a complex with cognate toxin MazF9.
Mildy induced (5-fold) when grown in a non-replicating state.
Belongs to the cation transport ATPase (P-type) (TC 3.A.3) family. Type IB subfamily.
Involved in heavy metal homeostasis. Probably exports nickel and cobalt ions out of the cell (By similarity).
Catalyzes the conversion of precorrin-8X to hydrogenobyrinate.
Belongs to the N-acetylmuramoyl-L-alanine amidase 2 family.
Contains large globular domains required for ATP hydrolysis at each terminus and a third globular domain forming a flexible SMC hinge near the middle of the molecule. These domains are separated by coiled-coil structures.
Required for chromosome condensation and partitioning.
Catalyzes the activation of long-chain fatty acids as acyl-adenylates (acyl-AMP), which are then transferred to the multifunctional polyketide synthase PpsA for further chain extension (PubMed:15042094, PubMed:19182784, PubMed:20553505). Involved in the biosynthesis of phenolphthiocerol, which is an important intermediate in the biosynthesis of phenolic glycolipid (PGL), also called mycosid B (PubMed:20553505).
Disruption of the gene abolishes the production of phenolic glycolipid (PGL). Mutant can still produce phthiocerol dimycocerosate (DIM A) and phthiodiolone dimycocerosate (DIM B).
Putative antitoxin component of a possible type II toxin-antitoxin (TA) system. The cognate toxin is VapC13.
Belongs to the GTP cyclohydrolase I type 2/NIF3 family.
Binds 2 Zn(2+) ions per subunit. Three distinct zinc binding-sites were identified in the crystal structure, but the exact biological function of the third site remains to be determined. It could be an artifact of crystallization.
Global transcriptional regulator involved in zinc homeostasis. Represses the transcription of at least 32 genes, including genes involved in zinc homeostasis, by binding to promoter sequences that contain a conserved 26 bp palindrome, in the presence of zinc.
Induced by zinc. Repressed by SmtB in the absence of zinc.
The N-terminal domain binds DNA and the C-terminal domain is involved in metal-binding and dimerization.
Acyl:acyl-carrier protein ligase involved in the biosynthesis of a unique class of isonitrile lipopeptides (INLPs) that seem to function as virulence factors in M.tuberculosis and to play a role in metal acquisition (PubMed:28634299). Catalyzes the activation of medium/long-chain fatty acids as acyl-adenylates (acyl-AMP), which are then transferred to the phosphopantetheine arm of the acyl-carrier protein (ACP) Rv0100 (PubMed:22451903, PubMed:23625916). Can use octanoate (C8), decanoate (C10), dodecanoate (C12), tetradecanoate (C14) and hexadecanoate (C16), but not hexanoate (C6) in vitro (PubMed:22451903, PubMed:23625916). Long chain saturated fatty acids are the preferred substrates (PubMed:23625916, PubMed:22451903). Acts twice during the INLP pathway, catalyzing the activation of a (2E)-enoyl fatty acid as well as the corresponding (3R)-3-isocyanyl-fatty acid as acyl-adenylates (acyl-AMP), and then the acyl transfer to the dedicated acyl-carrier protein Rv0100 (By similarity). Cannot use coenzyme A to form acyl-CoA (PubMed:22451903, PubMed:23625916).
Cells lacking this gene are shown to be highly attenuated in a mouse tuberculosis model.
Retains a single open conformational state for both the apo- and ligand-bound forms.
Was originally thought to be a fatty acyl-CoA ligase (FACL) (PubMed:19182784). However, although FadD10 has a primary sequence similar to FACLs, it is indeed a fatty acyl-AMP ligase (FAAL) that is only able to acylate an ACP (Rv0100) rather than coenzyme A (PubMed:22451903, PubMed:23625916).
In the N-terminal section; belongs to the purine/pyrimidine phosphoribosyltransferase family.
Appears to be essential for Mtb pathogenesis.
Belongs to the 2-oxoacid dehydrogenase family.
Cells lacking this gene show severely retarded growth in vitro, and display no PDH activity. They are also more sensitive to nitrosative stress caused by NaNO(2), and to macrophage-induced killing in vitro. They also show at least 20-fold reduction in survival in a mouse tuberculosis model, and are unable to cause disease in a guinea pig model of tuberculosis infection. Disruption of dlaT leads to high up-regulation of the expression of the bkdABC operon.
Component of the pyruvate dehydrogenase (PDH) complex, that catalyzes the overall conversion of pyruvate to acetyl-CoA and CO(2).
Forms a 24-polypeptide structural core with octahedral symmetry (By similarity). Identified in a complex with AhpC, AhpD and Lpd. Part of the PDH complex, consisting of multiple copies of AceE (E1), DlaT (E2) and Lpd (E3).
Inhibited by rhodanine compounds. Some of them almost exclusively kill non-replicating mycobacteria in synergy with products of host immunity, such as nitric oxide and hypoxia, and are effective on bacteria within macrophages.
Is the only lipoylated protein in strain H37Rv grown on a standard rich medium. However, in a DlaT-deficient strain, another protein, BkdC, becomes lipoylated.
Together with AhpC, AhpD and Lpd, constitutes an NADH-dependent peroxidase active against hydrogen and alkyl peroxides as well as serving as a peroxynitrite reductase, thus protecting the bacterium against reactive nitrogen intermediates and oxidative stress generated by the host immune system.
Double espI-eccD1 mutants abolish EsxA and EsxB secretion, but not their expression (PubMed:14557547). One group has shown no growth in the human macrophage-like cell line THP-1, no cytotoxicity, attenutated infection in mice, nearly 100-fold less bacteria in lung and spleen of C57BL/6; Brodin et al., attribute this result to polar effects on the downstream gene (PubMed:14756778, PubMed:16368961). Another group has shown that inactivation does not abolish EsxA (ESAT-6) secretion, EsxA-specific immunogenicity or virulence (PubMed:16368961, PubMed:25039394).
Required to repress ESX-1-mediated secretion under low ATP conditions. This function requires the ATP-binding motif.
Residues 1-81 interact with EsxB while residues 35-186 interact with an artificial EsxB-EsxA heterodimer (PubMed:19854905).
Acts as a positive transcriptional regulator of the molybdopterin biosynthesis moa1 locus, promoting the expression of the moaA1B1C1D1 genes. Binds directly to the moaA1 promoter.
Belongs to the AfsR/DnrI/RedD regulatory family.
Expression of MoaR1 appears to be modulated by oxygen availability since it is up-regulated in both microaerophilic (NRP1) and anaerobic (NRP2) cultures compared with aerobic cultures; thus, seems to be up-regulated during the shift into the persistent state in the human host.
ATP-dependent specificity component of the Clp protease. It directs the protease to specific substrates. Can perform chaperone functions in the absence of ClpP (By similarity). Degrades anti-sigma-D factor RsdA when present in a complex with ClpP1 and ClpP2. Does not seem to act on anti-sigma-L factor RslA.
Component of the ClpX-ClpP complex. Forms a hexameric ring that, in the presence of ATP, binds to fourteen ClpP subunits assembled into a disk-like structure with a central cavity, resembling the structure of eukaryotic proteasomes (By similarity). Forms a complex with ClpP1 and ClpP2. Interacts with RseA but does not seem to help degrade it.
3-beta-HSD is a bifunctional enzyme, that catalyzes the oxidation and isomerization of cholesterol, pregnenolone, and dehydroepiandrosterone (DHEA) into cholest-4-en-3-one, progesterone, and androsterone, respectively.
Disruption reduces the cholesterol oxidation activity at least 90-fold.
Inhibited by EDTA, zinc, silver, copper, and activated by magnesium and calcium. A competitive inhibition is observed with NAD at concentrations higher than 5.6 mM, and with trilostane (3,17-dihydroxy-4,5-epoxyandrost-2-ene-2-carbonitrile).
Belongs to the non-flavoprotein flavin reductase family.
Catalyzes the reduction of free flavins (FMN or FAD) by NADH. Subsequently, the reduced flavins diffuse to the HsaA oxygenase subunit.
Cholesterol metabolism contributes to the survival of M.tuberculosis in the host by helping the bacterial multiplication during earlier stages of infection and to the dissemination of the pathogen in the host.
HsaAB monooxygenase consists of an oxygenase component HsaA and a reductase component HsaB.
Interacts with UvrB in an incision complex.
The UvrABC repair system catalyzes the recognition and processing of DNA lesions. UvrC both incises the 5' and 3' sides of the lesion. The N-terminal half is responsible for the 3' incision and the C-terminal half is responsible for the 5' incision.
During M.tuberculosis and HIV-1 co-infection, can stimulate transcription from the long terminal repeat (LTR) of HIV-1 in monocyte/macrophage cells. Interaction with human TLR2 activates the NF-kappa-B transcription factor, which binds to the promoter region of the HIV-1 and induces HIV-1 gene expression.
Induces pro-inflammatory responses (PubMed:22427668, PubMed:27481848). Induces host TLR1/2 heterodimerization, which causes an increased recruitment of IRAK1, MYD88, and protein kinase C epsilon (PRKCE) to the downstream TLR-signaling complex that translocates PRKCE into the nucleus in an IRAK1-dependent manner. PRKCE-mediated phosphorylation allowed the nuclear IRAK3 to be exported to the cytoplasm, leading to increased activation of ERK1/2, stabilization of MAPK phosphatase 1 (MKP1), and induction of TNF-alpha with concomitant down-regulation of MAP kinase p38 (PubMed:27481848).
Interacts with LRR motifs 15-20 of host Toll-like receptor 2 (TLR2).
Shows a strong immunoreactivity toward tuberculosis (TB) patient sera compared to that of BCG-vaccinated controls. Could be an attractive candidate for serodiagnosis to discriminate patients with active tuberculosis from BCG-vaccinated individuals. Could diagnose both pulmonary and extrapulmonary tuberculosis cases (PubMed:18400969, PubMed:26364913, PubMed:28651002). Can also be used as a novel serodiagnostic marker to detect latent tuberculosis infection (LTBI) (PubMed:30475863). Antibody responses elicited in TB patients are directed mostly towards the N-terminal domain of PPE17, suggesting that the N-terminal domain of PPE17 protein is immunodominant and could be used as a better serodiagnostic marker than the full-length PPE17 protein (PubMed:28651002). Antibodies directed against N-terminal domain of PPE17 in active TB patients do not significantly cross-react with N-terminal domains of other PPE proteins (PubMed:28651002).
The N-terminal domain is essential for interaction with TLR2 and activation of HIV-1 LTR (PubMed:22427668). The PPE region contains the information necessary for targeting and anchorage to the cell wall (PubMed:23469198).
Up-regulated under microaerophilic and anaerobic conditions, nutrient starvation and in the presence of palmitic acid (PubMed:18400969). Coexpressed with PE11 (PubMed:23469198).
Catalyzes the transfer of pyrophosphate from adenosine triphosphate (ATP) to 6-hydroxymethyl-7,8-dihydropterin, an enzymatic step in folate biosynthesis pathway.
HK1 and HK2 are incomplete as individual proteins but can complement each other's function.
HK1 and HK2 are merged into a single protein with a distinct N-terminal sequence in strain CDC 1551 / Oshkosh.
Homodimer. Each monomer interacts with HK1 and the receiver domain of TcrA.
Member of the three-protein two-component system HK1/HK2/TcrA. HK2 transfers its phosphoryl group to TcrA.
Inhibited by the beta-lactam antibiotic meropenem.
Probably cleaves the terminal D-Ala-D-Ala dipeptide of the peptidoglycan stem peptide (Probable). Shows weak D,D-carboxypeptidase activity in vitro (PubMed:22906310). Acts on the synthetic penta-peptide substrate Penta-DAP (L-Ala-gamma-D-Gln-DAP-D-Ala-D-Ala) (PubMed:22906310). The catalytic domain binds weakly to peptidoglycan in vitro (PubMed:25551456).
Belongs to the UDP-glycosyltransferase family.
Involved in glycosylation steps downstream of mono-O-methyl-glycosyl-p-hydroxybenzoic acid derivative (p-HBAD I) and 2-O-methyl-rhamnosyl-phenolphthiocerol dimycocerosate (mycoside B) during the p-hydroxybenzoic acid derivatives (p-HBAD) and glycosylated phenolphthiocerol dimycocerosates (PGL) biosynthesis.
A cognate anti-sigma factor for alternative sigma factor SigF. Alternative sigma factors are held in an inactive form by an anti-sigma factor. Binds ATP and GTP, may hydrolyze both.
A double rsbW-sigF disruption shows no effect in the presence or absence of rifampicin.
Belongs to the anti-sigma-factor family.
Homodimer (Probable). Interacts with cognate RNA polymerase sigma factor SigF with a possible 2:1 RbsW:SigF stoichiometry; this inhibits the interaction of SigF with the RNA polymerase catalytic core. Interacts with anti-sigma-F factor antagonist RsfA with a possible 2:1 RbsW:RsfA stoichiometry; this blocks binding to SigF, thus indirectly activating transcription. Interacts with GTPase Obg (PubMed:21352546).
The cytosolic domain interacts with sigma factor SigF.
Represses transcription of the catalase-peroxidase gene katG and its own transcription by binding to the promoter region in a redox-dependent manner.
By DNA damage, and by ADP-ribosylation catalyzed by DarT (at protein level).
Can catalyze the hydrolysis of ATP in the presence of single-stranded DNA, the ATP-dependent uptake of single-stranded DNA by duplex DNA, and the ATP-dependent hybridization of homologous single-stranded DNAs. It interacts with LexA causing its activation and leading to its autocatalytic cleavage.
Interacts with UvrD1 and UvrA (PubMed:20455546). Co-immunoprecipitates with DarG in the presence and absence of darT (PubMed:32634279).
This protein undergoes a protein self splicing that involves a post-translational excision of the intervening region (intein) followed by peptide ligation.
Belongs to the metallo-dependent hydrolases superfamily. DHOase family. Class I DHOase subfamily.
Catalyzes the reversible cyclization of carbamoyl aspartate to dihydroorotate.
Toxic component of a type II toxin-antitoxin (TA) system. An RNase. The cognate antitoxin is VapB12 (By similarity).
Belongs to the protein kinase superfamily. ADCK protein kinase family.
Belongs to the aconitase/IPM isomerase family.
Involved in the catabolism of short chain fatty acids (SCFA) via the tricarboxylic acid (TCA)(acetyl degradation route) and probably via the 2-methylcitrate cycle I (propionate degradation route). Catalyzes the reversible isomerization of citrate to isocitrate via cis-aconitate. The apo form of AcnA functions as a RNA-binding regulatory protein which binds to selected IRE-like sequences present within the UTRs (untranslated regions) of 3' trxC and 5' IdeR mRNA (PubMed:17384188). Could catalyze the hydration of 2-methyl-cis-aconitate to yield (2R,3S)-2-methylisocitrate (By similarity).
The natural substrate for this enzyme may be peptidyl-tRNAs which drop off the ribosome during protein synthesis.
Belongs to the cyclic nucleotide phosphodiesterase class-III family.
Ca(2+) acts as an activator of the enzymatic activity and is able to promote the hydrolysis of substrates even in the absence of transition-metal ions, thus providing an effective strategy for the regulation of the enzymatic activity. Two Ca(2+) ions bind at a site different from the dinuclear transition-metal-ion binding site (PubMed:26662456). Activity is enhanced by magnesium or manganese. Activity decreases in the presence of orthovanadate and phosphotyrosine (PubMed:16313172).
Cyclic nucleotide phosphodiesterase with a dual-specificity for the second messengers cAMP and cGMP (PubMed:16313172, PubMed:18757371). Can use 2',3'-cAMP, 2',3'-cGMP, 3',5'-cAMP, 3',5'-cGMP and 3',5'-cUMP (PubMed:16313172, PubMed:18757371, PubMed:19801656). Hydrolysis of 2',3'-cAMP produces a mixture of 3'-AMP (major product) and 2'-AMP (minor product) (PubMed:18757371). In vitro, is 150-fold more active in hydrolyzing 2',3'-cAMP than 3',5'-cAMP (PubMed:18757371). Can also hydrolyze the model substrates p-nitrophenyl phosphate (pNPP), bis-(p-nitrophenyl phosphate) (bis(pNPP)) and p-nitrophenyl phenylphosphonate (pNPPP) (PubMed:16313172, PubMed:18757371, PubMed:19801656). Plays an important regulatory role in modulating the intracellular concentration of cAMP, thereby influencing cAMP-dependent processes (PubMed:16313172). May play a role in pathogenicity, not only by hydrolyzing cAMP, but also by altering properties of the cell wall (PubMed:19801656).
Overexpression elicits a transcriptional response that is independent of the phosphodiesterase activity. It does not alter the levels of cAMP-CRP regulated genes, even though cAMP levels are reduced in cells.
Phosphorylated on Thr-309 by the eukaryotic-type serine/threonine-protein kinases PknA, PknB and PknL. Phosphorylation does not affect the enzymatic activity, but it renders negative charge to the protein, promoting its localization on cell wall.
The C-terminal extension (CTE) is used to better adjust the substrates into the active sites and mediates in vivo subcellular localization of the protein (PubMed:19801656, PubMed:24970891). It also modulates expression levels of Rv0805 in mycobacteria (PubMed:24970891).
Belongs to monofunctional group I BPL as it lacks the N-terminal helix-turn-helix (HTH) DNA-binding domain.
Belongs to the biotin--protein ligase family.
Binding of biotin and ATP significantly increases the thermal stability of BirA and leads to the formation of a high affinity holoenzyme complex.
Catalyzes the transfer of biotin onto a conserved lysine residue of the biotin carboxyl carrier protein (BCCP) domain of acetyl-CoA carboxylase and converts it to active holo-BCCP (PubMed:18509457, PubMed:24723382). Forms an acyl-adenylate intermediate (PubMed:18509457, PubMed:24723382). Cannot use GTP or desthiobiotin (PubMed:18509457).
Identified as a drug target (PubMed:22118677, PubMed:26299766, PubMed:28942842). Inhibited by Bio-AMS, an acylsulfamide bisubstrate inhibitor, and analogs (PubMed:22118677, PubMed:26299766). Bio-AMS displays potent subnanomolar enzyme inhibition and antitubercular activity against multidrug resistant and extensively drug resistant Mtb strains (PubMed:22118677).
Monomer in solution (PubMed:18509457, PubMed:20169168, PubMed:24723382). Forms dimers under specific crystallization conditions (PubMed:18540066, PubMed:20169168).
Belongs to the CRISPR-associated endoribonuclease Cas2 protein family.
CRISPR (clustered regularly interspaced short palindromic repeat) is an adaptive immune system that provides protection against mobile genetic elements (viruses, transposable elements and conjugative plasmids). CRISPR clusters contain spacers, sequences complementary to antecedent mobile elements, and target invading nucleic acids. CRISPR clusters are transcribed and processed into CRISPR RNA (crRNA). The type III-A Csm effector complex binds crRNA and acts as a crRNA-guided RNase, DNase and cyclic oligoadenylate synthase; binding of target RNA cognate to the crRNA is required for all activities (Probable). This CRISPR-Cas system protects bacteria against transformation with plasmids containing DNA homologous to its spacer regions (PubMed:29979631).
Deletion of the entire CRISPR-Cas locus (cas6 to cas2, Rv2824c to Rv2816c) decreases resistance to plasmids encoding spacer elements about 6-fold.
Homodimer, forms a heterotetramer with a Cas1 homodimer.
Expression in M.smegmatis leads to enhanced growth rate and altered colony morphology, and promotes the survival of bacteria under acidic and nutritive stress conditions.
Shows histone acetyl transferase (HAT) activity with recombinant eukaryotic H3 histone expressed in bacteria as substrate and acetyl-CoA as donor (PubMed:35175508). May be involved in survival under stress conditions (PubMed:35175508).
Up-regulated in acidic and nutritive stress conditions (PubMed:35175508). Detected exclusively in intraphagosomally grown mycobacteria (PubMed:35175508).
Belongs to the class IV-like SAM-binding methyltransferase superfamily. RNA methyltransferase TrmH family.
Belongs to the aldo/keto reductase family.
Catalyzes the NADPH-dependent reduction of dicarbonyls (PubMed:20188740). Exhibits narrow substrate specificity, with preferential activity against the dicarbonyl substrates methylglyoxal and phenylglyoxal (PubMed:20188740). May play an important role in the detoxification of methylglyoxal (PubMed:20188740).
Identified as a multidrug-resistant tuberculosis (MDRTB) immunogenic protein.
Inhibited by the antituberculosis drug isoniazid (INH).
Belongs to the bacterial ribosomal protein bL27 family.
Belongs to the class-I pyridine nucleotide-disulfide oxidoreductase family.
Catalyzes the NAD(P)H-dependent reduction of mycothione (the oxidized disulfide form of mycothiol) to mycothiol.
A 50S ribosomal subunit assembly protein with GTPase activity, required for 50S subunit assembly at low temperatures, may also play a role in translation. Binds GTP and analogs. Binds the 70S ribosome between the 30S and 50S subunits, in a similar position as ribosome-bound EF-G; it contacts a number of ribosomal proteins, both rRNAs and the A-site tRNA.
Belongs to the TRAFAC class translation factor GTPase superfamily. Classic translation factor GTPase family. BipA subfamily.
Differentially expressed under different growth conditions.
EsxJI deletion mutant shows extremely slow growth in broth cultures.
Forms a tight 1:1 complex with EsxW. The complex is destabilized at low pH. Unfolding of the proteins is required for dissociation of the complex and membrane binding.
Potent T-cell antigen that could be a subunit vaccine candidate.
Probable virulence factor. In mice, elicits increased levels of IFN-gamma, IL-12 and IgG(2a), indicating a dominant Th1 host immune response.
Belongs to the transglycosylase family. Rpf subfamily.
Expressed in actively growing cells, activated by CRP.
Factor that stimulates resuscitation of dormant cells. Has peptidoglycan (PG) hydrolytic activity. Active in the pM concentration range. Has little to no effect on actively-growing cells. PG fragments could either directly activate the resuscitation pathway of dormant bacteria or serve as a substrate for endogenous Rpf, resulting in low molecular weight products with resuscitation activity. Stimulates growth of stationary phase M.bovis (a slow-growing Mycobacterium), reduces the lag phase of diluted fast-growers M.smegmatis and Micrococcus luteus.
Not essential, disruption of rpfA alone has no effect on growth or survival in liquid culture, nor in mouse infection models, although cells are clumpy after 2 weeks in stirred culture. Alterations in gene expression are seen. All 5 genes in this family can be deleted without affecting growth in culture, however triple deletion mutants (rpfA-rpfC-rpfB or rpfA-rpfC-rpfD) are not able to resuscitate spontaneously in the presence or absence of O(2), and are attenuated in a mouse infection model.
Belongs to the transketolase family. DXPS subfamily.
Belongs to the precorrin methyltransferase family.
Auxotrophic for all of the 3 branched-chain amino acids (isoleucine, leucine and valine), when grown with either C6 or C2 carbon sources. Depletion of these branched chain amino acids in the medium led to loss of viability.
Binds 1 thiamine pyrophosphate per subunit.
Catalyzes the conversion of 2 pyruvate molecules into acetolactate in the first common step of the biosynthetic pathway of the branched-amino acids such as leucine, isoleucine, and valine. Also involved in condensing pyruvate and 2-ketobutyrate to form 2-aceto-2-hydroxybutyrate.
Heterodimer of large catalytic subunit and small regulatory subunit.
Inhibited by valine, sulfometuron methyl (SM), sulfonylureas (SU) and imidazolinones (IM). Pyrazosulfuron ethyl (PSE), promisulfuron methyl (PSM), sulfometuron methyl (SMM), metsulfuron methyl (MSM), and chlorimuron ethyl (CE) inhibited more than 80% of the activity.
The expression is high during the mid-exponential phase and low during the stationary phase.
2 residues (Tyr-53 and Arg-56) present in a large hydrophobic pocket are probably involved in substrate specificity. They are important for desuccinylation activity, but dispensable for deacetylation activity.
Belongs to the sirtuin family. Class III subfamily.
Inhibited by 2-hydroxy-1-naphthaldehyde and nicotinamide.
Interacts with both Ku and LigD; may form a trimeric complex during NHEJ.
Involved in non-homologous end joining (NHEJ) repair of blunt, 5' overhang and 3' overhang DNA double strand breaks (DSB).
NAD-dependent lysine deacetylase and desuccinylase that specifically removes acetyl and succinyl groups on target proteins. Modulates the activities of several proteins which are inactive in their acylated form.
Probably desuccinylates succinylated HupB.
Reactivates acetylated acetyl-CoA synthetase (ACS) through an NAD-dependent deacetylation (PubMed:21896569, PubMed:21627103). Is able to auto-ADP-ribosylate (PubMed:19747094). Deacetylates acetylated HupB (PubMed:29345920).
Belongs to the glycosyltransferase 28 family.
Disruption abolishes EsxA and EsxB secretion, but not their expression (PubMed:14557536). It results in a lack of antigen specific immunogenicity and leads to attenuated virulence (PubMed:16368961). Mutants exhibit defects in bacterial growth during the acute phase of a mouse infection (PubMed:14557536). No growth in the human macrophage-like cell line THP-1, no cytotoxicity; bacteria grow within cells but do not kill them and do not spread to other host cells (PubMed:14756778).
EsxB binding to the second FtsK domain of EccCb1 causes multimerization; a subsequent unknown step relieves the allosteric inhibition of linker 2 on FtsK domain 1 (this subunit), activating the ATPase activity (PubMed:25865481).
Part of the ESX-1 / type VII secretion system (T7SS), which is composed of cytosolic and membrane components. The ESX-1 membrane complex is composed of EccB1, EccCa1, EccCb1, EccD1 and EccE1 (PubMed:14557536, PubMed:16368961, PubMed:19876390). Interacts with EccCb1 (PubMed:14557536). Residues 62-332 interact with EsxB and an artificial EsxB-EsxA heterodimer (PubMed:19854905).
Part of the ESX-1 specialized secretion system, which delivers several virulence factors to host cells during infection, including the key virulence factors EsxA (ESAT-6) and EsxB (CFP-10).
Involved in the biosynthesis of isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP), two major building blocks of isoprenoid compounds. Catalyzes the conversion of 4-diphosphocytidyl-2-C-methyl-D-erythritol 2-phosphate (CDP-ME2P) to 2-C-methyl-D-erythritol 2,4-cyclodiphosphate (ME-CPP) with a corresponding release of cytidine 5-monophosphate (CMP).
Belongs to the glucose-6-phosphate dehydrogenase family.
Catalyzes the oxidation of glucose 6-phosphate to 6-phosphogluconolactone.
Belongs to the beta-class carbonic anhydrase family.
Catalyzes the reversible hydration of carbon dioxide to form bicarbonate.
Homotetramer at pH 8.4 and homodimer at pH 7.4.
Inhibited by sulfonamides and sulfamates.
Part of the ESX-2 / type VII secretion system (T7SS), which is composed of cytosolic and membrane components (By similarity). Residues 522-619 interact with an artificial EsxB-EsxA heterodimer from the adjacent ESX-1 locus (PubMed:19854905).
Shows ATPase activity. Could provide energy for export of ESX-2 substrates (By similarity).
Interacts specifically with ESX-2-dependent PE/PPE proteins.
Specific chaperone for cognate PE/PPE proteins. Plays an important role in preventing aggregation of PE/PPE dimers.
Catalyzes the conversion of (8S)-3',8-cyclo-7,8-dihydroguanosine 5'-triphosphate to cyclic pyranopterin monophosphate (cPMP) (By similarity). Probably plays a role in host phagosome maturation arrest (PubMed:20844580).
Expression is positively regulated by the transcriptional regulator MoaR1.
Grows normally in liquid culture, traffics into host (human and mouse) acidified compartments early after phagocytosis, suggesting it no longer arrests phagosome maturation as well as wild-type, impaired growth in mouse macrophages (PubMed:20844580).
Activated by PrpR and repressed by RamB.
Cells lacking this gene show an attenuated bacterial persistence and virulence in immune-competent mice without affecting bacterial growth during the acute phase of infection.
Inhibited by 3-nitropropionate (3-NP) and 3-bromopyruvate when M.tuberculosis grows on acetate, but not on glucose. Inhibition of ICL by 3-bromopyruvate is accomplished via dehalogenation of the inhibitor to form a covalent adduct with the active site Cys-191. Also inhibited by zinc and calcium ions.
Involved in the persistence and virulence of M.tuberculosis. Catalyzes the reversible formation of succinate and glyoxylate from isocitrate, a key step of the glyoxylate cycle, which operates as an anaplerotic route for replenishing the tricarboxylic acid cycle during growth on fatty acid substrates (PubMed:10932251, PubMed:10963599, PubMed:18275086, PubMed:24354272). It could also catalyze the formation of pyruvate and succinate from 2-methylisocitrate, a key step in the methylcitrate cycle (propionate degradation route) (By similarity).
Pupylated at Lys-334 by the prokaryotic ubiquitin-like protein Pup, which leads to its degradation by the proteasome.
Was identified as a natural substrate of the M.tuberculosis proteasome.
Binding of Ca(2+) to PE_PGRS61 induces conformational changes and increases affinity for TLR2.
Mediates Ca(2+)-dependent up-regulation of the anti-inflammatory cytokine IL-10.
Belongs to the argininosuccinate synthase family. Type 1 subfamily.
Forms a tight 1:1 complex with EsxF (PubMed:20085764).
Activated by inorganic phosphate, and to a lesser extent by sulfate ions (PubMed:21085589, PubMed:21045009). In addition to form a complex with ATP, Mg(2+) also acts as a cofactor (PubMed:21085589, PubMed:21045009). Strongly inhibited by ADP and GDP through competitive binding at the activation site and at a specific allosteric site (PubMed:21085589, PubMed:21045009, PubMed:22745722). Competitively inhibited by Ca(2+), Cu(2+) and Fe(2+) (PubMed:21085589, PubMed:21045009).
Belongs to the ribose-phosphate pyrophosphokinase family. Class I subfamily.
Binds 2 Mg(2+) ions per subunit (Potential). Can also use Mn(2+) (PubMed:21085589, PubMed:21045009).
Involved in the biosynthesis of the central metabolite phospho-alpha-D-ribosyl-1-pyrophosphate (PRPP) and of the decaprenylphosphoryl-arabinose (DPA), an essential precursor for the mycobacterial cell wall biosynthesis. Catalyzes the transfer of pyrophosphoryl group from ATP to 1-hydroxyl of ribose-5-phosphate (Rib-5-P) to yield phosphoribosyl diphosphate (PRPP) and AMP. It can also use GTP, CTP and UTP as diphosphoryl donors (PubMed:22745722).
Belongs to the acetyltransferase family. MshD subfamily.
Catalyzes the transfer of acetyl from acetyl-CoA to desacetylmycothiol (Cys-GlcN-Ins) to form mycothiol.
The N-terminal acetyl-CoA does not function as substrate in the catalyzed reaction, but is believed to have a structural role.
Activity can be increased by one order of magnitude by adding bovine serum albumin in vitro. This result suggests that the enzyme is activated in vivo by protein-protein or interactions with other cellular components.
Belongs to the FAD-binding monooxygenase family.
Exists as a mixture of relatively large homooligomers ranging from 200 to 600 kDa.
Inactivation of this gene leads to a strong resistance to ETH.
Is responsible for the activation of several thiocarbamide-containing pro-drugs into cytotoxic species. Thus, catalyzes the oxidation of the antitubercular pro-drug ethionamide (ETH) to the corresponding sulfoxide, which is further oxidized by EthA to 2-ethyl-4-amidopyridine, presumably via the unstable doubly oxidized sulfinic acid intermediate; the final metabolite 2-ethyl-4-amidopyridine has no antitubercular activity, so the cytotoxic species is a metabolite intermediate formed by EthA. Also oxidizes thiacetazone (TAC), thiobenzamide, and isothionicotinamide and therefore is probably responsible, as suggested by the observation of crossover resistance, for the oxidative activation of these other thioamide antitubercular drugs.
Monooxygenase able to convert a wide range of ketones to the corresponding esters or lactones via a Baeyer-Villiger oxidation reaction. Can act on long-chain aliphatic ketones (2-hexanone to 2-dodecanone) and on aromatic ketones (phenylacetone and benzylacetone). Is also able to catalyze enantioselective sulfoxidation of methyl-p-tolylsulfide. In vivo, likely functions as a BVMO, but the exact nature of the physiological substrate(s) remains to be established.
Repressed by the transcriptional regulator EthR.
A member of the dormancy regulon, expression is controlled by devR (PubMed:12953092, PubMed:19487478). Induced in response to reduced oxygen tension (hypoxia) (PubMed:11416222, PubMed:12953092, PubMed:19487478). Induced in response to low levels of nitric oxide (NO) and carbon monoxide (CO) (PubMed:12953092, PubMed:18400743). It is hoped that this regulon will give insight into the latent, or dormant phase of infection. Member of the Rv3134c-devR-devS operon (PubMed:10970762).
A tyrosine residue (Tyr-171) is required for discrimination between bound gaseous ligands (PubMed:18975917). The Tyr is part of a probable hydrogen bonding network which includes Glu-87, His-89 and Arg-204 that is probably also important for signaling to the kinase domain (PubMed:19276084, PubMed:27235395).
Binds 1 heme group per monomer (PubMed:16213520, PubMed:17371046, PubMed:17600145, PubMed:21536032, PubMed:27729224).
Cells lacking this gene show no changes in gene induction following hypoxia, or exposure to NO or CO (PubMed:11416222, PubMed:15033981, PubMed:18474359). Another publication shows a severely attenuated response to CO (PubMed:18400743). Cells lacking both this gene and DosT have no response to hypoxia, or exposure to NO or CO showing both proteins are required for the hypoxic, NO and CO responses (PubMed:15033981). 95% decreased induction of the DevR (DosR) regulon during anaerobic growth, 50% decreased induction of the DevR regulon upon exposure to NO during aerobic growth (PubMed:19487478).
Member of the two-component regulatory system DevR/DevS (DosR/DosS) involved in onset of the dormancy response (PubMed:12953092). Regulates an approximately 48-member regulon (PubMed:12953092, PubMed:11416222, PubMed:15033981, PubMed:18400743). Required for full induction of the DevR (DosR) regulon; acts later than DosT to positively regulate expression of the DevR regulon during adaptation to anaerobiosis (PubMed:19487478). Characterized as an oxygen sensor; O(2) acts as a switch, with O(2)-bound Fe(2+) protein inactive in autophosphorylation (PubMed:17371046, PubMed:17600145, PubMed:18975917, PubMed:19463006, PubMed:28977726). Has also been suggested to act as a redox sensor, or perhaps as a dual oxygen/redox sensor (PubMed:17609369). Autophosphorylates under anaerobic but not aerobic conditions, binding of NO or CO does not dramatically change the level of autophosphorylation of Fe(2+) protein, binding of O(2) inactivates kinase activity (PubMed:17600145, PubMed:18975917, PubMed:27235395). Binds O(2), NO, CO (PubMed:17371046, PubMed:17609369, PubMed:17600145, PubMed:18975917, PubMed:27235395). It is probably reduced by flavin nucleotides such as FMN and FAD (PubMed:19276084). May be the primary sensor for CO (PubMed:18400743). Donates a phosphate group to transcriptional regulator DevR (DosR) (PubMed:15033981, PubMed:15073296, PubMed:28977726).
Mn(2+) will also substitute in autophosphorylation assays, while Ca(2+) is a poor substitute (PubMed:17600145).
The dev nomenclature derives from the increased expression (differentially expressed in virulent strain, dev) of these genes in virulent H37Rv versus avirulent H37Ra. The dos nomenclature derives from experiments in M.bovis showing the same genes are essential for dormancy survival.
The first GAF domain protects the heme moiety from auto-oxidation, contributing to the full-length protein's very long half-life (more than 36 hours in buffers without transition metals) (PubMed:19463006). The isolated ATP-binding subdomain (residues 454-578) crystallized in a closed form that is unable to bind ATP, suggesting that ATP-binding requires conformational changes in this loop region; in this closed conformation it binds a zinc atom (PubMed:23486471). The isolated histidine kinase core (HKC, residues 386-578) both autophosphorylates and phosphorylates the isolated histidine acceptor subdomain (residues 386-452) (PubMed:23486471). The relative arrangements of the 2 subdomains of the HKC may control not only kinase activity but exposure of the ATP binding site (PubMed:23486471).
The isolated histidine kinase core (HKC, residues 386-578) is a dimer and autophosphorylates, suggesting the protein may function as a homodimer (PubMed:23486471).
Belongs to the zinc-containing alcohol dehydrogenase family.
Probable antitoxin component of a type II toxin-antitoxin (TA) system. The cognate toxin is VapC5.
The C-terminal domain (residues 55-86) does not neutralize non-cognate antitoxin VapC4; exchanging the N-terminus (residues 1-54) with VapB4 however allows neutralization of VapC4, while exchanging the C-terminal domain (residues 55-86) does not.
Component of the F(0) channel, it forms part of the peripheral stalk, linking F(1) to F(0).
To M.leprae ML2435 and S.coelicolor SCO3349.
Belongs to the glycosyl hydrolase 13 family. GlgB subfamily.
Cysteine residues of GlgB form structural disulfide bond(s), which allow the protein to exist in two different redox-dependent conformational states. Although the conformational change do not affect the branching enzyme activity, the change in surface hydrophobicity could influence the interaction or dissociation of different cellular proteins with GlgB in response to different physiological states.
Disruption of glgB is lethal for the bacteria in vitro. Affects the production of both extracellular alpha-D-glucan and intracellular glycogen.
Essential enzyme that catalyzes the formation of the alpha-1,6-glucosidic linkages in glucan chains by scission of a 1,4-alpha-linked oligosaccharide from growing alpha-1,4-glucan chains and the subsequent attachment of the oligosaccharide to the alpha-1,6 position. Is involved in the biosynthesis of both glycogen and capsular alpha-D-glucan.
Is inhibited by divalent cations such as Zn(2+) and Cu(2+), but not by Mg(2+), Mn(2+) and Ca(2+). Is not inhibited by several known inhibitors of the GH13 family such as ADP, ADP glucose, tunicamycin, castenospermine, nojirimycin, or acarbose.
Monomer. Interacts with WhiB1 via an intermolecular disulfide bond.
Belongs to the haloalkane dehalogenase family. Type 1 subfamily.
Catalyzes hydrolytic cleavage of carbon-halogen bonds in halogenated aliphatic compounds, leading to the formation of the corresponding primary alcohols, halide ions and protons.
Activated by magnesium and calcium, and inhibited by zinc, nickel and cobalt.
Belongs to the 3-hydroxyacyl-CoA dehydrogenase family.
Catalyzes the NAD-dependent oxidation of beta-hydroxybutyryl-CoA to acetoacetyl-CoA in vitro at pH 10. Also catalyzes the reverse reaction albeit in a lower pH range of 5.5-6.5. The reverse reaction is able to use NADPH as well as NADH.
Up-regulated upon acid shock and SDS stress.
Belongs to the F420H(2)-dependent quinone reductase family.
Activates the tRNA-splicing ligase complex by facilitating the enzymatic turnover of catalytic subunit RtcB. Acts by promoting the guanylylation of RtcB, a key intermediate step in tRNA ligation. Can also alter the NTP specificity of RtcB such that ATP, dGTP or ITP is used efficiently (By similarity).
Belongs to the class-II aminoacyl-tRNA synthetase family.
Catalyzes the attachment of alanine to tRNA(Ala) in a two-step reaction: alanine is first activated by ATP to form Ala-AMP and then transferred to the acceptor end of tRNA(Ala). Also edits incorrectly charged Ser-tRNA(Ala) and Gly-tRNA(Ala) via its editing domain.
Consists of three domains; the N-terminal catalytic domain, the editing domain and the C-terminal C-Ala domain. The editing domain removes incorrectly charged amino acids, while the C-Ala domain, along with tRNA(Ala), serves as a bridge to cooperatively bring together the editing and aminoacylation centers thus stimulating deacylation of misacylated tRNAs.
Belongs to the complex I 23 kDa subunit family.
NDH-1 is composed of 14 different subunits. Subunits NuoA, H, J, K, L, M, N constitute the membrane sector of the complex.
NDH-1 shuttles electrons from NADH, via FMN and iron-sulfur (Fe-S) centers, to quinones in the respiratory chain. The immediate electron acceptor for the enzyme in this species is believed to be menaquinone. Couples the redox reaction to proton translocation (for every two electrons transferred, four hydrogen ions are translocated across the cytoplasmic membrane), and thus conserves the redox energy in a proton gradient.
Probable amino-acid or metabolite transport protein.
Toxic component of a type II toxin-antitoxin (TA) system. An RNase (By similarity). Upon expression in M.smegmatis inhibits colony formation. Its toxic effect is neutralized by coexpression with cognate antitoxin VapB39.
Forms a complex with cognate toxin MazE6, which neutralizes the toxin. Interacts physically with non-cognate antitoxins VapB27 and VapB40 which neutralize the toxin.
Individual deletion of mazF3, mazF6 and mazF9 have little to no phenotype, but a triple mutant shows increased sensitivity to oxidative and antibiotic stress and starvation, decreased formation of persisters cells, and a decreased bacterial load and pathogenic damage in infected guinea pigs.
Strongly induced (17 to 25-fold) by nitrosative stress, starvation, when grown in a non-replicating state, in the presence of gentamycin or rifampicin.
Toxic component of a type II toxin-antitoxin (TA) system. Upon expression in E.coli and in M.smegmatis partially inhibits cell growth and colony formation; its toxic effect is neutralized by coexpression with cognate antitoxin MazE6. Acts as an mRNA interferase on ssRNA, cleaving between the second and third bases in the sequences CUCCU and UUCCU (PubMed:18485066). Further experiments demonstrate that it digests between the first and second bases of UCCUU, yielding a 5'-hydroxyl end; digests M.tuberculosis mRNA (in coding as well as the 5'- and 3'-UTR regions) and 23S rRNA, digests E.coli 16S rRNA both alone and in the 70S ribosome but no data for M.tuberculosis 16S rRNA cleavage was presented. 23S and 16S rRNA digestion occurs in predicted single-stranded regions, the 16S rRNA UCCUU site is in the anti-Shine-Dalgarno site and would cleave off the last 7 nucleotides (PubMed:24709835). Non-cognate antitoxins VapB27 and VapB40 partially neutralize toxicity in vivo (PubMed:20876537).
Antigen that activates dendritic cells (DCs), increasing their expression of cell surface molecules and augmenting their production of TNF-alpha, IL-1beta, IL-6, IL-23 and IL-12p70. Rv3628 mediates these effects by binding to TLR2 and activating downstream MyD88-, MAPK- and NF-kappaB-dependent signaling pathways. Rv3628-stimulated DCs induce the expansion of OVA-specific CD4+ and CD8+ T cells which secrete IFN-gamma and IL-2, and the generation of effector/memory T cells. Thus, Rv3628 polarizes DCs toward a Th1 immune response and promotes protective immunity against M.tuberculosis infection. Is not able to bind to TLR4 molecules on the cell surface.
Catalyzes the hydrolysis of inorganic pyrophosphate (PPi) forming two phosphate ions.
Displays vaccine potential against the hyper-virulent M.tuberculosis Beijing K strain. Protective efficacy is correlated with the generation of Rv3628-specific CD4+ T cells co-producing IFN-gamma, TNF-alpha and IL-2 and exhibiting an elevated IFN-gamma recall response.
Is constitutively expressed and is not up-regulated upon macrophage infection or by exposure to environmental stress when grown in vitro.
Other metal ions such as Mn(2+) and Zn(2+) can support activity, but at a much lower rate (PubMed:16239227). Three metal ions appear to be required for the activation of the enzyme and the substrate during the catalytic cycle (PubMed:26296329).
Belongs to the complex I subunit 1 family.
Belongs to the bacterial ribosomal protein bL36 family.
Belongs to the prokaryotic ubiquitin-like protein family.
Fusion of Pup to a nonproteasome substrate targets it for proteasomal degradation in an Mpa- and proteasome-dependent manner.
Is modified by deamidation of its C-terminal glutamine to glutamate by the deamidase Dop, a prerequisite to the subsequent pupylation process.
Protein modifier that is covalently attached to lysine residues of substrate proteins, thereby targeting them for proteasomal degradation. The tagging system is termed pupylation. Among the identified substrates are the FabD, PanB and Mpa proteins.
Strongly interacts with the proteasome-associated ATPase ARC (Mpa) through a hydrophobic interface; the interacting region of Pup lies in its C-terminal half. There is one Pup binding site per Mpa hexamer ring; the K(D) measured is about 3.8 uM.
The N-terminal unstructured half of Pup provides a signal required to initiate unfolding and degradation by the proteasome but is not needed for pupylation, while the C-terminal helical half of Pup interacts with Mpa to target proteins to the proteasome.
The glutamate must be located at the C-terminal position to be coupled to the lysine substrate.
Catalyzes the transfer of the phosphoenolpyruvate moiety from enoylpyruvoyl-2-diphospho-5'-guanosine (EPPG) to 7,8-didemethyl-8-hydroxy-5-deazariboflavin (FO) with the formation of dehydro coenzyme F420-0 and GMP.
Inhibits intracellular mycobacterial growth by inducing apoptosis in infected macrophages. Induces macrophage apoptosis by triggering reactive oxygen species (ROS) production, release of cytochrome c, and activation of caspase-3 via a TLR4-dependent pathway. FbiA-mediated apoptosis may act as a host defense response.
Belongs to the amino acid-polyamine-organocation (APC) superfamily.
Belongs to the fatty acid desaturase type 1 family.
Expected to bind 2 Fe(2+) ions per subunit.
Inhibited by the anti-tuberculosis drug isoxyl (ISO).
Interacts with the electron transfer protein Rv3230c to form a functional acyl-CoA desaturase complex.
Is expressed during the exponential growth.
Is likely involved in the aerobic desaturation system responsible for the synthesis of oleic acid from stearoyl-CoA; oleic acid is a precursor of mycobacterial membrane phospholipids and triglycerides. Catalyzes the conversion of stearoyl-CoA to oleoyl-CoA by introduction of a cis double bond between carbons 9 and 10 of the acyl chain. Requires the electron transfer partner Rv3230c to pass two electrons from NADPH to its active site diiron center. Is also able to catalyze the 9-desaturation of palmitoyl-CoA to palmitoleoyl-CoA.
Is rapidly degraded by a mycobacterial protein degradation system that specifically targets the residues LAA at the C-terminus, leading to a post-translational proteolytic regulation of DesA3 essential activity.
Strains lacking this gene are shown to be attenuated in a mouse tuberculosis model.
Antitoxin component of a type II toxin-antitoxin (TA) system. Upon expression in E.coli and in M.smegmatis counteracts the ribonuclease activity of cognate toxin MazF6.
Forms a complex with cognate toxin MazF6 which neutralizes the toxin. Interacts physically with non-cognate toxins VapC27 and VapC40.
Strongly induced (about 10-fold) by nitrosative stress.
Belongs to the ATP-dependent DNA ligase family.
DNA ligase that seals nicks in double-stranded DNA during DNA replication, DNA recombination and DNA repair.
Not essential for growth (in strain Erdman).
Belongs to the universal ribosomal protein uS8 family.
One of the primary rRNA binding proteins, it binds directly to 16S rRNA central domain where it helps coordinate assembly of the platform of the 30S subunit.
Part of the 30S ribosomal subunit. Contacts proteins S5 and S12.
Belongs to the HAD-like hydrolase superfamily.
Belongs to the complex I subunit 5 family.
NDH-1 shuttles electrons from NADH, via FMN and iron-sulfur (Fe-S) centers, to quinones in the respiratory chain. The immediate electron acceptor for the enzyme in this species is believed to be menaquinone. Couples the redox reaction to proton translocation (for every two electrons transferred, four hydrogen ions are translocated across the cytoplasmic membrane), and thus conserves the redox energy in a proton gradient (By similarity).
Shows trans-enoyl-CoA hydratase/3-hydroxyacyl-CoA dehydratase activity (PubMed:17240207). In vitro, can hydrate various enoyl-CoA such as (2E)-hexenoyl-CoA, (2E)-octenoyl-CoA, (2E)-decenoyl-CoA, (2E)-dodecenoyl-CoA and (2E)-hexadecenoyl-CoA (PubMed:17240207, PubMed:19136596). May contribute to the persistence of the tuberculosis infection by inducing COX-2 expression in macrophages through MAPK-NF-kappaB signaling pathway (PubMed:24907510).
Regulated by Coenzyme A (CoA) through feedback inhibition.
Reversibly transfers an adenylyl group from ATP to 4'-phosphopantetheine, yielding dephospho-CoA (dPCoA) and pyrophosphate.
Component of the pyruvate dehydrogenase (PDH) complex, that catalyzes the overall conversion of pyruvate to acetyl-CoA and CO(2). AceE has reductase activity with pyruvate but does not react with 2-oxoglutarate.
Homodimer (By similarity). Part of the PDH complex, consisting of multiple copies of AceE (E1), DlaT (E2) and Lpd (E3).
Interacts with (phosphorylated) MviN and (phosphorylated) PknB via the FHA domain. Binds to the PknB juxtamembrane domain with an affinity that is modulated by the degree and the pattern of phosphorylation of this juxtamembrane domain.
Regulates cell growth and peptidoglycan synthesis by binding to MviN. May inhibit the late stages of peptidoglycan synthesis.
The structure of the N-terminal domain remains unchanged upon phosphorylation.
Autoregulated. Differentially up-regulated under different stress conditions, such as low concentrations of detergents and alkaline pH. Induced by low concentrations of sodium dodecyl sulfate (SDS) in a SigE-dependent manner. In strain ATCC 25618 / H37Rv, repressed during growth in macrophages.
Member of the two-component regulatory system MprB/MprA which contributes to maintaining a balance among several systems involved in stress resistance and is required for establishment and maintenance of persistent infection in the host. Functions as a transcriptional regulator that recognizes a 19-bp nucleotide motif comprizing two loosely conserved 8-bp direct DNA-binding motif repeats separated by a 3-bp spacer region. MprB/MprA is involved in regulation of numerous stress-responsive genes, including up-regulation of two sigma factors, sigE and sigB as well as pepD and mprA, and repression of multiple genes from regulons associated with hypoxia, starvation and iron metabolism. The majority of genes regulated by MprB/MprA under a particular stress condition are different from those induced during normal growth, but several genes are commonly regulated under more than one condition.
Monomer. Interaction with each conserved 8-bp repeat requires tandem binding by two protein monomers (Probable).
Phosphorylated and dephosphorylated by MprB.
Phosphorylation is not required for binding to DNA in vitro. However, phosphorylation enhances DNA binding and is required for activity in vivo.
Belongs to the PapA acyltransferase family.
Deletion of the gene prevents PAT synthesis.
Involved in the biosynthesis of polyacyltrehalose (PAT), a pentaacylated, trehalose-based glycolipid that could have a role in anchoring the bacterial capsule. Catalyzes the sequential transfer of two palmitoyl groups onto a single glucose residue of trehalose generating the diacylated product 2,3-diacyltrehalose (trehalose dipalmitate). Although palmitoyl-CoA (PCoA) seems to be the physiological acyl donor, PapA3 can also use docosanoyl (22-carbon saturated fatty acid) coenzyme A as acyl donor.
Catalyzes the conversion of glucosamine-6-phosphate to glucosamine-1-phosphate.
Belongs to the CDP-alcohol phosphatidyltransferase class-I family.
Probably catalyzes the synthesis of phosphatidylglycerophosphate by transferring a phosphatidyl group from CDP-diacylglycerol to glycerol 3-phosphate.
Disruption of the gene reduces the expression of PE13 and PPE18. It allows mice to survive for significant longer, with substantially reduced lung pathology.
Positively regulates the expression of PE13 and PPE18. Can also regulate expression of some other genes. Plays a role in modulation of innate immune responses.
Belongs to the universal ribosomal protein uL14 family.
Binds to 23S rRNA. Forms part of two intersubunit bridges in the 70S ribosome.
Part of the 50S ribosomal subunit. Forms a cluster with proteins L3 and L19. In the 70S ribosome, L14 and L19 interact and together make contacts with the 16S rRNA in bridges B5 and B8.
Expression is positively regulated by Rv0485 (PubMed:19651861). Induced by different stress conditions such as surface stress, oxidative stress and acidic pH stress (PubMed:27147522).
May play a pivotal role in the interaction between M.tuberculosis and host. Can enhance the survival within macrophages under stress conditions such as H(2)O(2), SDS and low pH. Increases the production of IL-6 and IL-1beta from macrophages, and decreases the secretion of suppressor of cytokine signaling 3 (SOCS-3). These changes probably involve the p38-ERK-NF-kappa-B signaling pathway. Also precipitates the macrophage death.
Forms a complex with cognate antitoxin MazE4 (By similarity). Interacts with DNA topoisomerase I (PubMed:20724443).
RNA cleavage is inhibited by the C-terminal domain of DNA topoisomerase I.
Residues 29-56 inhibit ssDNA cleavage by DNA topoisomerase. This fragment does not have mRNA cleavage activity but it inhibits growth upon overexpression in M.smegmatis.
Toxic component of a type II toxin-antitoxin (TA) system. Acts as an endoribonuclease (mRNA interferase) on single-strand mRNA, cleaving between the first and second bases in the sequence UCGCU. Overexpression in M.smegmatis but not E.coli inhibits growth, this effect is neutralized by coexpression with cognate toxin MazE4.
Catalyzes an early step in the biosynthesis of tetrapyrroles. Binds two molecules of 5-aminolevulinate per subunit, each at a distinct site, and catalyzes their condensation to form porphobilinogen (By similarity).
Transcription is repressed by NmtR. Induced by nickel and, to some extent, cobalt.
Activity is highest with Rb(+), followed by K(+), NH4(+) and Cs(+).
Belongs to the IMPDH/GMPR family. GuaB1 subfamily.
Involved in the purine-salvage pathway (PubMed:35338694). Catalyzes the NADPH-dependent conversion of GMP to IMP (PubMed:35338694). Has no inosine-5'-monophosphate dehydrogenase (IMPDH) activity (PubMed:21081761).
Belongs to the ATPase epsilon chain family.
F-type ATPases have 2 components, CF(1) - the catalytic core - and CF(0) - the membrane proton channel. CF(1) has five subunits: alpha(3), beta(3), gamma(1), delta(1), epsilon(1). CF(0) has three main subunits: a, b and c.
Produces ATP from ADP in the presence of a proton gradient across the membrane.
Joins adenosylcobinamide-GDP and alpha-ribazole to generate adenosylcobalamin (Ado-cobalamin). Also synthesizes adenosylcobalamin 5'-phosphate from adenosylcobinamide-GDP and alpha-ribazole 5'-phosphate (By similarity).
To M.leprae ML2432 and S.coelicolor SCO3347.
Inhibited by alpha-ethyl-N-4-pyridinyl-benzeneacetamide (EPBA) and 4,4'-dihydroxybenzophenone (DHBP).
Sterol 14alpha-demethylase whose physiological substrate is not known. Accepts electrons from the iron-sulfur ferredoxin Fdx encoded by an adjacent gene (PubMed:10430874, PubMed:16819841). In vitro, catalyzes C14-demethylation of lanosterol, 24,25-dihydrolanosterol and obtusifoliol, to produce the 8,14-dienes stereoselectively (PubMed:10430874).
Deletion mutant does not exhibit a low iron growth phenotype, but has attenuated virulence compared to the wild-type strain. Deletion of both mmpS4 and mmpS5 drastically decreases synthesis and secretion of siderophores, and greatly reduces virulence in mice.
Interacts with MmpL4. Can also interact with MmpL5.
Part of an export system, which is required for biosynthesis and secretion of siderophores. Essential for virulence.
Transcriptionally regulated by MmpR5 (PubMed:24737322). Repressed by iron and IdeR (PubMed:12065475).
Part of the Sec protein translocase complex. Interacts with the SecYEG preprotein conducting channel. Has a central role in coupling the hydrolysis of ATP to the transfer of proteins into and across the cell membrane, serving as an ATP-driven molecular motor driving the stepwise translocation of polypeptide chains across the membrane.
Part of the essential Sec protein translocation apparatus which comprises SecA, SecYEG and auxiliary proteins SecDF. Other proteins may also be involved (By similarity). Monomer and homodimer.
Belongs to the glycosyl hydrolase 13 family.
Catalyzes the conversion of maltooligosaccharide into the non-reducing saccharide, maltooligosyl trehalose (alpha-maltooligosyl alpha-D-glucoside) by intramolecular transglycosylation.
Part of the PpsABCDE complex involved in the biosynthesis of the lipid core common to phthiocerols and phenolphthiocerols by successive additions of malonyl-CoA or methylmalonyl-CoA extender units (PubMed:15749014, PubMed:20553505). PpsA can accept as substrate the activated forms of either icosanoyl (C20), docosanoyl (C22) or lignoceroyl (C24) groups from FadD26, or a (4-hydroxyphenyl)-C17 or (4-hydroxyphenyl)-C19 fatty acyl from FadD29 (PubMed:15749014, PubMed:20553505). PpsA initiates the biosynthesis and extends its substrate using a malonyl-CoA extender unit. The PpsB and PpsC proteins add the second and third malonyl-CoA extender units. PpsD adds an (R)-methylmalonyl unit and PpsE adds a second (R)-methylmalonyl unit. The incorporation of the methylmalonyl units results in formation of two branched methyl groups in the elongated product (PubMed:15749014).
Belongs to the cytidine and deoxycytidylate deaminase family.
Recycles cytidine and 2-deoxycytidine for uridine and 2-deoxyuridine synthesis, respectively. Catalyzes the hydrolytic deamination of cytidine and 2-deoxycytidine to form, respectively, uridine and 2-deoxyuridine.
Catalyzes the interconversion of ribulose-5-P and ribose-5-P. It has not isomerase activity towards D-allose 6-phosphate.
In mycobacterial enzymes, the usual proton acceptor is not a cysteine, but is remplaced by a glutamate.
Weakly inhibited by phosphate and completely inhibited by iodoacetate.
Belongs to the ribonucleoside diphosphate reductase small chain family.
Initially decreases as oxygen levels drop, then rises again.
Provides the precursors necessary for DNA synthesis. Catalyzes the biosynthesis of deoxyribonucleotides from the corresponding ribonucleotides. Two genes for this protein are present in M.tuberculosis; this is the active form. When coexpressed in E.coli with nrdE the 2 proteins complement a temperature-sensitive E.coli mutant.
Tetramer of two alpha and two beta subunits.
Catalyzes the Claisen rearrangement of chorismate to prephenate. Probably involved in the aromatic amino acid biosynthesis.
The formation of the complex with AroG activates the chorismate mutase activity by more than two orders of magnitude to a catalytic efficiency (kcat/Km) typical for chorismate mutase. This activation is primarily caused by a more than 30-fold-decreased Km value, but also by a four-fold increase in kcat. The activity of the complex is inhibited by phenylalanine and tyrosine by about 70 and 40%, respectively.
Belongs to the class-II pyridoxal-phosphate-dependent aminotransferase family. BioF subfamily.
Catalyzes the decarboxylative condensation of pimeloyl-[acyl-carrier protein] and L-alanine to produce 8-amino-7-oxononanoate (AON), [acyl-carrier protein], and carbon dioxide (By similarity). Can also use pimeloyl-CoA instead of pimeloyl-ACP as substrate. To a lesser extent, can also utilize D-alanine instead of L-alanine as substrate.
Cells lacking this gene are shown to be highly attenuated in a mouse tuberculosis model (PubMed:14569030). Essential for growth even in liquid culture; growth does not occur on biotin-containing medium after biotin deprivation (PubMed:20565114).
Inhibited by D-alanine and D-7-keto-8-amino-pelargonic acid.
Competitively inhibited by lysophosphatidic acid.
Overexpression of this gene in M.smegmatis increases its survival within infected human macrophages (PubMed:35314194). Overexpression also protects the M.smegmatis spheroplasts, which are cell wall-deficient mycobacterial forms, from membrane disruption/lysis by pLPC, by rapidly catabolizing it and depleting it from the media (PubMed:35314194).
Specifically hydrolyzes the vinyl ether bond of lysoplasmenylcholine (pLPC) and lysoplasmenylethanolamine (pLPE) to release a fatty aldehyde and glycerophospho-choline or glycerophospho-ethanolamine (PubMed:35314194). The cleavage activity is specific for lysoplasmalogen substrates, and there is no activity on 1-alkenyl-sn-2-acyl-glycerophospho-ethanolamine or 1-alkenyl-sn-2-acyl-glycerophospho-choline (plasmalogen) substrates (PubMed:35314194). Confers a growth advantage for mycobacteria in host macrophages, possibly by cleaving toxic host pLPC into potentially energy-producing products (PubMed:35314194).
Degradation of the cholesterol side chain involves 3 multistep beta-oxidation cycles, this may be involved in the second cycle (Probable). Hydrates 3-OCDO-CoA ((22E)-3-oxo-chol-4,22-dien-24-oyl-CoA) to make (22R)-HOCO-CoA (3-oxo-chol-4-ene-(22R)-hydroxy-24-oyl-CoA). Also acts on octenoyl-CoA. Not active on (E)-3-OCDS-CoA ((E)-3-oxocholest-4,24-dien-26-oyl-CoA) or 3-OPDC-CoA (3-oxo-4,17-pregnadiene-20-carboxyl-CoA). Hydrates the same substrate as ChsH3, but the 2 enzymes make different stereoisomers of the product (PubMed:32649175, PubMed:33826843).
Homotrimer; substrate probably binds in elongated tunnels between the subunits.
Not required for growth in a mouse tuberculosis model (PubMed:14569030). Not required for growth on cholesterol (PubMed:21980284).
Succinylated in vitro at pH 8.1, succinylation reduces specific activity of the enzyme 5.5-fold; succinyl-CoA is a downstream by-product of cholesterol degradation. Can be de-succinylated in vitro by NAD-dependent protein deacylase (AC P9WGG3). Succinylation may be a negative feedback regulator of cholesterol metabolism.
Antitoxin component of a type II toxin-antitoxin (TA) system. Upon expression in M.smegmatis neutralizes the effect of cognate toxin VapC31.
Induced in persister cells in response to D-cycloserine.
Belongs to the urease beta subunit family.
Heterotrimer of UreA (gamma), UreB (beta) and UreC (alpha) subunits. Three heterotrimers associate to form the active enzyme.
A translation factor that gates the progression of the 70S ribosomal initiation complex (IC, containing tRNA(fMet) in the P-site) into the translation elongation cycle by using a mechanism sensitive to the ATP/ADP ratio. Binds to the 70S ribosome E-site where it modulates the state of the translating ribosome during subunit translocation. ATP hydrolysis probably frees it from the ribosome, which can enter the elongation phase.
Belongs to the ABC transporter superfamily. ABCF family. Translational throttle EttA subfamily.
Monomer. Probably contacts ribosomal proteins L1, L5, L33 and S7, the 16S and 23S rRNA and the P-site containing tRNA(fMet).
The P-site tRNA interaction motif (PtIM domain) probably interacts with the P-site tRNA(fMet) as well as the 23S rRNA.
The arm domain is inserted in the first ABC transporter domain. Probably contacts ribosomal protein L1.
Expression is regulated by ClgR (PubMed:25899163). Induced by carbonyl cyanide m-chlorophenyl hydrazone (CCCP) (PubMed:25899163). Induced by the cell envelope stressor SDS (PubMed:27002134).
Involved in resistance to stress (PubMed:25899163, PubMed:27002134). Facilitates intracellular growth of M.tuberculosis (PubMed:25899163). Associates with and regulates lipid droplets (LDs) homeostasis under conditions of stress and may regulate non-replicating persistence (NRP) (PubMed:27002134). Could be involved in preservation of envelope integrity and tolerance to surface stress (PubMed:25899163). Has an inhibitory effect on ClgR activity (PubMed:25899163). May block ClgR activity after stress and then, form a multiprotein complex with Rv2743c-Rv2742c, leading to the release of ClgR (PubMed:25899163).
Levels are regulated by proteolytic cleavage by PepD to help maintain cell envelope homeostasis.
Loss of the gene does not alter resistance to cell envelope stressors.
Overexpression of PspA results in altered lipid droplet morphology.
Self-associates and forms homooligomeric complexes of high molecular weight in vitro (PubMed:27002134). Datta et al. show that PspA interacts with ClgR and Rv2743c, but Armstrong et al. fail to observe interaction with either ClgR or Rv2743c in E.coli in vivo when assayed using a bacterial adenylate two-hybrid assay (PubMed:25899163, PubMed:27002134). Also interacts with the serine protease PepD (PubMed:21445360).
Belongs to the ABC-3 integral membrane protein family.
Catalyzes a salvage reaction resulting in the formation of AMP, that is energically less costly than de novo synthesis.
Catalyzes the synthesis of alpha-ribazole-5'-phosphate from nicotinate mononucleotide (NAMN) and 5,6-dimethylbenzimidazole (DMB).
A probable intramembrane site-2 protease (S2P) that cleaves type-2 transmembrane proteins within their membrane-spanning domains. Cleaves PbpB (PBP3, FtsI) near 'Ala-102' and 'Ala-103' in response to oxidative stress; cleavage is inhibited by Wag31-PbpB interaction. Probably also cleaves anti-sigma factors RskA, RslA and RsmA but not RsdA.
Inhibited by metal chelator o-phenanthroline.
Regulated intramembrane proteolysis (RIP) occurs when an extracytoplasmic signal (possibly oxidative stress) triggers a concerted proteolytic cascade to transmit information and elicit cellular responses. The membrane-spanning regulatory substrate protein (includes anti-sigma factors RskA, RslA, RsmA, and PbpB in M.tuberculosis) is first cut extracytoplasmically (site-1 protease, S1P), then within the membrane itself (site-2 protease, S2P, this entry), while cytoplasmic proteases finish degrading the regulatory protein, liberating the effector protein (ECF sigma factors SigK, SigL and SigM).
Belongs to the AB hydrolase superfamily. Epoxide hydrolase family.
Could be involved in detoxification of extraneous host-cell epoxides. Catalyzes the hydrolysis of epoxide-containing substrates.
Toxic component of a type II toxin-antitoxin (TA) system. An RNase. The cognate antitoxin is VapB50.
Belongs to the class-I aminoacyl-tRNA synthetase family.
A covalent CysO-cysteine adduct is formed by the action of CysM. The structure of the adduct seems to be first a S-(glycyl)-cysteinate which leads to a N-(glycyl)-cysteinate after a S->N acyl shift.
Belongs to the sulfur carrier protein CysO family.
In its thiocarboxylated form (CysO-COSH), is the sulfur donor in the CysM-dependent cysteine biosynthetic pathway. May be of particular importance for cysteine biosynthesis in the persistent phase of M.tuberculosis.
Up-regulated under oxidative stress conditions.
Belongs to the MbcA/ParS/Xre antitoxin family.
Forms a heterotetramer with cognate toxin Rv3189.
Probable antitoxin component of a type II toxin-antitoxin (TA) system. Neutralizes the activity of cognate toxin Rv3189 by blocking access to the toxin active site.
Could be a nuclease involved in processing of the 5'-end of pre-16S rRNA.
Involved in coproporphyrin-dependent heme b biosynthesis (PubMed:25646457). Catalyzes the insertion of ferrous iron into coproporphyrin III to form Fe-coproporphyrin III (PubMed:25646457). Has weaker activity with coproporphyrin I, protoporphyrin IX, deuteroporphyrin, 2,4 hydroxyethyl and 2,4 disulfonate (PubMed:25646457, PubMed:11948160).
5'-3' exonuclease acting preferentially on double-stranded DNA.
Elicits a high humoral and a low T-cell response. Could be involved in directing the host toward development of a more humoral type of immune response.
Belongs to the TRAFAC class translation factor GTPase superfamily. Classic translation factor GTPase family. IF-2 subfamily.
One of the essential components for the initiation of protein synthesis. Protects formylmethionyl-tRNA from spontaneous hydrolysis and promotes its binding to the 30S ribosomal subunits. Also involved in the hydrolysis of GTP during the formation of the 70S ribosomal complex (By similarity).
Component of a biotin-dependent acyl-CoA carboxylase complex. This subunit transfers the CO2 from carboxybiotin to the CoA ester substrate.
Does not show significant changes in expression throughout M.tuberculosis growth phases.
The biotin-dependent acyl-CoA carboxylase complex is composed of an AccA protein, which contains the biotin carboxylase (BC) and biotin carboxyl carrier protein (BCCP) domains, and an AccD protein, which contains the carboxyl transferase (CT) domain.
Belongs to the GHMP kinase family. IspE subfamily.
Catalyzes the phosphorylation of the position 2 hydroxy group of 4-diphosphocytidyl-2C-methyl-D-erythritol.
Metal-responsive transcriptional repressor for the cmt operon. Binding of cadmium or lead causes the repressor to dissociate from the DNA.
Belongs to the class-I aminoacyl-tRNA synthetase family. Glutamate--tRNA ligase type 1 subfamily.
Catalyzes the attachment of glutamate to tRNA(Glu) in a two-step reaction: glutamate is first activated by ATP to form Glu-AMP and then transferred to the acceptor end of tRNA(Glu).
Cells lacking KdpD and KdpE show an increase in virulence in mouse model of infection, with significantly shorter survival times.
Member of the two-component regulatory system KdpD/KdpE involved in the regulation of the kdp operon. Upon phosphorylation by KdpD, functions as a transcription regulator by direct binding to promoter regions of target genes to positively regulate their expression.
Involved in the biosynthesis of the tuberculostearic acid (10-methylstearic-acid or TSA), a constituent lipid of the mycobacterial cell wall. Catalyzes the transfer of the methyl group from S-adenosyl-L-methionine (SAM) to the double bond of oleic acid in phosphatidylethanolamine or phosphatidylcholine to produce TSA.
Belongs to the mycobacterial A85 antigen family.
Cells lacking this gene produce normally mycoloylated cell wall components.
The antigen 85 proteins (FbpA, FbpB, FbpC) are responsible for the high affinity of mycobacteria for fibronectin, a large adhesive glycoprotein, which facilitates the attachment of M.tuberculosis to murine alveolar macrophages (AMs). They also help to maintain the integrity of the cell wall by catalyzing the transfer of mycolic acids to cell wall arabinogalactan, and through the synthesis of alpha,alpha-trehalose dimycolate (TDM, cord factor). They catalyze the transfer of a mycoloyl residue from one molecule of alpha,alpha-trehalose monomycolate (TMM) to another TMM, leading to the formation of TDM. FbpA mediates triacylglycerol (TAG) formation with long-chain acyl-CoA as the acyl donor and 1,2-dipalmitoyl-sn-glycerol (1,2-dipalmitin) as the acyl acceptor. It has a preference for C26:0-CoA over C18:1-CoA.
Belongs to the universal ribosomal protein uS7 family.
One of the primary rRNA binding proteins, it binds directly to 16S rRNA where it nucleates assembly of the head domain of the 30S subunit. Is located at the subunit interface close to the decoding center, probably blocks exit of the E-site tRNA.
Part of the 30S ribosomal subunit. Contacts proteins S9 and S11.
May directly or indirectly regulate the accessibility of the key branch point intermediate, monoacyl phosphatidylinositol tetramannoside (AcPIM4), to the elongating alpha-1,6 mannosyltransferases which could regulate the lipoarabinomannans (LAMs) biosynthesis.
Disruption mutant shows a significant decrease in the biosynthesis and accumulation of lipid droplets containing triacylglycerol and in its tolerance to rifampicin.
May play a critical role in the homeostasis of triacylglycerol-containing lipid droplets in M.tuberculosis and influence the entry of the pathogen into a dormant state.
Together with AceAb, they could catalyze the formation of succinate and glyoxylate from isocitrate.
Facilitates a shift in the ensuing immunity toward the Th2 phenotype and could aid in immune evasion by mycobacteria. Interacts with human Toll-like receptor 2 (TLR2) and triggers functional maturation of human dendritic cells (DCs), leading to secretion of IL-4, IL-5 and IL-10 from CD4(+) T cells and induction of Th2 immune response. Maturation of DCs involves PI3K, ERK1/2, p38 MAPK and NF-kappa-B signaling pathways.
Metal-dependent DNA-binding protein that controls transcription of many genes involved in iron metabolism. Acts as a repressor of siderophore biosynthesis and as a positive modulator of iron storage. Also regulates expression of transporters, proteins involved in siderophore synthesis, iron storage and transcriptional regulators.
Binding to c-di-GMP activates PdtaS autophosphorylation and by extension phosphotransfer to PdtaR (PubMed:33772870). At the opposite, autophosphorylation and signaling cascade are inhibited by NO, copper and zinc (PubMed:34003742). Activity is not inhibited by calcium or iron (PubMed:34003742). Full inhibition of PdtaR/PdtaS signaling cascade requires the transduction of a cell surface signal by the intramembrane protease Rip1 (PubMed:34003742).
In addition, the PdtaR/PdtaS two-component system controls copper and nitric oxide (NO) resistance downstream of the intramembrane protease Rip1 (PubMed:34003742). This coupled Rip1/PdtaS/PdtaR circuit controls NO resistance and acute lung infection in mice by relieving PdtaR/PdtaS-mediated repression of isonitrile chalkophore biosynthesis (PubMed:34003742). Two signals are required to fully inactivate the PdtaR/PdtaS system and mediate NO resistance: a cytoplasmic inhibitory signal through the PdtaS kinase mediated by direct sensing of NO and the production of PPE1-5', an NO-induced small RNA, to sequester PdtaR (PubMed:34003742).
Member of the two-component regulatory system PdtaR/PdtaS (PubMed:16026786, PubMed:33772870, PubMed:34003742). This two-component system plays an essential role in mycobacterial adaptation to poor nutrient conditions (PubMed:33772870). Nutrient deprivation results in increasing intracellular concentrations of cyclic diguanosine monophosphate (c-di-GMP), which binds to the PdtaS sensor and promotes its autophosphorylation, leading to the activation of the signaling cascade (PubMed:33772870). The phosphate group is then transferred to PdtaR (PubMed:16026786, PubMed:33772870, PubMed:34003742).
The N-terminal sensor region consists of closely linked GAF and PAS domains (PubMed:22115998). Binds c-di-GMP via the GAF domain (PubMed:33772870). Copper and NO are detected through a dicysteine motif in the GAF domain (PubMed:34003742).
The N-terminal sensor region is a monomer in solution, but it forms non-covalently linked dimers over time.
Allosterically inhibited by NADP, NADPH, and NADH, at concentrations lower than 0.5 mM. Completely inhibited by p-chloromercuribenzoate.
Involved in the regulation of the intracellular balance of NAD and NADP, and is a key enzyme in the biosynthesis of NADP. Catalyzes specifically the phosphorylation on 2'-hydroxyl of the adenosine moiety of NAD to yield NADP. It can use ATP and other nucleoside triphosphates as well as inorganic polyphosphate (poly(P)) as a source of phosphorus.
Deletion does not affect EsxN and PPE41 secretion.
Interacts specifically with ESX-5-dependent PE/PPE proteins. Forms a 1:1:1 heterotrimeric complex with the PE25/PPE41 dimer, via PPE41. Binding of EspG5 does not cause conformational changes in the PE25/PPE41 dimer.
Required for the formation of a threonylcarbamoyl group on adenosine at position 37 (t(6)A37) in tRNAs that read codons beginning with adenine. Is involved in the transfer of the threonylcarbamoyl moiety of threonylcarbamoyl-AMP (TC-AMP) to the N6 group of A37, together with TsaD and TsaB. TsaE seems to play an indirect role in the t(6)A biosynthesis pathway, possibly in regulating the core enzymatic function of TsaD (By similarity).
Part of the twin-arginine translocation (Tat) system that transports large folded proteins containing a characteristic twin-arginine motif in their signal peptide across membranes. Together with TatC, TatB is part of a receptor directly interacting with Tat signal peptides. TatB may form an oligomeric binding site that transiently accommodates folded Tat precursor proteins before their translocation.
The Tat system comprises two distinct complexes: a TatABC complex, containing multiple copies of TatA, TatB and TatC subunits, and a separate TatA complex, containing only TatA subunits. Substrates initially bind to the TatABC complex, which probably triggers association of the separate TatA complex to form the active translocon.
May play a pivotal role in the evasion of host immune response by M.tuberculosis. Mediates production of IL-10 via activation of the p38 and ERK1/2 mitogen-activated protein kinase (MAPK) signaling pathways.
Belongs to the thiolase-like superfamily. Thiolase family.
Cells lacking this gene display an attenuated disease phenotype with reduced colony-forming units in comparison to the wild-type. This mutant is unable to metabolize cholesterol to androst-4-ene-3,17-dione (AD) and androsta-1,4-diene-3,17-dione (ADD).
Induced by cholesterol and repressed by KstR.
Involved in the beta-oxidation of the cholesterol side chain (PubMed:19822655). It is important for utilization of cholesterol as a sole carbon source in vitro and for full virulence in the chronic stage of mouse lung infection (PubMed:19822655). Catalyzes the thiolysis of 3,22-dioxochol-4-en-24-oyl-CoA to yield 3-oxo-4-pregnene-20-carboxyl-CoA (3-OPC-CoA) and acetyl-CoA (PubMed:25482540). Also able to use acetoacetyl-CoA (AcAcCoA) as substrate (PubMed:19822655).
Belongs to the mycobacteriales LppA/LppB family.
Belongs to the thymidylate kinase family.
Binds 1 Mg(2+) ion per subunit. This ion is required for catalysis, binding to the active site transiently (at the TMP-binding site), and probably acting as a clamp between the phosphoryl donor and acceptor.
Catalyzes the reversible phosphorylation of deoxythymidine monophosphate (dTMP) to deoxythymidine diphosphate (dTDP), using ATP as its preferred phosphoryl donor. Situated at the junction of both de novo and salvage pathways of deoxythymidine triphosphate (dTTP) synthesis, is essential for DNA synthesis and cellular growth. Has a broad specificity for nucleoside triphosphates, being highly active with ATP or dATP as phosphate donors, and less active with ITP, GTP, CTP and UTP.
Competitively inhibited at the phosphate acceptor site by 3'-azido-3'-deoxythymidine monophosphate (AZT-MP) (in contrast to other TMPKs such as E.coli, in which it is a good substrate). Inhibition seems to result from the impossibility of magnesium binding.
The LID domain is a solvent-exposed domain that closes over the site of phosphoryl transfer upon ATP binding.
Attaches a formyl group to the free amino group of methionyl-tRNA(fMet). The formyl group appears to play a dual role in the initiator identity of N-formylmethionyl-tRNA by promoting its recognition by IF2 and preventing the misappropriation of this tRNA by the elongation apparatus.
Constitutive repression of the RicR regulon by a 'copper-blind' RicR results in extreme copper sensitivity in vitro and attenuation of virulence in mice.
Disruption of the gene results in the constitutive expression of the entire RicR regulon and hyper-resistance of the cell to copper.
Negatively autoregulated. Induced by copper.
Under low copper conditions, represses the expression of lpqS, Rv2963, mymT, socA, socB, mmcO and its own expression. In the presence of copper, RicR dissociates from DNA, leading to the expression of the target genes. Members of the RicR regulon are important for copper resistance during infections and full virulence in a mouse model of infection.
Activity is potentiated by the SL-1 transporter MmpL8. Inhibited by the lipase inhibitor tetrahydrolipstatin (THL).
Inactivation of the mmpL8 gene interrupts the normal biosynthesis of SL-1 and leads to the accumulation of the precursor SL1278.
Involved in the final steps of the cell wall sulfolipid-1 (SL-1) biosynthesis. Catalyzes two successive acylations of the precursor 2-palmitoyl-3-(C43)-phthioceranyl-alpha, alpha'-D-trehalose-2'-sulfate (SL1278) to yield the tetraacylated sulfolipid SL-1.
Co-immunoprecipitates with DarG in the presence and absence of darT.
The RecF protein is involved in DNA metabolism; it is required for DNA replication and normal SOS inducibility. RecF binds preferentially to single-stranded, linear DNA. It also seems to bind ATP (By similarity).
Contains a number of strongly recognized T-cell epitopes distributed throughout the protein sequence and induces high level of IFN-gamma, indicating this might be a good vaccine candidate (PubMed:10603390, PubMed:12228269, PubMed:16714570). A fusion protein (p846) of 3 well-defined antigens (EspC, EsxH and Rv2660c) induces robust specific T-cell immune response and could be an effective vaccine (PubMed:24280763).
EsxH, in complex with EsxG, disrupts ESCRT function and impairs host phagosome maturation, thereby promoting intracellular bacterial growth. The complex acts by interacting, via EsxH, with the host hepatocyte growth factor-regulated tyrosine kinase substrate (HGS/HRS), a component of the ESCRT machinery.
Forms a tight 1:1 complex with EsxG (PubMed:15336430, PubMed:18430736, PubMed:19854905, PubMed:20085764, PubMed:21730061, PubMed:24204276). When it is complexed to EsxG, interacts directly with host HGS/HRS (PubMed:24204276).
To improve expression in E.coli the proteins were cloned as a single protein in the order esxH-esxG with a cleavable thrombin tag (PubMed:19854905).
Belongs to the 'GDXG' lipolytic enzyme family.
Esterase that can hydrolyze short-chain esters with the carbon chain containing 2 to 10 carbon atoms. Does not have lipase activity. Is highly immunogenic and elicits strong humoral immune responses in both HIV-negative (HIV-) and HIV-positive (HIV+) tuberculosis (TB) patients. Also elicits pro-inflammatory cytokine and chemokine responses from macrophages and pulmonary epithelial cells (PubMed:22038913). May participate in the progression of active tuberculosis both by contributing to the utilization of lipid substrates for bacterial growth and replication, and by modulating immune responses (PubMed:22038913).
Expressed only during active M.tuberculosis infection.
Involved in a F420-dependent anti-oxidant mechanism that protects M.tuberculosis against oxidative stress and bactericidal agents. Catalyzes the F420H(2)-dependent two-electron reduction of quinones to dihydroquinones, thereby preventing the formation of cytotoxic semiquinones obtained by the one-electron reduction pathway. Since menaquinone is the sole quinone electron carrier in the respiratory chain in M.tuberculosis, the physiological electron acceptor for Fqr-mediated F420H(2) oxidation is therefore likely to be the endogenous menaquinone found in the membrane fraction of M.tuberculosis.
Belongs to the universal ribosomal protein uS17 family.
One of the primary rRNA binding proteins, it binds specifically to the 5'-end of 16S ribosomal RNA.
Expression is controlled by VirS. Induced at acidic pH and in macrophages, and in response to low levels of nitric oxide (NO).
Inactivation of the mymA operon causes altered cell wall structure, reduced contents and altered composition of mycolic acids along with the accumulation of saturated C24 and C26 fatty acids, and enhanced susceptibility to antibiotics, detergents and acidic pH. Also impairs ability to survive in macrophages.
Required for maintaining the appropriate mycolic acid composition and permeability of the envelope on its exposure to acidic pH. Upon expression in E.coli functions weakly as a triacylglycerol synthase, making triacylglycerol (TG) from diolein and long-chain fatty acyl-CoA. Has no wax synthase activity.
Shows weak esterase activity with the p-nitrophenol-linked aliphatic ester pNP-butyrate. Does not exhibit cutinase activity.
Part of the ABC transporter complex Rv2686c/Rv2687c/Rv2688c involved in fluoroquinolones export. Confers resistance to ciprofloxacin and, to a lesser extent, norfloxacin, moxifloxacin and sparfloxacin. Probably responsible for energy coupling to the transport system.
The complex is composed of 2 ATP-binding proteins (Rv2688c) and 2 transmembrane proteins (Rv2686c and Rv2687c).
The glycine cleavage system catalyzes the degradation of glycine. The P protein binds the alpha-amino group of glycine through its pyridoxal phosphate cofactor; CO(2) is released and the remaining methylamine moiety is then transferred to the lipoamide cofactor of the H protein (By similarity).
The glycine cleavage system is composed of four proteins: P, T, L and H.
Catalyzes the activation of medium/long-chain fatty acids as acyl-coenzyme A (acyl-CoA).
Toxic component of a type II toxin-antitoxin (TA) system. Upon expression in M.smegmatis inhibits colony formation. Its toxic effect is neutralized by coexpression with cognate antitoxin Rv0298/MT0312.
Belongs to the HAD-like hydrolase superfamily. SerB family.
Binds 1 Mg(2+) ion per subunit (By similarity). Can also use Mn(2+) (PubMed:25037224, PubMed:25521849).
Catalyzes the dephosphorylation of O-phospho-L-serine into L-serine, a step in the L-serine biosynthetic pathway (PubMed:25037224, PubMed:25521849). Exhibits high specificity for L-phosphoserine compared to substrates like L-phosphothreonine (5% relative activity) and L-phosphotyrosine (1.7% relative activity) (PubMed:25521849).
Clofazimine, a drug being evaluated for XDR and MDR tuberculosis, inhibits SerB2 phosphatase activity and reverses the various functional effects described above and interactions with host proteins (PubMed:26984196). Is inhibited by known PSP inhibitors such as chlorpromazine, DL-AP3 and sodium orthovanadate, but not by okadaic acid (PubMed:25037224, PubMed:25521849). By binding to the ACT domains, amino-acids have various effects on enzyme activity: L-serine and L-glycine act as inhibitors, whereas L-lysine, L-tyrosine and L-phenylalanine are activators (PubMed:25521849). High throughput screen has been performed to identify specific PSP inhibitors with activity against intracellular bacteria; the two best hits identified in this screen, clorobiocin and rosaniline, are bactericidal and kill bacteria in infected macrophages in a dose-dependent manner (PubMed:25037224).
Folds into three domains, i.e. two ACT domains occurring in tandem at the N-terminus followed by the classical phosphatase (PSP) domain. The PSP domain alone is capable of hydrolyzing L-phosphoserine, albeit with much reduced efficacy. The ACT domains are involved in amino acid binding and play an important role in modulating enzymatic activity.
Homodimer. The dimeric population shifts to a tetramer in the presence of L-serine, which inactivates the enzyme.
In the host, induces significant cytoskeleton rearrangements through cofilin dephosphorylation and its subsequent activation, and affects the expression of genes that regulate actin dynamics. It specifically interacts with HSP90, HSP70 and HSP27 that block apoptotic pathways but not with other HSPs. Also interacts with GAPDH. It actively dephosphorylates MAP kinase p38 and NF-kappa B p65 (specifically at Ser-536) that play crucial roles in inflammatory and immune responses. This in turn leads to down-regulation of Interleukin 8, a chemotactic and inflammatory cytokine. Thus might help the pathogen to evade the host's immune response (PubMed:26984196). Exogenous addition of purified SerB2 protein to human THP-1 cells (that can be differentiated into macrophage-like cells) induces microtubule rearrangements; the phosphatase activity is co-related to the elicited rearrangements, while addition of the ACT-domains alone elicits no rearrangements (PubMed:25521849).
Transposon mutagenesis experiments have identified that SerB2 is essential for the pathogen's viability while SerB1 is not.
Antitoxin component of a type II toxin-antitoxin (TA) system. Upon expression in M.smegmatis neutralizes the effect of cognate toxin VapC30.
Autophosphorylated. In vitro, incorporates up to four phosphate groups on Thr-23, Thr-32 and Thr-63 and/or Thr-64 and/or Ser-65. In vivo, is probably phosphorylated only on Thr-63.
Belongs to the protein kinase superfamily. Ser/Thr protein kinase family.
Contains an N-terminal rubredoxin domain, a central kinase domain and a C-terminal TPR domain.
Disruption causes delayed mortality in mice. Mutant accumulates glutamate and glutamine.
Homodimer. Interacts with the FHA domain of GarA.
Kinase activity is regulated by the redox status of the environment via the rubredoxin domain. Autophosphorylation is not essential for kinase activity, but it promotes binding to GarA. The C-terminal domain also contributes to the regulation of activity. Inhibited by a specific small molecular-weight inhibitor, the tetrahydrobenzothiophene AX20017.
Phosphorylates GarA. May play a role in metabolic regulation via control of the phosphorylation status of GarA. Plays a crucial role in the survival of mycobacteria within host macrophages, by blocking the intracellular degradation of mycobacteria in lysosomes. Required for intrinsic antibiotic resistance.
Belongs to the Nudix hydrolase family. NudC subfamily.
Divalent metal cations. Mg(2+) or Mn(2+).
mRNA decapping enzyme that specifically removes the nicotinamide adenine dinucleotide (NAD) cap from a subset of mRNAs by hydrolyzing the diphosphate linkage to produce nicotinamide mononucleotide (NMN) and 5' monophosphate mRNA. The NAD-cap is present at the 5'-end of some mRNAs and stabilizes RNA against 5'-processing. Has preference for mRNAs with a 5'-end purine. Catalyzes the hydrolysis of a broad range of dinucleotide pyrophosphates.
Belongs to the bacterial/plant glucose-1-phosphate adenylyltransferase family.
Inactivation of glgC reduces by half the extracellular (capsular) alpha-D-glucan and intracellular glycogen contents (PubMed:18808383, PubMed:27513637). Cells lacking this gene are not affected in their multiplication or persistence in the BALB/c mouse infection model (PubMed:18808383). Combined inactivation of both glgC and treS results in a complete absence of maltose-1-phosphate (M1P) and alpha-glucan, whereas combined inactivation of both glgC and otsA results only in a complete absence of alpha-glucan (PubMed:27513637).
Involved in the biosynthesis of ADP-glucose building block required in the biosynthesis of maltose-1-phosphate (M1P) and in the elongation reactions to produce linear alpha-1,4-glucans. Catalyzes the reaction between ATP and alpha-D-glucose 1-phosphate (G1P) to produce pyrophosphate and ADP-Glc.
Maltose-1-phosphate (M1P) is generated by two alternative routes: the TreS-Pep2 branch and the GlgC-GlgM branch, however it seems that TreS-Pep2 branch provides most of M1P for the GlgE pathway in M.tuberculosis.
Belongs to the CRISPR-associated Csm6 family.
CRISPR (clustered regularly interspaced short palindromic repeat) is an adaptive immune system that provides protection against mobile genetic elements (viruses, transposable elements and conjugative plasmids). CRISPR clusters contain spacers, sequences complementary to antecedent mobile elements, and target invading nucleic acids. CRISPR clusters are transcribed and processed into CRISPR RNA (crRNA). The type III-A Csm effector complex binds crRNA and acts as a crRNA-guided RNase, DNase and cyclic oligoadenylate synthase; binding of target RNA cognate to the crRNA is required for all activities (Probable). This CRISPR-Cas system protects bacteria against transformation with plasmids containing DNA homologous to its spacer regions (PubMed:29979631). This subunit is a single-strand-specific endoribonuclease (ssRNase) that is stimulated by cyclic oligoadenylates (cOA) produced by the Cas10 subunit of the Csm effector complex (By similarity).
Homodimer; the composite ssRNase active site is formed at the dimer interface.
Non-specific ssRNase activity is allosterically activated by cyclic oligoadenylates (cOA), a second messenger produced by Cas10 of the ternary Csm effector complex in the presence of a cognate target RNA.
The N-terminal CRISPR-associated Rossman fold (CARF) probably binds the cOA effector. ssRNase activity resides in the C-terminal HEPN domain.
Disruption impairs growth under conditions of limited iron avaibility, but does not affect virulence in mice.
H(+)-stimulated, divalent metal cation uptake system. Transports zinc and iron. Can also interact with manganese and copper.
Up-regulated in response to iron and copper.
Belongs to the type IA topoisomerase family.
Monomer (By similarity). Interacts with mRNA interferase MazF4 (PubMed:20724443). Interacts with DNA-binding protein HupB (By similarity).
Releases the supercoiling and torsional tension of DNA, which is introduced during the DNA replication and transcription, by transiently cleaving and rejoining one strand of the DNA duplex (PubMed:8921893, PubMed:20724443). Introduces a single-strand break via transesterification at a target site in duplex DNA. The scissile phosphodiester is attacked by the catalytic tyrosine of the enzyme, resulting in the formation of a DNA-(5'-phosphotyrosyl)-enzyme intermediate and the expulsion of a 3'-OH DNA strand. The free DNA strand then undergoes passage around the unbroken strand, thus removing DNA supercoils. Finally, in the religation step, the DNA 3'-OH attacks the covalent intermediate to expel the active-site tyrosine and restore the DNA phosphodiester backbone.
The C-terminus (residues 622-934) inhibits RNA cleavage by MazF4.
ssDNA cleavage is inhibited by MazF4 (PubMed:20724443). Relaxation of supercoiling is stimulated by DNA-binding protein HupB (By similarity).
Endonuclease that specifically degrades the RNA of RNA-DNA hybrids.
Manganese or magnesium. Binds 1 divalent metal ion per monomer in the absence of substrate. May bind a second metal ion after substrate binding.
Involved in the hydrocarbon hydroxylating system, which transfers electrons from NADH to rubredoxin reductase and then through rubredoxin to alkane 1 monooxygenase.
Belongs to the phosphoglycerate mutase family.
Homodimer (PubMed:22355692). Dimerization of the enzyme is essential for its dephosphorylation activity (PubMed:24914210).
Involved in the biosynthesis of mycobacterial methylglucose lipopolysaccharides (MGLPs). Catalyzes the dephosphorylation of glucosyl-3-phosphoglycerate (GPG) to glucosylglycerate (GG). GPG is the preferred substrate, but GpgP also exhibits low dephosphorylation activity on mannosyl-3-phosphoglycerate (MPG) and mannosylglucosyl-3-phosphoglycerate (MGPG) in vitro. Shows only trace of phosphoglycerate mutase (PGM) activity.
Progressively inhibited by cobalt ions at concentrations between 10-50 mM and by copper ions at any concentration between 1-50 mM.
Belongs to the D-isomer specific 2-hydroxyacid dehydrogenase family.
Interacts specifically with ESX-3-dependent PE/PPE proteins.
Belongs to the bacterial ribosomal protein bS1 family.
Binds mRNA, facilitating recognition of most mRNAs by the 30S ribosomal subunit during translation initiation (By similarity). Probably plays a role in trans-translation; binds tmRNA (the product of the ssrA gene) (PubMed:21835980). In trans-translation Ala-aminoacylated transfer-messenger RNA (tmRNA, product of the ssrA gene; the 2 termini fold to resemble tRNA(Ala) while it encodes a short internal open reading frame (the tag peptide)) acts like a tRNA, entering the A-site of the ribosome and displacing the stalled mRNA (which is subsequently degraded). The ribosome then switches to translate the ORF on the tmRNA, the nascent peptide is terminated with the 'tag peptide' encoded by the tmRNA and thus targeted for degradation (By similarity).
Binds pyrazinoic acid (POA), the active form of the prodrug pyrazinamide (PZA); POA disrupts tmRNA binding (at 50 ug/ml in vitro) and also trans-translation (at 25 ug/ml in vitro using purified H37Ra ribosomes).
Full-length S1 protein and the C-terminal domain (residues 285-481) bind tmRNA; the interaction is disrupted in a concentration-dependent manner by POA. 2 POA molecules bind to the C-terminal domain (residues 285-481) and S1 motif 4 (residues 285-368).
Mutations in this gene that alter POA binding may cause antibiotic resistance.
Expressed in log phase cells. Induced by treatment with rifampicin and gentamicin as well as by oxidative, nitrosative and nutritional stress. Induced in the lungs of mice infected for 4 weeks. A member of the relFG operon.
In combination with cognate antitoxin RelF represses its own promoter. Has been seen to bind DNA in complex with antitoxin RelF but not alone.
Interacts with cognate antitoxin RelF, which neutralizes the toxin. Also interacts with non-cognate antitoxin RelB in vitro, in M.smegmatis this neutralizes the toxicity of this toxin.
No visible phenotype in culture or upon infection of mice. Significantly fewer persister cells are generated in vitro following exposure to rifampicin and gentamicin, but in infected mice no differences are seen.
Toxic component of a type II toxin-antitoxin (TA) system. Has RNase activity and preferentially cleaves at the 3'-end of purine ribonucleotides (By similarity). Overexpression in M.tuberculosis or M.smegmatis inhibits colony formation in a bacteriostatic rather than bacteriocidal fashion. Its toxic effect is neutralized by coexpression with cognate antitoxin RelB2 (shown only for M.smegmatis). Overexpression also increases the number of gentamicin-tolerant and levofloxacin-tolerant persister cells.
Belongs to the WXG100 family. CFP-10 subfamily.
Differentially expressed under different growth conditions. Highly expressed in sputum bacteria.
EsxKL deletion mutant shows reduced intracellular growth in primary human macrophages. Also shows growth defects in the absence of host cells.
Strongly interacts with EsxL to form a heterodimeric complex under reducing conditions. The complex is regulated by the redox state of EsxL.
Belongs to the helicase family. PriA subfamily.
Compared to other bacterial PriA, it has a very divergent helicase domain.
Involved in the restart of stalled replication forks. Recognizes and binds the arrested nascent DNA chain at stalled replication forks. It can open the DNA duplex, via its helicase activity, and promote assembly of the primosome and loading of the major replicative helicase DnaB onto DNA.
Inactivation of the gene leads to a 4- to 8-fold decrease in minimal inhibitory concentrations (MICs) for ethidium bromide, novobiocins, biarylpiperazines, bisanilopyrimidines, pyrroles and pyridones.
Probably part of the ABC transporter complex Rv1217c-Rv1218c involved in the resistance to a wide range of structurally unrelated drugs (PubMed:20921309, PubMed:23143285). Could be involved in the efflux of substrates belonging to the diverse chemical classes of novobiocins, biarylpiperazines, pyridines, bisanilinopyrimidines, pyrroles and, to a smaller extent, pyrazolones (PubMed:20921309). Probably responsible for energy coupling to the transport system (Probable).
The complex is probably composed of two ATP-binding proteins (Rv1218c) and a transmembrane protein (Rv1217c).
Transcriptionally regulated by RaaS (Rv1219c) (PubMed:24424575). Expression increases in multidrug-resistant clinical strains (MDR-TB) compared to drug-susceptible strains (PubMed:23143285).
Antitoxin component of a type II toxin-antitoxin (TA) system. Upon expression in M.smegmatis neutralizes the effect of cognate toxin VapC39.
A host TLR2 agonist (toll-like receptor), shown experimentally for human and mouse (PubMed:19362712). Inhibits primary human macrophage MHC-II Ag processing via TLR2 (PubMed:15294983). Both lipidated and nonlipidated protein act as TLR2 agonists in antigen-presenting cells, although lipidated protein is more efficient (PubMed:20694006). In resting human CD4+ T-cells lipidated but not nonlipidated protein is a costimulatory ligand (with anti-CD3 and anti-CD28) for T-cell proliferation and IFN-gamma and IL-2 production, leading to increased expression of early T-cell activation markers, TLR2 and NFKB3 phosphorylation (PubMed:21078852). Human CD4+ T-cells use TLR1/TLR2 heterodimers to respond to this and probably other mycobacterial lipoproteins (PubMed:21078852). Able to stimulate proliferation of CD4+ T-cells derived from a human leprosy patient following protein processing/presentation by MHC class II molecules in peripheral blood mononuclear cells (PubMed:18424702). Requires both host TLR1 and TLR2 as coreceptors to elicit host response in mouse, although TLR6 may play a redundant role, has a partial requirement for CD14 as an accessory receptor (PubMed:19362712).
A single deletion mutant leads to loss of expression of efflux pump Rv1410c due to polar effects; in infected BALB/c mice 1.5 and 2.5 log decrease in bacterial load 15 and 35 days after infection (PubMed:14998516). The single mutant increases sensitivity to malachite green, sodium dodecyl sulfate (SDS), isoniazid, ethambutal and ethidium bromide, alters the permeability of the cell wall; both genes of the operon are required to fully restore the phenotypes (PubMed:21762531). Single deletion mutant (probably without Rv1410c) has decreased surface-exposed glycolipid lipoarabinomannan (LAM), although cellular LAM, LM and PIM content is normal (PubMed:25232742, PubMed:25356793). Disruption of either Rv1410c or the lrpG-Rv1410c operon leads to increased levels of many triacylglyceride (TAG) alkylforms; up to 100-fold increase depending on the exact TAG form (PubMed:26751071). It also forms smaller colonies on agar (PubMed:25232742). Loss of surface LAM has several consequences; bacteria enter mouse macrophages with reduced efficiency and block mouse macrophage phagosome-lysosome fusion less efficiently than wild-type (PubMed:25232742). Reduced efficiency of mouse macrophage phagosome-lysosome fusion was seen in another study (PubMed:25356793). C57BL/6 mice infected with mutant bacteria have 10-fold less bacterial burden after 10 days and about 2700-fold less burden after 70 days; attenuation of mutant is not rescued in macrophages impaired for reactive oxygen or nitrogen generation (disruption of Ncf1 or iNOS) (PubMed:25232742).
Bacterial LAM blocks host cell phagosome-lysosome fusion and is one way in which M.tuberculosis evades the host immune system.
Belongs to the LppX/LprAFG lipoprotein family.
Forms a U-shaped beta-half-barrel with a small hydrophobic cavity (1500 Angstroms (3)) which holds a triacylated PIM in 1 crystal structure; the 3 acyl chains are within the cavity while the sugar moieties bind to the protein surface (PubMed:20694006). In the structure bound to triacylglycerides (TAG) 2 of the 3 acyl chains are buried in the cavity, the third is solvent exposed (PubMed:26751071). A flexible lid region may move to accommodate different TAG molecules (PubMed:26751071). Fragments of the mature protein (residues 81-100, 141-160 and 218-236) prevent uptake of M.tuberculosis by a human macrophage-like cell line; lesser effects are seen on bacterial uptake by a human lung epithelial cell line (PubMed:25041568).
Modified by Lgt on Cys-27 with an S-linked diacylglyceral, signal peptide is removed by LspA, Cys-27 is further modifed with a fatty acid on its amino group by Lnt yielding a triacylated protein (Probable). Probably glycosylated, which is required for T-cell activation (PubMed:18424702).
Probably helps membrane protein Rv1410c (P55) transport triacylglycerides (TAG) across the inner cell membrane into the periplasm; TAG probably regulates lipid metabolism and growth regulation (PubMed:26751071). Binds TAG and transfers it between lipid bilayers, probably to the outer membrane in vivo (PubMed:26751071). Binds di- and triacylated phosphatidyl-myo-inositol mannosides (PIMs), and glycolipid lipoglycan modulins lipoarabinomannan (LAM) and lipomannan (LM), facilitating their recognition by TLR2 (PubMed:20694006, PubMed:25356793). Binds LM > PIM6 > ManLAM > PI-LAM > PIM2 (mannose-capped LAM and phospho-myo-inositol-capped LAM, E.coli expressed without acyl-groups); deacylated LM and LAM also bind to this protein via their mannose moieties, showing LprG has at least 2 different ways to bind glycolipids (PubMed:25356793). Binds triacylglycerides (TAG) in the same cavity, is able to transfer TAG between lipid bilayers (PubMed:26751071). Overexpression of LprG and Rv1410c leads to increased levels of TAG in the culture medium (PubMed:26751071). Required for Rv1410c-mediated export of drugs (PubMed:18156250, PubMed:21762531). Required, probably with Rv1410c, for normal surface localization of LAM (PubMed:25232742).
Triacylglycerides accumulate in lipid droplets in the cytoplasm of M.tuberculosis stationary phase and dormant bacteria, and are used as an energy source during starvation (PubMed:26751071).
Belongs to the universal ribosomal protein uS14 family.
Binds 16S rRNA, required for the assembly of 30S particles and may also be responsible for determining the conformation of the 16S rRNA at the A site.
Part of the 30S ribosomal subunit. Contacts proteins S3 and S10.
Belongs to the bacterial ribosomal protein bL25 family. CTC subfamily.
Part of the 50S ribosomal subunit; part of the 5S rRNA/L5/L18/L25 subcomplex. Contacts the 5S rRNA. Binds to the 5S rRNA independently of L5 and L18.
This is one of the proteins that binds to the 5S RNA in the ribosome where it forms part of the central protuberance.
Belongs to the ABC transporter superfamily. Molybdate importer (TC 3.A.1.8) family.
Part of the ABC transporter complex ModABC involved in molybdenum import. Responsible for energy coupling to the transport system.
The complex is composed of two ATP-binding proteins (ModC), two transmembrane proteins (ModB) and a solute-binding protein (ModA).
A monovalent cation. Ammonium or potassium.
Belongs to the type III pantothenate kinase family.
Catalyzes the phosphorylation of pantothenate (Pan), the first step in CoA biosynthesis.
Binds 2 heme c groups covalently per subunit.
Cytochrome b subunit of the cytochrome bc1 complex, an essential component of the respiratory electron transport chain required for ATP synthesis. The bc1 complex catalyzes the oxidation of ubiquinol and the reduction of cytochrome c in the respiratory chain. The bc1 complex operates through a Q-cycle mechanism that couples electron transfer to generation of the proton gradient that drives ATP synthesis.
The cytochrome bc1 complex is composed of a cytochrome b (QcrB), the Rieske iron-sulfur protein (QcrA) and a diheme cytochrome c (QcrC) subunit.
Belongs to the dGTPase family. Type 2 subfamily.
Belongs to the universal ribosomal protein uS3 family.
Binds the lower part of the 30S subunit head. Binds mRNA in the 70S ribosome, positioning it for translation.
Part of the 30S ribosomal subunit. Forms a tight complex with proteins S10 and S14.
Antitoxin component of a type II toxin-antitoxin (TA) system. Upon expression in M.smegmatis neutralizes the effect of cognate toxin VapC15 (PubMed:20011113). Partially inhibits the RNase activity of VapC15 (PubMed:25450593).
Crystallizes as a VapB15-VapC15(2) heterotrimer and as a VapB15(2)-VapC15(2) heterotetramer; each toxin pair forms a homodimer which creates a channel in which the antitoxin binds.
The heterotrimer binds 1 Mg(2+)-Mn(2+) pair while the heterotetramer binds 2 pairs. Both metals are shared by the toxin-antitoxin pair.
Cell wall formation. Catalyzes the addition of glutamate to the nucleotide precursor UDP-N-acetylmuramoyl-L-alanine (UMA).
Belongs to the ABC-4 integral membrane protein family.
Belongs to the class-V pyridoxal-phosphate-dependent aminotransferase family. SerC subfamily.
Binds 1 pyridoxal phosphate per subunit.
Catalyzes the reversible conversion of 3-phosphohydroxypyruvate to phosphoserine and of 3-hydroxy-2-oxo-4-phosphonooxybutanoate to phosphohydroxythreonine.
Belongs to the metallo-beta-lactamase superfamily. Glyoxalase II family.
Stealth proteins are part of a protein family that is conserved from bacteria to higher eukaryotes. Family members were first identified in microbes as proteins that help pathogens to elude the host innate immune system. Microbial stealth proteins are involved in the biosynthesis of exopolysaccharides. Stealth proteins are predicted to function as hexose-1-phosphoryltransferases (PubMed:16299590).
Cytochrome P450 that accepts electrons from the iron-sulfur ferredoxin FdxE encoded by an adjacent gene.
Interacts with the ferredoxin FdxE with high affinity (Kd=84 nM).
Belongs to the universal ribosomal protein uS9 family.
Belongs to the acetolactate synthase small subunit family.
Catalyzes the conversion of 2 pyruvate molecules into acetolactate in the first common step of the biosynthetic pathway of the branched-amino acids such as leucine, isoleucine, and valine.
The expression gradually decreases as growth progresses.
Belongs to the Nudix hydrolase family. PCD1 subfamily.
4'-phosphopantetheine is transferred from CoA to a specific serine of apo-AcpM by PptT.
Acyl carrier protein involved in meromycolate extension.
Belongs to the acyl carrier protein (ACP) family.
Despite its similarity with the trehalose-phosphate phosphatase enzymes, it does not display trehalose-phosphate phosphatase activity.
In the C-terminal section; belongs to the glycosyl hydrolase 65 family.
In the N-terminal section; belongs to the trehalose phosphatase family.
Activity in enhanced in the presence of K(+) and Mn(2+) and reduced by about 40% in the presence of Cu(2+).
Has a dual function in both nitrogen assimilation and in protection against acid stress during infection through asparagine hydrolysis and NH4(+) release (PubMed:24586151). Catalyzes asparagine hydrolysis (PubMed:24586151, PubMed:33412160). Cannot use glutamine (PubMed:24586151, PubMed:33412160). Required for intracellular survival inside macrophages during host colonization (PubMed:24586151). Mediates phagosome acidification arrest and resistance to acid stress through the formation of acid-neutralizing NH4(+) ions (PubMed:24586151). In addition, may induce stress to primary immune cells and compromise the host immune response (PubMed:33412160).
Homodimer (PubMed:33412160). Can form tetramers and higher multimers, probably resulting from the dynamic association of dimers (PubMed:33412160).
Not essential. The growth of the knockout mutant is impaired, although not fully abolished, when asparagine is provided as sole nitrogen donor. Nitrogen assimilation from asparagine into glutamate and glutamine is fully abrogated in the knockout mutant at acidic pH. Mutant is impaired in host tissue colonization.
Belongs to the ETF beta-subunit/FixA family.
Heterodimer of an alpha and a beta subunit.
The electron transfer flavoprotein serves as a specific electron acceptor for other dehydrogenases. It transfers the electrons to the main respiratory chain via ETF-ubiquinone oxidoreductase (ETF dehydrogenase) (By similarity).
Belongs to the ABC transporter superfamily. Siderophore-Fe(3+) uptake transporter (SIUT) (TC 3.A.1.21) family.
In IrtA the ATP-binding domain (NBD) and the transmembrane domain (TMD) are fused (PubMed:16385031). In addition, IrtA contains an N-terminal siderophore interaction domain (SID) that binds FAD (PubMed:19948799).
Part of the ABC transporter complex IrtAB involved in the import of iron-bound mycobactin (Fe-MBT) and carboxymycobactin (Fe-cMBT) (PubMed:16385031, PubMed:19948799) (By similarity). Mycobactins are then reduced by the siderophore interaction domain to facilitate iron release in the bacterial cell (By similarity). Transmembrane domains (TMD) form a pore in the membrane and the ATP-binding domain (NBD) is responsible for energy generation (By similarity). Required for replication in human macrophages and in mouse lungs (PubMed:16385031).
PubMed:18461140 reports that IrtA is a siderophore exporter, however this activity could be due to functional differences of IrtA in the molecular context of M.smegmatis and M.tuberculosis.
Belongs to the ABC transporter superfamily. UvrA family.
Forms a heterotetramer with UvrB during the search for lesions (By similarity). Interacts with RecA.
Greatly increased sensitivity to UV light, mitomycin C, slightly less sensitive to nitrosative and oxidative stress; a double uvrA/uvrD1 mutant is even more sensitive. Single uvrA mutant is only slightly attenuated in mouse infection, the double uvrA/uvrD1 mutant is strongly attenuated at all stages of infection.
The UvrABC repair system catalyzes the recognition and processing of DNA lesions. UvrA is an ATPase and a DNA-binding protein. A damage recognition complex composed of 2 UvrA and 2 UvrB subunits scans DNA for abnormalities. When the presence of a lesion has been verified by UvrB, the UvrA molecules dissociate. Alone it slightly inhibits RecA-mediated DNA strand exchange, in concert with UvrD1 greatly inhibits RecA-mediated DNA strand exchange.
Belongs to the inorganic phosphate transporter (PiT) (TC 2.A.20) family. Pit subfamily.
Low-affinity inorganic phosphate transporter.
Disruption of the gene leads to growth defects and attenuates the virulence of Mtb (PubMed:18172199, PubMed:19011036). Disruption of the gene enhances host innate immune responses, compromises the intracellular survival of Mtb in macrophages, and increases its susceptibility to lysozyme. It prolongs survival and reduces lung immunopathology of infected mice (PubMed:18172199). Disruption leads to earlier and significantly higher levels of key pro-inflammatory cytokines and chemokines (PubMed:21947769). Mutant induces enhanced levels of the key Th1-inducing cytokine IL-12, as well as other pro-inflammatory cytokines (IL-23, IL-6, TNF-alpha, IL-1beta, and IL-18) in DCs via MyD88- and TLR2/9-dependent pathways (PubMed:24659689). Infection with the hip1 mutant also induces higher levels of MHC class II and costimulatory molecules CD40 and CD86 (PubMed:24659689). At low pH, mutants are hypersensitive to antibiotics, sodium dodecyl sulfate, heat shock, and reactive oxygen and nitrogen intermediates (PubMed:19011036). GroEL2 remains uncleaved in the hip1 mutant (PubMed:24830429).
Hip1 is an attractive target for developing immunomodulatory therapeutics against Mtb.
Key immunomodulatory virulence factor, which promotes survival in host macrophages and modulates host immune responses (PubMed:18172199, PubMed:21947769, PubMed:24659689). Impacts host innate immune responses by preventing robust macrophage activation (PubMed:18172199, PubMed:21947769). Dampens macrophage pro-inflammatory responses by limiting toll-like receptor 2 (TLR2) activation. It also dampens TLR2-independent activation of the inflammasome and limits secretion of interleukin-18 (IL-18). May act by masking cell surface interactions between TLR2 agonists on Mtb and TLR2 on macrophages (PubMed:21947769). In addition, impacts host adaptive immune responses. It prevents robust maturation of infected dendritic cells (DCs), limits the secretion of key pro-inflammatory cytokines such as IL-12, impairs Ag presentation, and modulates the nature of Ag-specific T-cell responses (PubMed:24659689).
Protease activity is inhibited by serine protease inhibitors but not by cysteine protease inhibitors.
Serine protease that promotes tuberculosis (TB) pathogenesis by promoting the processing and the extracellular release of the M.tuberculosis (Mtb) heat-shock protein GroEL2 (PubMed:18172199, PubMed:24830429, PubMed:28346784). Hip1-dependent cleavage of multimeric GroEL2 results in release of cleaved monomeric GroEL2 into the extracellular milieu. Conversion of multimeric GroEL2 into monomeric GroEL2 is likely to be a mechanism for regulating GroEL2 functions during Mtb pathogenesis (PubMed:24830429). In vitro, exhibits proteolytic activity against synthetic peptides and the general protease substrate azocasein, and exhibits esterase activity against the ester substrate p-nitrophenylbutyrate (PubMed:24830429, PubMed:28346784).
Shows esterase activity in active, dormant, and reactivating Mtb cultures.
The active site region is accessed through a large opening that suggests that the enzyme has endopeptidase activity rather than exopeptidase activity.
Expressed in log phase cells. Induced by treatment with rifampicin and gentamicin as well as by nitrosative and oxidative stress. Expressed in human macrophages 110 hours after infection. Induced in the lungs of mice infected for 4 weeks. A member of the relJK operon.
Forms a toxin-antitoxin complex with RelJ, perhaps RelJ(2)-RelK, in which the toxin is probably inactive. Also interacts with antitoxins RelB and RelF in vitro, in M.smegmatis coexpression with non-cognate antitoxin RelB increases the toxicity of RelK while little change is seen in the RelFK pair.
In combination with RelJ represses its own promoter. Several DNA-protein complexes are formed in vitro depending on the RelJ:RelK ratio.
No visible phenotype in culture or upon infection of mice. Significantly fewer persister cells are generated following exposure to gentamicin, levofloxacin and isoniazid.
Toxic component of a type II toxin-antitoxin (TA) system. Has RNase activity and preferentially cleaves at the 3'-end of purine ribonucleotides (By similarity). Overexpression in M.tuberculosis or M.smegmatis inhibits colony formation in a bacteriostatic rather than bacteriocidal fashion. Its toxic effect is neutralized by coexpression with antitoxin RelJ (shown only for M.smegmatis). Overexpression also increases the number of rifampcin-tolerant persister cells.
Belongs to the class-I pyridoxal-phosphate-dependent aminotransferase family.
The transhydrogenation between NADH and NADP is coupled to respiration and ATP hydrolysis and functions as a proton pump across the membrane.
Remains active in dormant M.tuberculosis.
Belongs to the heme-copper respiratory oxidase family.
Cytochrome c oxidase is the component of the respiratory chain that catalyzes the reduction of oxygen to water. Subunits 1-3 form the functional core of the enzyme complex. CO I is the catalytic subunit of the enzyme. Electrons originating in cytochrome c are transferred via the copper A center of subunit 2 and heme A of subunit 1 to the bimetallic center formed by heme A3 and copper B (By similarity).
Contains an ATPase chaperone domain along with a nucleoside triphosphate hydrolase domain.
Could be a moonlighting protein that uses a multipronged approach to dampen host-directed immunity for efficient replication, survival and pathogenesis (PubMed:36799069). Can enhance virulence by inhibiting autophagy and apoptosis, and disrupting cellular bioenergetics (PubMed:36799069). Binds and activates host TLR4 on the surface of macrophage cells, leading to the activation of the host NFKB and MAPK signaling cascades and enhanced secretion of proinflammatory cytokines (PubMed:36799069). Inhibits autophagic flux via activation of PI3K-AKT-MTOR-ULK1 signaling cascade and represses apoptosis via inhibiting protooncogene c-FOS and MAPK JNK1/2 (PubMed:36799069). Also induces robust disruption of cellular bioenergetics by metabolic reprogramming to rewire the citric acid cycle intermediates for its benefit (PubMed:36799069).
Displays ATP-enhanced chaperone activity (PubMed:26933057). Required for the proper folding of the peptidoglycan endopeptidase RipA and its secretion through the TAT secretion system (PubMed:26933057). In vitro, prevents thermal aggregation of MalZ protein and protects the functional activity of the restriction enzyme NdeI from thermal inactivation (PubMed:26933057).
Interacts with RipA (PubMed:26933057). Interacts with host Toll-like receptor 4 (TLR4) (PubMed:36799069).
Belongs to the ArfB membrane protein family.
Required for wild-type expression of ArfA and ammonia secretion, not however part of an ammonia transporter.
Upon operon disruption no reduction of serine uptake at pH 6.9, no visible effect on outer membrane permeability, however severe delays in ammonia secretion, medium pH neutralization and growth also occur at pH 5.5. Reduced expression of ArfA.
Fatty acyl-AMP ligase activity and transferase activity onto Pks13 are both inhibited by phosphorylation (PubMed:27590338). The acyl-AMP ligase activity is inhibited by the alkylphosphate ester of AMP, adenosine 50-dodecylphosphate (AMPC12) (PubMed:19477415, PubMed:26900152). Also inhibited by eicosyl-AMP (AMPC20) (PubMed:26900152). Loading of the acyl-AMP onto Pks13 is inhibited by 5'-O-[N-(11-phenoxyundecanoyl)sulfamoyl]adenosine (PhU-AMS) (PubMed:27547819).
Involved in the biosynthesis of mycolic acids (PubMed:19436070, PubMed:19477415). Catalyzes the activation of long-chain fatty acids as acyl-adenylates (acyl-AMP), which are then transferred to the phosphopantetheine arm of the polyketide synthase Pks13 for further chain extension (PubMed:15042094, PubMed:19436070, PubMed:19477415, PubMed:27547819, PubMed:27590338). Can use dodecanoate (C12), tetradecanoate (C14) and hexadecanoate (C16) (PubMed:19182784, PubMed:19436070, PubMed:19477415, PubMed:23364516, PubMed:26900152, PubMed:27590338). In vitro, displays a preference for long-chain over medium and short-chain fatty acid substrates (PubMed:19477415).
Phosphorylated on Thr-552 by PknA, PknB, PknD and PknF. Dephosphorylated by PstP. Phosphorylation regulates activity.
Was identified as a drug target (PubMed:23364516, PubMed:23798446, PubMed:30316633). Inhibited by a series of 4,6-diaryl-5,7-dimethyl coumarins that directly inhibit the acyl-acyl carrier protein synthetase activity of FadD32 and kill M.tuberculosis. They effectively block bacterial replication both in vitro and in animal models of tuberculosis (PubMed:23798446). Quinoline-2-carboxamides have also potent anti-tubercular activity (PubMed:30316633).
Belongs to the major facilitator superfamily. Drug:H(+) antiporter-3 (DHA3) (TC 2.A.1.21) family.
Efflux pump that contributes to intrinsic antibiotic resistance (PubMed:9811639, PubMed:12520088, PubMed:20525733, PubMed:30837962). The pump uses the electrochemical gradient as a source of energy (By similarity). Confers resistance to rifampicin (PubMed:20525733). Confers low-level resistance to tetracycline and to several aminoglycosides, including streptomycin, gentamicin, 2'-N-ethylnetilmicin and 6'-N-ethylnetilmicin (PubMed:9811639, PubMed:12520088).
Inhibited by piperine, verapamil and verapamil analogs.
Point mutations found in this efflux pump in clinical isolates can play an important role in conferring clinically relevant resistance to multiple drugs, including pyrazinamide, and could explain some previously unaccounted drug resistance in clinical strains.
Belongs to the transferase hexapeptide repeat family.
May be involved in the biosynthesis of 6-O-methylglucosyl-containing lipopolysaccharides (MGLP).
Regulates host peroxisome homeostasis in response to intracellular redox levels to favor mycobacterial infection in macrophage (PubMed:32388919). Induces the expression of host peroxisome biogenesis and proliferation factors as well as peroxisome associated enzymes. Inhibits the induction of host pexophagy mechanism by down-regulating the expression of pexophagy associated proteins and adapter molecules in infected macrophages. However, during increased oxidative stress conditions, it induces degradation of dysfunctional and damaged peroxisomes. Regulation of peroxisome biogenesis and degradation is dependent upon host p-mTORC1 mediated signaling pathway (PubMed:32388919).
Interacts with MmpS5. Can also interact with MmpS4.
Overexpression of the system confers non-target based resistance to azoles, clofazimine and bedaquiline, via an efflux mechanism.
Part of an export system, which is required for biosynthesis and secretion of siderophores.
Repressed by MmpR5 (PubMed:24590481, PubMed:24737322). Repressed by iron (PubMed:12065475). Regulation is IdeR-independent (PubMed:12065475).
Consists of a large Rossmann fold domain and a small domain, which are connected by a flexible linker.
Probably involved in fatty acid metabolism. Binds to fatty acyl-CoAs of varying carbon chain lengths, with the highest binding affinity for palmitoyl-CoA (C16:0). In vitro, alters the cell wall lipid profile and protects mycobacteria from acidic, oxidative and antibiotic stress. May play a significant role in host-pathogen interaction.
Activity is not influenced by the addition of S-adenosylmethionine, the allosteric activator of TS from Arabidopsis thaliana.
Belongs to the threonine synthase family.
Catalyzes the gamma-elimination of phosphate from L-phosphohomoserine and the beta-addition of water to produce L-threonine.
Belongs to the complex I subunit 3 family.
EspD deficiency results in decreased cellular levels of EspA and EspC, but does not affect their transcription.
Required for ESX-1 function (PubMed:16135231, PubMed:22155774). Required for the maintenance of adequate cellular levels of both EspA and EspC (PubMed:22155774). Facilitates EsxA secretion (PubMed:22155774).
Transcriptionally activated by EspR (PubMed:18685700, PubMed:22389481, PubMed:25536998). Repressed by the MprB/MprA two-component system, by direct regulation and via EspR (PubMed:23104803, PubMed:25536998). Up-regulated by the PhoP/PhoR two-component system, via EspR (PubMed:16573683, PubMed:25536998).
Belongs to the thiolase-like superfamily. Chalcone/stilbene synthases family.
Involved in the biosynthesis of tri- and tetraketide alpha-pyrones. Pks18 catalyzes the extension of medium- and long-chain aliphatic acyl-CoA substrates by using malonyl-CoA as an extender molecule to synthesize polyketide products.
78 interactors between PstP and Mtb proteins were identified using Mtb proteome microarray, including proteins involved in diverse aspects of cellular pathways and biological processes, which contain cellular metabolic process, biosynthetic process, gene expression and transcription regulation processes (PubMed:31958639). Interacts with EthR and may interfere with its DNA binding activity (PubMed:31958639).
Activity is modulated by phosphorylation (PubMed:21423706). Phosphorylated phosphatase is more active than its unphosphorylated equivalent (PubMed:21423706). Inhibited partially by NaF and cyclosporine (PubMed:14575702). Also inhibited by zinc ions and inorganic phosphate (PubMed:21423706).
Binds 3 Mn(2+) ions per subunit (PubMed:15530359). The third manganese ion is unlikely to be involved in catalysis but contributes instead to stabilize a flap segment, which is partially disordered in the absence of bound metal (PubMed:17961594).
Depletion of PstP compromises mycobacterial growth and causes marginal elongation of cells. Depletion of PstP in M.tuberculosis negatively impacts its survival in mice and decreases the bacillary load even in an established infection.
It is uncertain whether Met-1 or Val-4 is the initiator.
Overexpression leads to elongated cells and partially compromised survival.
Phosphorylated on several threonine residues by PknA and PknB.
Plays an important role in regulating cell division and growth by reversible phosphorylation signaling (PubMed:14575702, PubMed:12950916, PubMed:27758870). May play important roles in regulating cellular metabolism and signaling pathways, which could mediate the growth and development of the cell (PubMed:31958639). Plays a role in establishing and maintaining infection (PubMed:27758870). Dephosphorylates several proteins, including the kinases PknA, PknB, PknD, PknE, PknF, PknH, PknJ and Pyk, the transcriptional regulatory proteins EmbR and EthR, the osmosensory protein OprA and the dimycocerosyl transferase PapA5 (PubMed:14575702, PubMed:12950916, PubMed:15967413, PubMed:16817899, PubMed:17411339, PubMed:19826007, PubMed:20520732, PubMed:21423706, PubMed:31958639). In vitro, dephosphorylates the phosphorylated Ser/Thr residues of myelin basic protein (MBP), histone and casein phosphorylated at Ser/Thr residues, but fails to dephosphorylate phosphotyrosine residue of these substrates (PubMed:14575702, PubMed:12950916).
Was reported to dephosphorylate the penicillin-binding protein PBPA. However, this publication has been retracted because the published versions of some figures were modified prior to publication.
Belongs to the UPP synthase family. Z-FPP synthase subfamily.
Catalyzes the condensation of only one isopentenyl pyrophosphate (IPP) unit in the cis configuration to E-geranyl diphosphate (E-GPP) generating the 15 carbon product (2Z,6E)-farnesyl diphosphate (Z-FPP or EZ-FPP). Z-FPP is the precursor of decaprenyl diphosphate, which has a central role in the biosynthesis of the mycobacterial cell wall.
Expressed in growing cells (at protein level). A member of the dormancy regulon. Induced in response to reduced oxygen tension (hypoxia), low levels of nitric oxide (NO) and carbon monoxide (CO). It is hoped that this regulon will give insight into the latent, or dormant phase of infection.
Has been detected by antibody binding and Western blot in the cell wall fraction but no signal sequence is predicted by bioinformatic programs.
Some isolated peptides of this protein are able to bind to human U937 monocytoblastic and A549 epithelial cell lines.
Belongs to the glycerate kinase type-1 family.
Belongs to the C/M/P thioester hydrolase family.
A single deletion is more sensitive to oxidative stress (cumene hydroperoxide but not plumbagin). A double bfrA-bfrB mutant grows 40% less well in the presence of an iron chelator, is more sensitive to oxidative stress, has significantly reduced pathological effects in guinea pigs and a marked reduction in its survival in human macrophages.
As this protein can be easily produced at high concentrations upon expression in E.coli and is highly stable, it is a good model protein for testing new microscopes.
Belongs to the ferritin-like superfamily. Prokaryotic family.
Homooligomer of 24 subunits that are packed together to form an approximately spherical molecule 12-13 nm in diameter with a central cavity, in which large amounts of iron can be stored.
Induced by 1 mM reactive nitrogen intermediate sodium nitroprusside dihydrate (at protein level). Induced by exposure to 50 uM FeCl(3). A possible member of the dormancy regulon. Induced in response to reduced oxygen tension (hypoxia), repressed by carbon monoxide (CO). It is hoped that this regulon will give insight into the latent, or dormant phase of infection.
Possible cargo protein of a type 1 encapsulin nanocompartment involved in protection against oxidative stress (Probable). Iron-storage protein that displays ferroxidase activity, catalyzing the oxidation of Fe(2+) ions into Fe(3+) ions, that can then be deposited as a ferric-oxide mineral core within the central cavity of the protein complex (PubMed:21494619, PubMed:24855650). Retains ferroxidase activity inside the encapsulin nanocompartment with a slight decrease in rate. It is not known if this protein is normally found in the encapsulin nanocompartment (PubMed:24855650).
The C-terminus (residues 163-181) targets the protein to the encapsulin nanocompartment (PubMed:24855650). Interestingly the C-terminus is localized iside the ferritin cage, in theory it does not touch the interior of the nanocompartment (PubMed:34342280).
Catalyzes the hydrolysis of the adenine ring of phosphoribosyl-AMP.
Mutants show increased copper sensitivity.
Necessary for copper homeostasis and likely functions as a copper exporter. Also required for full virulence.
Belongs to the radical SAM superfamily. MoaA family.
Binds 2 [4Fe-4S] clusters. Binds 1 [4Fe-4S] cluster coordinated with 3 cysteines and an exchangeable S-adenosyl-L-methionine and 1 [4Fe-4S] cluster coordinated with 3 cysteines and the GTP-derived substrate.
Catalyzes the cyclization of GTP to (8S)-3',8-cyclo-7,8-dihydroguanosine 5'-triphosphate.
A host TLR2 agonist (toll-like receptor), shown experimentally for human and mouse (PubMed:1906192, PubMed:19362712). Requires both host TLR1 and TLR2 as coreceptors to elicit host response in mouse (TLR6 may also play a role) neither CD14 or CD36 function as accessory receptors (PubMed:19362712). Protein purified from culture filtrate induces host (human) monocytes to produce TNF-alpha, IL-6 and IL-12 p40 (IL12B) via ERK1/2 (MAPK3 and MAPK1) and p38 MAPK pathways; MEK inhibitors U0126 and PD98059 and p38 inhibitor SB203580 block most cytokine production (PubMed:16622205). Host ERK1/2 and p38 MAPK activation is mediated mainly by TLR2, but also partially by TLR4, and unlike the case for lipoprotein LpqH the protein moiety of PstS1 seems to be the antigenic agent (PubMed:16622205). Greater activation of ERK1/2 and p38 MAPK is seen in patients with active pulmonary tuberculosis than in tuberculin-negative patients (PubMed:16622205). Induces apoptosis when incubated with human monocyte-derived macrophages via TLR2 (PubMed:19140873). Protein purified from culture filtrate acts via TLR2 and TLR4 to induce host macrophage (shown for mouse) endoplasmic reticulum stress-mediated apoptosis via MAPK (at least JNK), C-C motif chemokine 2 (MCP-1, Ccl2) and ZC3H12 endoribonucleases (MCPIP, Zc3h12) (PubMed:25544271). Functions as an adhesin, binds to human and mouse macrophages via mannose residues, binds to the mouse macrophage mannose receptor (possibly Mrc1) and mediates bacterial phagocytosis (PubMed:25359607).
Functions in inorganic phosphate uptake, although probably not the main uptake protein under phosphate starvation (PubMed:15731097, PubMed:20933472). Binds phosphate; probably able to bind both H(2)PO(4)(-) and HPO(4)(2-) (PubMed:8294447, PubMed:12842040). Part of the ABC transporter complex PstSACB involved in phosphate import (Probable).
Glycosylated, probably with mannose residues; treatment with alpha-D-mannosidase abolishes its interaction with concanavalin A.
No growth phenotype in phosphate-rich medium (3.6 mM Pi), decreased phosphate uptake in phosphate-depleted medium (PubMed:15731097). Grows faster than wild-type in restricted (Sauton) phosphate-free medium, even after nutrient starvation (PubMed:20933472). Decreased growth in infected BALB/c and C57BL/6 mice for up to 5 months after infection (PubMed:15731097).
The ABC transporter complex is composed of two ATP-binding proteins (PstB), two transmembrane proteins (PstC and PstA) and a solute-binding protein (PstS).
Transcription slightly induced by phosphate starvation, part of the pstB3-pstS2-pstC1-pstA2 operon (PubMed:20933472). Strongly induced by phosphate starvation (at protein level) (PubMed:1612766). Also shown to be only slightly induced by phosphate starvation; results may depend on growth media (at protein level) (PubMed:20933472).
When used as a vaccine has immunostimulatory properties; it stimulates the differentiation of unrelated antigen memory CD4+ T-cells to produce IFN-gamma, IL-17 and IL-22.
The HXXXXD motif is essential for acyltransferase activity and may constitute the binding site for the phosphate moiety of the glycerol-3-phosphate.
Involved in endoplasmic reticulum (ER) stress-mediated apoptosis through human Toll-like receptor 4 (TLR4) signaling pathway. Localizes to the host ER, leading to ER stress, disruption of intracellular Ca(2+) homeostasis and increase of nitric oxide (NO) and reactive oxygen species (ROS) levels. Stress response results in caspase-8 activation and apoptosis of macrophage cells. Apoptosis may lead to dissemination of the bacteria, thereby spreading the disease.
The PGRS region is important for localization and function.
Binds 3 Mg(2+) ions per subunit (PubMed:12906832). Activity is highest with Mn(2+). Can also use Zn(2+) or Co(2+), with lower efficiency (PubMed:27683242).
Catalyzes the hydrolysis of ADP-ribose (ADPR) to AMP and ribose-5-phosphate. Can also hydrolyze ADP-mannose and ADP-glucose, with lower efficiency. Has weaker activity with NAD, GDP-sugars and UDP-sugars (PubMed:27683242). Also catalyzes the conversion of 8-oxo-dGDP to 8-oxo-dGMP, and 8-oxo-GDP to 8-oxo-GMP. Functions in concert with MutT1 to detoxify 8-oxo-dGTP to 8-oxo-dGMP and may play an important role in supporting cellular growth under oxidative stress (PubMed:23463507). The catalytic efficiency is much higher for the hydrolysis of ADPR than 8-oxo-dGTP, suggesting a more relevant biological role in hydrolysis of ADPR (PubMed:27683242).
Contains an extra N-terminal domain, a S1-like RNA-binding domain and a conserved P-loop NTPase domain.
Facilitates transcription termination by a mechanism that involves Rho binding to the nascent RNA, activation of Rho's RNA-dependent ATPase activity, and release of the mRNA from the DNA template. Shows poor RNA-dependent ATP hydrolysis and inefficient DNA-RNA unwinding activities, but exhibits robust and fast transcription termination, which suggests that the transcription termination function of M.tuberculosis Rho is not correlated with its helicase/translocase activities and that these functions may not be important for its RNA release process.
Homohexamer. The homohexamer assembles into an open ring structure. Does not bind NusG.
The antibiotic bicyclomycin inhibits ATPase activity but does not affect termination function.
May be non-functional, contains only the C-terminal section of a formamidopyrimidine-DNA glycosylase and has no detectable DNA-binding activity.
Toxic component of a type II toxin-antitoxin (TA) system. An RNase. Its cognate antitoxin is VapB51.
Belongs to the chorismate synthase family.
Catalyzes the anti-1,4-elimination of the C-3 phosphate and the C-6 proR hydrogen from 5-enolpyruvylshikimate-3-phosphate (EPSP) to yield chorismate, which is the branch point compound that serves as the starting substrate for the three terminal pathways of aromatic amino acid biosynthesis. This reaction introduces a second double bond into the aromatic ring system.
Expression depends on the two-component regulatory system MtrA/MtrB.
Plays an important role in the initiation and regulation of chromosomal replication. Binds to the origin of replication; it binds specifically double-stranded DNA at a 9 bp consensus (dnaA box): 5'-TTATC[CA]A[CA]A-3'. DnaA binds to ATP and to acidic phospholipids (By similarity). Binds its own promoter.
Belongs to the class IV-like SAM-binding methyltransferase superfamily. RNA methyltransferase TrmH family. TrmL subfamily.
Could methylate the ribose at the nucleotide 34 wobble position in tRNA.
Lacks conserved residue(s) required for the propagation of feature annotation.
Belongs to the LysR transcriptional regulatory family.
Belongs to the metallo-dependent hydrolases superfamily. TatD-type hydrolase family.
Binds 2 divalent metal cations per subunit.
Belongs to the anthranilate synthase component I family.
Heterotetramer consisting of two non-identical subunits: a beta subunit (TrpG) and a large alpha subunit (TrpE).
Part of a heterotetrameric complex that catalyzes the two-step biosynthesis of anthranilate, an intermediate in the biosynthesis of L-tryptophan. In the first step, the glutamine-binding beta subunit (TrpG) of anthranilate synthase (AS) provides the glutamine amidotransferase activity which generates ammonia as a substrate that, along with chorismate, is used in the second step, catalyzed by the large alpha subunit of AS (TrpE) to produce anthranilate. In the absence of TrpG, TrpE can synthesize anthranilate directly from chorismate and high concentrations of ammonia (By similarity).
Belongs to the class-I aminoacyl-tRNA synthetase family. ValS type 1 subfamily.
Catalyzes the attachment of valine to tRNA(Val). As ValRS can inadvertently accommodate and process structurally similar amino acids such as threonine, to avoid such errors, it has a 'posttransfer' editing activity that hydrolyzes mischarged Thr-tRNA(Val) in a tRNA-dependent manner.
The C-terminal coiled-coil domain is crucial for aminoacylation activity.
ValRS has two distinct active sites: one for aminoacylation and one for editing. The misactivated threonine is translocated from the active site to the editing site.
Binds 1 Mg(2+) ion per subunit. The magnesium is bound as Mg-PRPP.
Catalyzes the conversion of uracil and 5-phospho-alpha-D-ribose 1-diphosphate (PRPP) to UMP and diphosphate.
Belongs to the peptide chaperone MftB family.
Peptide chaperone involved in the biosynthesis of the enzyme cofactor mycofactocin (MFT). Binds MftA and MftC with high affinity, and is essential for MftC activity on MftA, likely via the formation of a ternary complex.
Belongs to the creatininase superfamily.
MftE appears to bind one Fe(2+) and one Zn(2+) ion per subunit. Fe(2+) seems to be catalytically active while Zn(2+) could play an auxiliary role.
Peptidase involved in the biosynthesis of the enzyme cofactor mycofactocin (MFT). Catalyzes cleavage of the MftC-modified MftA peptide to liberate its final two residues, which consist of a cross-linked valine-decarboxylated tyrosine dipeptide (named 3-amino-5-[(4-hydroxyphenyl)methyl]-4,4-dimethyl-2-pyrrolidin-2-one or ADHP).
Belongs to the RecA family. RadA subfamily.
DNA-dependent ATPase involved in processing of recombination intermediates, plays a role in repairing DNA breaks. Stimulates the branch migration of RecA-mediated strand transfer reactions, allowing the 3' invading strand to extend heteroduplex DNA faster. Binds ssDNA in the presence of ADP but not other nucleotides, has ATPase activity that is stimulated by ssDNA and various branched DNA structures, but inhibited by SSB. Does not have RecA's homology-searching function.
Has a putative N-terminal zinc-finger, a middle region with homology to RecA with ATPase motifs including the RadA KNRFG motif, while the C-terminus is homologous to Lon protease.
Allows the formation of correctly charged Asn-tRNA(Asn) or Gln-tRNA(Gln) through the transamidation of misacylated Asp-tRNA(Asn) or Glu-tRNA(Gln) in organisms which lack either or both of asparaginyl-tRNA or glutaminyl-tRNA synthetases. The reaction takes place in the presence of glutamine and ATP through an activated phospho-Asp-tRNA(Asn) or phospho-Glu-tRNA(Gln) (By similarity).
Belongs to the GatB/GatE family. GatB subfamily.
CoA-dependent KG oxidoreductase activity is absent in a mutant strain deleted for both genes korA and korB, and this strain is impaired for aerobic growth in the absence of sufficient amounts of CO(2). Inhibition of the glyoxylate shunt or exclusion of exogenous fatty acids alleviates this growth defect. Simultaneous disruption of korAB and kgd results in strict dependence upon the glyoxylate shunt for growth.
Component of KG oxidoreductase (KOR) that catalyzes the CoA-dependent oxidative decarboxylation of 2-oxoglutarate (alpha-ketoglutarate, KG) to succinyl-CoA. Methyl viologen can act as electron acceptor in vitro; the physiologic electron acceptor is unknown. Is involved in the alternative TCA pathway that functions concurrently with fatty acid beta-oxidation. Since a growing body of evidence indicates that lipids (for example cholesterol and fatty acids) are a predominant growth substrate for M.tuberculosis during infection, flux through KOR likely represents an important step in intermediary metabolism in vivo. KOR-dependent decarboxylation of KG also appears to be an important source of CO(2) in M.tuberculosis metabolism.
Is extremely stable under aerobic conditions.
KG oxidoreductase (KOR) is composed of KorA and KorB subunits.
Knockdown of this gene in cells with simultaneous deletion of PPE25/PE18/PPE26/PPE27/PE19 genes result in a severely impaired growth in phosphate-limiting media.
Belongs to the amino acid-polyamine-organocation (APC) superfamily. Amino acid transporter (AAT) (TC 2.A.3.1) family.
Catalyzes the attachment of glycine to tRNA(Gly).
Activated by certain divalent metal cations, such as cobalt, manganese, nickel or magnesium. Zinc or iron ions do not affect activity.
Autophosphorylated. Dephosphorylated by PstP.
In vitro, phosphorylates various substrates such as EmbR, PepE, MmaA4, Pyk, LldD and GroEL2.
Cells are more sensitive to azole inhibition.
Essential for recycling GMP and indirectly, cGMP.
Belongs to the metallo-dependent hydrolases superfamily. Adenosine and AMP deaminases family. Adenosine deaminase subfamily.
Catalyzes the hydrolytic deamination of adenosine and 2-deoxyadenosine.
Toxic component of a type II toxin-antitoxin (TA) system. The cognate antitoxin is VapB1 (By similarity). Has ribonuclease activity.
Member of the two-component regulatory system PrrB/PrrA that is involved specifically in early intracellular multiplication of Mycobacterium and is essential for its viability (PubMed:11953357, PubMed:22081401). Upon phosphorylation by PrrB, functions as a transcription regulator by direct binding to promoter regions of target genes to positively regulate their expression. Autoregulates its own expression (PubMed:14702417, PubMed:29101285).
Phosphorylated by PrrB at Asp-58. Also phosphorylated on Thr-6 by PknG/PknK/PknJ. The two phosphorylations act synergistically to activate the DNA-binding activity of PrrA.
Belongs to the bacterial ribosomal protein bS6 family.
Binds together with bS18 to 16S ribosomal RNA.
Involved in the synthesis of both phthiocerol dimycocerosates (PDIMs) and phenolic glycolipids (PGLs), which are structurally related lipids non-covalently bound to the outer cell wall layer of M.tuberculosis and are important virulence factors (PubMed:30292819). In vitro, TesA has both thioesterase and esterase activities (PubMed:30292819, PubMed:31388991). Exhibits thioesterase activity on acyl-CoA derivatives such as palmitoyl-CoA and decanoyl-CoA (PubMed:30292819, PubMed:31388991). Also displays hydrolytic activity on ester substrates, being more active on pNP esters with short carbon chain lengths (C2-C5) than with those bearing medium and long carbon chain lengths (C8-C18) (PubMed:30292819).
Monomer. Can form homodimers in the presence of palmitoyl-CoA (PubMed:31388991). Interacts with the C-terminal region of PpsE (PubMed:15668773).
Strongly inhibited in vitro by CyC17, a monocyclic enol phosphate analog to Cyclipostins, which binds covalently to the catalytic Ser-104 residue leading to a total loss of enzyme activity (PubMed:30292819). Methyl arachidonyl fluorophosphonate (MAFP) inhibits esterase activity but it only reduces by approximately 50% thioesterase activity with palmitoyl-CoA as substrate (PubMed:31388991). Thioesterase activity is inhibited by tetrahydrolipstatin (THL) (PubMed:31388991).
Catalyzes the cleavage of sphingomyelin, a major lipid in eukaryotic cells, into ceramide and phosphocholine, which are then utilized by M.tuberculosis as carbon, nitrogen and phosphorus sources, respectively. Thus, enables M.tuberculosis to utilize sphingomyelin as a source of several essential nutrients for intracellular growth during infection. Furthermore, lyses erythrocytes and constitutes the main hemolytic factor of M.tuberculosis.
Cells lacking this gene do not grow on sphingomyelin as a sole carbon source anymore and replicate poorly in macrophages indicating that M.tuberculosis utilizes sphingomyelin during infection. Moreover, deletion of this gene reduces lysis of erythrocytes by twofold compared with wild-type.
Consists of a surface-exposed C-terminal sphingomyelinase domain and a putative outer membrane-spanning N-terminal channel domain able to mediate glucose and phosphocholine uptake across the outer membrane.
Rv0888 protein levels are increased by 5-fold after contact with erythrocytes for 24 hours, and by 100-fold in the presence of sphingomyelin as the sole carbon source.
Belongs to the universal ribosomal protein uL15 family.
Involved in both the histidine and tryptophan biosynthetic pathways.
Almost completely inhibited by paraoxon (PubMed:19225166). Inhibited by tetrahydrolipstatin (THL), a specific lipase inhibitor (PubMed:20103719).
Circulating B cells able to spontaneously generate specific antibodies directed against Culp1 are detected during active tuberculosis and in some latent-tuberculosis cases.
Induces a strong delayed-type hypersensitivity (DTH) response in animal model of tuberculosis, cellular and humoral immune responses (PubMed:9673225, PubMed:10076913, PubMed:16716602). Induces interferon-gamma (IFN-gamma) release in animal models and in human TB patients (PubMed:9673225, PubMed:10076913, PubMed:16716602). Also induces IL-12 responses in mouse model (PubMed:16716602).
Shows esterase activity, with a preference for short- and medium-chain fatty acids (PubMed:19225166, PubMed:20103719, PubMed:16716602, PubMed:23843969). Has also weak lipase activity, but does not exhibit cutinase activity (PubMed:19225166, PubMed:23843969). Hydrolyzes various p-nitrophenol-linked aliphatic esters, including pNP-butyrate (C4), pNP-valerate (C5), pNP-hexanoate (C6), pNP-octanoate (C8) and pNP-decanoate (C10) (PubMed:19225166, PubMed:20103719, PubMed:16716602). Can use pNP-laurate (C12) and pNP-myristate (C14), with lower efficiency (PubMed:19225166). Can also hydrolyze monocaprylin and triolein, with a slow turnover (PubMed:20103719).
Belongs to the BCCT transporter (TC 2.A.15) family.
Antitoxin component of a type II toxin-antitoxin (TA) system. A probable antitoxin for the putative mRNA interferase RelK. Upon expression in E.coli but not in M.smegmatis this protein neutralizes E.coli YoeB.
Binds to and represses its own promoter, in combination with RelK repression is somewhat lessened. Several DNA-protein complexes are formed in vitro depending on the RelJ:RelK ratio.
Expressed in log phase cells. A member of the relJK operon.
Homodimer (Probable). May form RelJ(2)-RelK toxin-antitoxin complexes, in which the toxin is probably inactive.
ATP is required for the deamidation and depupylation reactions but is not hydrolyzed during the reactions.
Belongs to the Pup ligase/Pup deamidase family. Pup deamidase subfamily.
Disruption of dop abolishes pupylation. Cells lacking this gene also become hypersensitive to reactive nitrogen intermediates (RNI) and are severely attenuated for survival and growth in mice. They also cannot depupylate proteasome substrates.
Interacts with the prokaryotic ubiquitin-like protein Pup.
Specifically catalyzes the deamidation of the C-terminal glutamine of the prokaryotic ubiquitin-like protein Pup to glutamate, thereby rendering Pup competent for conjugation. Also displays depupylase (DPUP) activity, removing conjugated Pup from target proteins; is thus involved in the recycling of Pup and may function similarly to deubiquitinases (DUBs) in eukaryotes to prevent or promote proteasomal degradation of certain proteins.
Catalyzes the transfer of endogenously produced octanoic acid from octanoyl-acyl-carrier-protein onto the lipoyl domains of lipoate-dependent enzymes. Lipoyl-ACP can also act as a substrate although octanoyl-ACP is likely to be the physiological substrate.
In the reaction, the free carboxyl group of octanoic acid is attached via an amide linkage to the epsilon-amino group of a specific lysine residue of lipoyl domains of lipoate-dependent enzymes.
Generates 3->3 cross-links in peptidoglycan, catalyzing the cleavage of the mDap(3)-D-Ala(4) bond of a tetrapeptide donor stem and the formation of a bond between the carbonyl of mDap(3) of the donor stem and the side chain of mDap(3) of the acceptor stem. Is specific for donor substrates containing a stem tetrapeptide since it cannot use pentapeptide stems.
In contrast to other LDT paralogs, LdtMt5 is not inactivated by the beta-lactams carbapenems, which don't form a covalent adduct with the enzyme.
Belongs to the glutamyl-tRNA reductase family.
Catalyzes the NADPH-dependent reduction of glutamyl-tRNA(Glu) to glutamate 1-semialdehyde (GSA).
During catalysis, the active site Cys acts as a nucleophile attacking the alpha-carbonyl group of tRNA-bound glutamate with the formation of a thioester intermediate between enzyme and glutamate, and the concomitant release of tRNA(Glu). The thioester intermediate is finally reduced by direct hydride transfer from NADPH, to form the product GSA.
Possesses an unusual extended V-shaped dimeric structure with each monomer consisting of three distinct domains arranged along a curved 'spinal' alpha-helix. The N-terminal catalytic domain specifically recognizes the glutamate moiety of the substrate. The second domain is the NADPH-binding domain, and the third C-terminal domain is responsible for dimerization.
Constitutively expressed during growth in culture (PubMed:10974545). Induced during growth in macrophages (PubMed:12366866).
Deletion mutant fails to secrete EsxA and EspB and replicates poorly in mice.
May play a dual role in regulation of ESX-1 secretion and virulence. Acts as a protease that cleaves EspB. Essential for ESX-1 function, required for early replication in macrophages and full virulence in mice.
Was originally thought to be proteolytically processed intracellularly.
Cells lacking this gene grow, albeit poorly, in standard medium with dextrose, glycerol, and fatty acids as carbon sources, but fail to grow on carbohydrates. They are less resistant than wild-type to exposition to mildly acidified nitrite, but are more resistant to oxidative stress in the form of H(2)O(2) in vitro. Lpd-deficient strains are severely attenuated in wild-type and immunodeficient mice. In contrast to wild-type or DlaT lacking strains, strains lacking Lpd are unable to grow on leucine or isoleucine. Disruption of this gene also leads to extraordinary accumulations of pyruvate and branched chain amino and keto acids.
Homodimer. Identified in a complex with AhpC, AhpD and DlaT. Also is part of the PDH complex, consisting of multiple copies of AceE (E1), DlaT (E2) and Lpd (E3), and of the BCKADH complex, consisting of multiple copies of BkdA/BkdB (E1), BkdC (E2) and Lpd (E3).
Lipoamide dehydrogenase is an essential component of the alpha-ketoacid dehydrogenase complexes, namely the pyruvate dehydrogenase (PDH) complex, the branched-chain alpha-ketoacid dehydrogenase (BCKADH) complex, and likely also the 2-oxoglutarate dehydrogenase (ODH) complex. Catalyzes the reoxidation of dihydrolipoyl groups which are covalently attached to the lipoate acyltransferase components (E2) of the complexes. Is also able to catalyze the transhydrogenation of NADH and thio-NAD(+) in the absence of D,L-lipoamide, and the NADH-dependent reduction of quinones in vitro.
The active site is a redox-active disulfide bond.
Together with AhpC, AhpD and DlaT, Lpd constitutes an NADH-dependent peroxidase active against hydrogen and alkyl peroxides as well as serving as a peroxynitrite reductase, thus protecting the bacterium against reactive nitrogen intermediates and oxidative stress generated by the host immune system.
Triazaspirodimethoxybenzoyls are high-nanomolar inhibitors of M.tuberculosis Lpd and are non-competitive versus NADH, NAD(+), and lipoamide and >100-fold selective compared to human Lpd.
Belongs to the bacterial ribosomal protein bS18 family.
Binds as a heterodimer with protein bS6 to the central domain of the 16S rRNA, where it helps stabilize the platform of the 30S subunit.
Part of the 30S ribosomal subunit. Forms a tight heterodimer with protein bS6.
Defective in persistence phenotype shown by increased susceptibility to tuberculosis (TB) drugs rifampicin and pyrazinamide in both minimum inhibitory concentration (MIC) testing and drug exposure assays. The MICs of rifampicin and pyrazinamide decreased 4-fold and 2-fold, respectively. Reduced persistence in the mouse model of TB infection. Mutant was less able to survive and persist in the mouse lungs and spleens as shown by an about 10- to 30-fold decrease in colony forming unit (cfu) counts compared with the virulent strain.
May be a drug target for designing new drugs that kill persister bacteria for more effective control of bacterial infections.
Plays a role in the regulation of phosphate uptake. In this role, it may bind, possibly as a chaperone, to PhoR, PhoP or a PhoR-PhoP complex to promote dephosphorylation of phospho-PhoP, or inhibit formation of the PhoR-PhoP transitory complex (By similarity). Important for tolerance to antibiotics.
Efficiently phosphorylated in vitro by several M.tuberculosis Ser/Thr protein kinases (STPKs), including PknA, PknB, PknD, PknE, and PknL. Thr-191 represents the primary phosphorylation site in vivo.
Homotetramer (PubMed:11932442, PubMed:12079383, PubMed:15977159, PubMed:17642518). Homodimer in solution (PubMed:17059223, PubMed:18155153).
Part of the mycobacterial fatty acid elongation system FAS-II, which is involved in mycolic acid biosynthesis (PubMed:11932442). Catalyzes the NADPH-dependent reduction of beta-ketoacyl derivatives, the second step of the FAS-II elongation cycle (PubMed:9802011, PubMed:11932442, PubMed:17059223, PubMed:18155153, PubMed:19685079). May preferentially metabolize long-chain substrates (C8-C20) (PubMed:11932442). Can use CoA derivatives as substrates in vitro (PubMed:9802011, PubMed:11932442, PubMed:17059223, PubMed:18155153).
Phosphorylation alters the activity, and subsequently mycolic acid biosynthesis (PubMed:20178986). In vitro, activity is efficiently inhibited by isoniazid. Acts by forming an isonicotinoyl-NADP adduct that binds to the MabA active site (PubMed:14693546).
Restores respiratory growth of S.cerevisiae oar1 deletion mutant.
Shows a significant rearrangement of the active site between a closed inactive conformation and an open and active form in presence of NADP. The C-terminus adopts a particular conformation that locks the conformational changes.
In the central section; belongs to the universal stress protein A family.
Induced at low K(+) concentrations (in M.tuberculosis); overexpression of LprF or LprJ increases expression of this gene at 0 and 250 uM K(+) (in M.smegmatis).
May interact with lipoproteins LprF and LprJ.
Member of the two-component regulatory system KdpD/KdpE involved in the regulation of the kdp operon. Functions as a sensor protein kinase which is autophosphorylated at a histidine residue and transfers its phosphate group to the conserved aspartic acid residue in the regulatory domain of KdpE in response to environmental signals such as low levels of potassium ion, osmotic imbalance, acid and nutrient stresses. In turn, KdpE binds to the upstream promoter regions of target genes to positively regulate their expression.
Binds 2 divalent metal cations per subunit, which may be Mg(2+) or Mn(2+), and which are essential for catalysis.
Catalyzes the hydrolysis of the phospho group from alpha-ribazole 5'-phosphate to form alpha-ribazole (PubMed:20363939). May also catalyze the conversion of adenosylcobalamin 5'-phosphate to adenosylcobalamin (vitamin B12) (By similarity). Has a possible role in B12 recycling, but the primary role of the C-terminal domain of this phosphatase enzyme could be phosphate generation to help bacterial survival within the macrophage, which is a phosphate-deprived environment (PubMed:20363939).
Endonuclease that displays both RNase H activity with a hybrid RNA/DNA substrate as well as double-stranded RNase activity. As the only authenticated RNase HI in M.tuberculosis, probably plays an important role in the physiology of this organism, being likely involved in bacterial replication.
In the C-terminal section; belongs to the histidine phosphatase superfamily.
In the N-terminal section; belongs to the RNase H family.
Is composed of two domains, the N-terminal domain displays RNase activity and the C-terminal domain has both acid phosphatase and CobC activity, together with a role in enhancing the RNase H and dsRNase activities of the N-terminal domain.
The N-terminal domain alone is monomeric in solution but associates in the crystal to form a dimer.
Catalyzes the dephosphorylation of inositol 1-phosphate (I-1-P) to yield free myo-inositol, a key metabolite in mycobacteria. Is also able to hydrolyze a variety of polyol phosphates such as glucitol-6-phosphate, inositol 2-phosphate (I-2-P), glycerol-2-phosphate, and 2'-AMP, albeit with reduced efficiency.
Homodimer. Dimerization is induced by Mg(2+) binding.
Inhibited by Li(+) with IC50 value of 0.9 mM but not by Na(+) or K(+). Also inhibited by Zn(2+) (IC50 value of 0.5 uM) and by concentrations of Mg(2+) higher than 100 mM.
Magnesium. Co(2+) and Fe(2+) can replace Mg(2+) but lead to a partial activity (30%), and Mn(2+) leads to a partial activity of 13%.
Strains lacking this gene show no difference in colony morphology and no differences in levels of phosphatidylinosotol mannosides (PIMs), lipomannan (LM), lipoarabinomannan (LAM) or mycothiol (in the absence of exogenous inositol).
Belongs to the NAD(P)-dependent epimerase/dehydratase family.
Involved in the metabolism of galactose. Catalyzes the conversion of UDP-galactose (UDP-Gal) to UDP-glucose (UDP-Glc) through a mechanism involving the transient reduction of NAD (By similarity).
Toxic component of a type II toxin-antitoxin (TA) system. An RNase. The cognate antitoxin is VapB14 (By similarity).
Belongs to the bacterial solute-binding protein ModA family.
Involved in the transport of molybdenum into the cell. Part of the binding-protein-dependent transport system ModABCD (By similarity).
Belongs to the major facilitator superfamily. EmrB family.
Cells lacking this gene show a reduced incorporation of nicotinamide. Double mutants lacking both pncB1 and pncB2 show an absence of incorporation of nicotinamide.
Involved in the Preiss-Handler pathway, which is a recycling route that permits the salvage of free nicotinamide (NM) and nicotinic acid (Na) involved in the NAD biosynthesis. Catalyzes the synthesis of beta-nicotinate D-ribonucleotide from nicotinate and 5-phospho-D-ribose 1-phosphate at the expense of ATP. It is not able to use nicotinamide. PncB1 contributes to basal NAD level.
Transiently phosphorylated on a His residue during the reaction cycle. Phosphorylation strongly increases the affinity for substrates and increases the rate of nicotinate D-ribonucleotide production. Dephosphorylation regenerates the low-affinity form of the enzyme, leading to product release.
Belongs to the cysteine synthase/cystathionine beta-synthase family.
Catalyzes the conversion of O-acetylserine (OAS) to cysteine through the elimination of acetate and addition of hydrogen sulfide.
Competitively inhibited by a four-residue peptide derived from the C-terminus of serine acetyltransferase (CysE). This suggests that CysK1 may associate with CysE in vivo to form a bi-enzyme complex, in which the OASS activity is down-regulated.
Belongs to the type-II 3-dehydroquinase family.
Catalyzes a trans-dehydration via an enolate intermediate.
Ferredoxins are iron-sulfur proteins that transfer electrons in a wide variety of metabolic reactions.
To M.bovis Mb1522c, M.leprae ML1804 and M.avium MAV321.
Catalyzes the hydrolysis of fructose 1,6-bisphosphate to fructose 6-phosphate (PubMed:15470127, PubMed:21451980). Seems to be the major FBPase of M.tuberculosis and to play a key role in gluconeogenesis for conversion of lipid carbon into cell wall glycans. Does not display activity against inositol 1-phosphate (PubMed:15470127).
Cells lacking this gene are shown to be highly attenuated in a mouse tuberculosis model (PubMed:14569030). However, another study shows that in a mouse model of M.tuberculosis infection, cells lacking this gene are able to replicate and persist in lungs similar to the wild-type strain (PubMed:26258286). The mutant cells grow on gluconeogenic carbon sources and have detectable FBPase activity, due to the alternative FBPase (Gpm2, Rv3214) (PubMed:26258286). A third study shows that disruption of glpX leads to a growth profile comparable to that of wild-type when grown on the standard enrichment media, but growth is dysgonic with individual gluconeogenic substrates such as oleic acid, glycerol and acetate, and the mutant strain fails to efficiently replicate during the acute phase (i.e. first 30 days post-infection) of infection and begins to die thereafter (PubMed:26397812). Cells lacking both glpX and gpm2 grow as well as wild-type on glucose, but are unable to grow on any of the gluconeogenic carbon sources tested (glycerol, acetate and butyrate); the growth defect on gluconeogenic carbon sources is fully complemented by restoring expression of either GlpX or Gpm2. This double mutant lacks detectable FBPase activity and accumulates FBP. It is also severely attenuated in a mouse model of infection, as it fails to replicate in mouse lungs during the first 10 days of infection and begins to die thereafter (PubMed:26258286).
Gluconeogenesis is critical to M.tuberculosis ability to establish infection and is necessary for its survival in the host.
Has an absolute requirement of bivalent metal ions Mg(2+) or Mn(2+).
Homooligomer (PubMed:21451980). Probably a dimer (PubMed:21636919).
Is expressed during exponential growth, with mRNA levels approximately half of the level of sigA.
Is inhibited by Li(+) and by inorganic phosphate.
Converts the D-glycero-alpha-D-manno-heptose 1,7-bisphosphate intermediate into D-glycero-alpha-D-manno-heptose 1-phosphate by removing the phosphate group at the C-7 position.
Was originally proposed to be fused with GmhA.
Belongs to the cytochrome c oxidase subunit 2 family.
Subunits I and II form the functional core of the enzyme complex. Electrons originating in cytochrome c are transferred via heme a and Cu(A) to the binuclear center formed by heme a3 and Cu(B) (By similarity).
Belongs to the phenylalanyl-tRNA synthetase beta subunit family. Type 1 subfamily.
Allows the formation of correctly charged Gln-tRNA(Gln) through the transamidation of misacylated Glu-tRNA(Gln) in organisms which lack glutaminyl-tRNA synthetase. The reaction takes place in the presence of glutamine and ATP through an activated gamma-phospho-Glu-tRNA(Gln) (By similarity).
Belongs to the amidase family. GatA subfamily.
Belongs to the RNA polymerase-binding protein RbpA family.
Binds to RNA polymerase (RNAP), stimulating and stabilizing the formation of stable RNAP promoter complexes up to 2-fold from principal sigma factor SigA-dependent but not alternative sigma factor SigF-dependent promoters. Increases the affinity of core RNAP for SigA, increasing the transcriptional activity of RNAP. Unlike the case in M.smegmatis or S.coelicolor, has no effect on rifampicin inhibition of transcription. Has no effect on E.coli RNAP.
Essential for growth, it cannot be disrupted.
Oligomerizes at more than 3 uM; this requires the C-terminal 32 residues. Forms a complex with the RNAP catalytic core, specifically with the beta subunit (rpoB). Interacts with free SigB, probably as a 1:1 complex, and also with free SigA, probably via its sigma-2 domain.
This protein is only found in actinomycetes; as it is essential in M.tuberculosis, it might make a potential drug target.
Unlike its ortholog in S.coelicolor, it is not seen to bind zinc.
Chaperone component of an atypical, type II toxin-antitoxin chaperone (TAC) system. Prevents antitoxin HigA1 aggregation in vitro at a 1:3 chaperone:antitoxin ratio, probably also protects antitoxin HigA1 from protease. Required for neutralization of toxin HigB1 upon ectopic expression in Mycobacterium marinum or E.coli. When expressed in E.coli complements a secB deletion, restores export of OmpA and MBP and inhibits aggregation of proOmpC although it is less efficient than endogenous SecB. Complements the general chaperone function of E.coli SecB less well.
Disruption results in slow growth. A triple higB1-higA1-Rv1957 disruption mutant has no visible phenotype.
Homotetramer, interacts with antitoxin HigA1.
Probably induced by the DNA damaging agent mitomycin C. Part of the Rv1954A-higB1-higA1-Rv1957 operon, as well as the higB1-higA1-Rv1957 operon, which is probably the mitomycin-induced operon; the former but not latter operon is autorepressed by HigA1 (PubMed:20585061).
Belongs to the cation transport ATPase (P-type) (TC 3.A.3) family.
Belongs to the protein N5-glutamine methyltransferase family. PrmC subfamily.
Methylates the class 1 translation termination release factors RF1/PrfA and RF2/PrfB on the glutamine residue of the universally conserved GGQ motif.
Belongs to the CRISPR-associated Csm5 family.
Part of the Csm effector complex that includes Cas10, Csm2, Csm3, Csm4 and Csm5.
This subunit might be involved in maturation of a crRNA intermediate to its mature form.
Allosterically activated by alpha-keto acids and the corresponding amino acids. L-leucine, L-valine, D-valine, L-isoleucine, L-phenylalanine, D-phenylalanine, L-tyrosine and L-valine are activators (with L-leucine and L-isoleucine being the strongest activators) whereas L-tryptophan, tryptophol, phenylacetic acid and indoleacetic acid have no effect.
Decarboxylates branched-chain and aromatic alpha-keto acids to aldehydes.
Belongs to the glucose-1-phosphate thymidylyltransferase family.
Catalyzes the conversion of glucose-1-phosphate and dTTP to dTDP-glucose and pyrophosphate (PubMed:9084178, PubMed:29076563, PubMed:33868202). Involved in the biosynthesis of the dTDP-L-rhamnose which is a component of the critical linker, D-N-acetylglucosamine-L-rhamnose disaccharide, which connects the galactan region of arabinogalactan to peptidoglycan via a phosphodiester linkage (PubMed:9084178, PubMed:17784859).
Phosphorylated on Thr-12, Thr-54 and Thr-197 by PknB (PubMed:33868202). Thr-12 is the primary phosphorylation site (PubMed:33868202).
Phosphorylation by the serine/threonine-protein kinase PknB down-regulates thymidylyltransferase activity.
Forms a complex with cognate antitoxin MazE8.
Putative toxic component of a type II toxin-antitoxin (TA) system, its cognate toxin is MaZE8. Probably an endoribonuclease (By similarity).
Belongs to the RNA polymerase beta chain family.
DNA-dependent RNA polymerase catalyzes the transcription of DNA into RNA using the four ribonucleoside triphosphates as substrates.
The RNAP catalytic core consists of 2 alpha, 1 beta, 1 beta' and 1 omega subunit. When a sigma factor is associated with the core the holoenzyme is formed, which can initiate transcription. Interacts with CarD, TRCF (Mfd) and RbpA.
Involved in the biosynthesis of 6-O-methylglucose lipopolysaccarides (MGLPs). Catalyzes the transfer of the glucose moiety from UDP-alpha-D-glucose (UDP-Glc) to the position 2 of 3-phospho-D-glycerate (3-PGA) to form glucosyl-3-phosphoglycerate (GPG).
Requires divalent cations for activity. Mg(2+) gives the maximal activity, but the enzyme can also use Ca(2+), Mn(2+), Fe(2+) or Co(2+) ions, but not Zn(2+) or Cu(2+) ions.
The glucosyltransferase GpgS does not possess a putative nucleophile residue that could result in the formation of a glycosyl-enzyme covalent intermediate. Therefore, it is expected that the reaction would proceed through a front-side substrate-assisted SNi-type mechanism where the breaking of the glucosidic bond is stabilized by the interaction of the acceptor hydrogen atom O3 of the acceptor 3-PGA with the beta-phosphate of the nucleotide sugar.
Belongs to the IPP isomerase type 1 family.
Binds 1 Mg(2+) ion per subunit. The magnesium ion binds only when substrate is bound.
Catalyzes the 1,3-allylic rearrangement of the homoallylic substrate isopentenyl (IPP) to its highly electrophilic allylic isomer, dimethylallyl diphosphate (DMAPP).
Cells lacking this gene transfer 40% fewer mycolates to the cell wall with no change in the types of mycolates esterified to arabinogalactan or in the composition of non-covalently linked mycolates. As a consequence, the diffusion of hydrophobic chenodeoxycholate and of hydrophilic glycerol through the cell envelope occurs much more rapidly in mutant cells than in wild-type.
Inhibited by 6-azido-6-deoxy-alpha,alpha-trehalose (ADT).
The antigen 85 proteins (FbpA, FbpB, FbpC) are responsible for the high affinity of mycobacteria to fibronectin, a large adhesive glycoprotein, which facilitates the attachment of M.tuberculosis to murine alveolar macrophages (AMs). They also help to maintain the integrity of the cell wall by catalyzing the transfer of mycolic acids to cell wall arabinogalactan and through the synthesis of alpha,alpha-trehalose dimycolate (TDM, cord factor). They catalyze the transfer of a mycoloyl residue from one molecule of alpha,alpha-trehalose monomycolate (TMM) to another TMM, leading to the formation of TDM.
DNA-bridging protein that has both architectural and regulatory roles (PubMed:18187505). Influences the organization of chromatin and gene expression by binding non-specifically to DNA, with a preference for AT-rich sequences, and bridging distant DNA segments (PubMed:20133735). Binds in the minor groove of AT-rich DNA (PubMed:21673140). Represses expression of multiple genes involved in a broad range of cellular processes, including major virulence factors or antibiotic-induced genes, such as iniBAC or efpA (PubMed:17590082), and genes important for adaptation of changing O(2) levels (PubMed:24895305). May also activate expression of some gene (PubMed:24895305). May coordinate global gene regulation and virulence (PubMed:20133735). Also protects mycobacteria against reactive oxygen intermediates during macrophage infection by acting as a physical barrier to DNA degradation (PubMed:19237572); the physical protection has been questioned (PubMed:24895305). A strain overexpressing this protein consumes O(2) more slowly than wild-type (PubMed:24895305).
Homodimer. May form higher oligomers via protease-activation.
No visible effect on nucleoid structure during anaerobic growth by whole cell staining. Sensitive to atmospheric O(2) levels, at 2% O(2) no difference in growth up to 14 days; required for adaptation to anaerobiosis, at 21 days nearly 1000-fold decrease in survival under anaerobic conditions. Consumes O(2) more rapidly. Has a significant lag in recovery from 7 or 14 days anaerobic growth. Decreased virulence in lungs of BALB/c mice; no visible lung disease at any time point. Increased sensitivity to reactive nitrogen species, not more sensitive to H(2)O(2) or mitomycin (PubMed:24895305).
The C-terminal domain binds DNA and the N-terminal domain is involved in dimerization. Both domains are essential for normal function.
The three N-terminal residues may be cleaved by proteases in response to external stress. This cleavage may be required for oligomerization, which leads to chromosome compaction and protection.
Belongs to the UbiA prenyltransferase family. Protoheme IX farnesyltransferase subfamily.
Carbon 2 of the heme B porphyrin ring is defined according to the Fischer nomenclature.
Converts heme B (protoheme IX) to heme O by substitution of the vinyl group on carbon 2 of heme B porphyrin ring with a hydroxyethyl farnesyl side group.
Belongs to the bacterial ribosomal protein bL32 family.
Cells lacking this gene appear to metabolize cholesterol normally, probably due to the ability of Cyp142 to compensate for loss of Cyp125.
Involved in the utilization of cholesterol as the sole carbon and energy source by degrading the side chain during infection (PubMed:20843794, PubMed:20545858). Primarily catalyzes the sequential oxidation of the terminal methyl of cholest-4-en-3-one into (25S)-26-hydroxycholest-4-en-3-one (alcohol), (25S)-26-oxocholest-4-en-3-one (aldehyde), to finally yield the carboxylic acid (25S)-3-oxocholest-4-en-26-oate (PubMed:19846551, PubMed:20843794, PubMed:20545858). Also able to sequentially oxidize cholesterol itself, not only cholest-4-en-3-one (PubMed:19846551, PubMed:20843794, PubMed:20545858).
Could be used for serodiagnosis of both pulmonary and extra-pulmonary tuberculosis.
Inactivation impairs expression of EsxA (ESAT-6) and EsxB (CFP-10).
Interacts with PPE68. PE35/PPE68 complex interacts with human TLR2.
Plays a major role in RD1-associated pathogenesis, and may contribute to the establishment and maintenance of M.tuberculosis infection. Together with PPE68, stimulates the secretion of IL-10 and MCP-1 from human macrophages, via the interaction with human Toll-like receptor 2 (TLR2).
Belongs to the elongation factor P family.
Involved in peptide bond synthesis. Stimulates efficient translation and peptide-bond synthesis on native or reconstituted 70S ribosomes in vitro. Probably functions indirectly by altering the affinity of the ribosome for aminoacyl-tRNA, thus increasing their reactivity as acceptors for peptidyl transferase (By similarity).
Part of the FGAM synthase complex composed of 1 PurL, 1 PurQ and 2 PurS subunits.
Part of the phosphoribosylformylglycinamidine synthase complex involved in the purines biosynthetic pathway. Catalyzes the ATP-dependent conversion of formylglycinamide ribonucleotide (FGAR) and glutamine to yield formylglycinamidine ribonucleotide (FGAM) and glutamate. The FGAM synthase complex is composed of three subunits. PurQ produces an ammonia molecule by converting glutamine to glutamate. PurL transfers the ammonia molecule to FGAR to form FGAM in an ATP-dependent manner. PurS interacts with PurQ and PurL and is thought to assist in the transfer of the ammonia molecule from PurQ to PurL.
Belongs to the trehalose phosphatase family.
Inhibited by EDTA and calcium. Diumycin and moenomycin stimulate activity at concentrations of up to 100 ug/ml, and then inhibit at higher concentrations.
Removes the phosphate from trehalose 6-phosphate to produce free trehalose.
Antitoxin component of a possible type II toxin-antitoxin (TA) system. The cognate toxin is VapC8.
Belongs to the GHMP kinase family. Homoserine kinase subfamily.
Catalyzes the ATP-dependent phosphorylation of L-homoserine to L-homoserine phosphate.
Belongs to the radical SAM superfamily. Lipoyl synthase family.
Binds 2 [4Fe-4S] clusters per subunit. One cluster is coordinated with 3 cysteines and an exchangeable S-adenosyl-L-methionine.
Catalyzes the radical-mediated insertion of two sulfur atoms into the C-6 and C-8 positions of the octanoyl moiety bound to the lipoyl domains of lipoate-dependent enzymes, thereby converting the octanoylated domains into lipoylated derivatives.
Forms a complex with GcvH, the H protein of the glycine cleavage system. The strength of association is dependent on the presence of S-adenosyl-L-methionine.
Antitoxin component of a type II toxin-antitoxin (TA) system. Its cognate toxin is VapC40. Upon expression in E.coli partially counteracts the ribonuclease activity of non-cognate toxins MazF6 and MazF9.
Physically interacts with cognate toxin VapC40.
Belongs to the UDP-glucose/GDP-mannose dehydrogenase family.
Belongs to the glycerophosphoryl diester phosphodiesterase family.
Glycerophosphodiester phosphodiesterase hydrolyzes glycerophosphodiesters into glycerol-3-phosphate (G3P) and the corresponding alcohol.
Forms a U-shaped beta-half-barrel with a small hydrophobic cavity which is large enough to hold a single diacylated glycolipid molecule.
Might be involved in transporting short diacylated glycolipids to the cell outer membrane (By similarity). Overexpression induces expression of sensor protein kdpD gene at low K(+) concentrations (0 and 250 uM, tested in M.smegatis).
Modified by Lgt on Cys-39 with an S-linked diacylglycerol with a mixture of C16, C18 and C19 fatty acids (palmitic, stearic and tuberculostearic acid respectively), signal peptide is removed by LspA, modified by Lnt with an amide-linked mixture of C16 and C19 fatty acids, expressed in M.bovis (PubMed:24093492). Hexose glycosylated in N-terminus between residues 39 and 63 (PubMed:24093492).
Belongs to the metallo-dependent hydrolases superfamily. Urease alpha subunit family.
Carboxylation allows a single lysine to coordinate two nickel ions.
Antitoxin for tuberculosis necrotizing toxin (TNT). Acts by binding directly to TNT, which inhibits NAD(+) glycohydrolase activity of TNT and protects M.tuberculosis from self-poisoning.
Interacts with the tuberculosis necrotizing toxin (TNT), the C-terminal domain of the outer membrane channel protein CpnT.
Heterotetramer (dimer of heterodimers) composed of FadE26 and FadE27.
Involved in the first cycle of side chain dehydrogenation in the beta-oxidation of cholesterol catabolism (PubMed:26161441). It contributes partly to the virulence by increasing the efficiency of beta-oxidation. Catalyzes the dehydrogenation of acyl-CoA ester side chains of (25S)-3-oxo-cholest-4-en-26-oyl-CoA (3-OCS-CoA) to yield (24E)-3-oxo-cholest-4,24-dien-26-oyl-CoA (PubMed:26348625, PubMed:26161441). Also able to dehydrogenate steroyl-CoA such as 3-oxo-chol-4-en-24-oyl-CoA (3-OCO-CoA) as well as 3-oxo-4-pregnene-20-carboxyl-CoA (3-OPC-CoA) (PubMed:26161441). It dehydrogenates only (25S)-OCS-CoA diastereomer (PubMed:26348625, PubMed:26161441).
Uncompetitively inhibited by high concentration of 3-OCS-CoA.
Involved in the catabolism of the rings C and D of cholesterol. Catalyzes the ATP-dependent CoA thioesterification of 3aalpha-H-4alpha(3'-propanoate)-7abeta-methylhexahydro-1,5-indanedione (HIP) to yield HIP-CoA. It can also use the hydroxylated analogs of HIP, 5alpha-OH HIP and 1beta-OH HIP. It requires that the side chain at C17 is completely removed.
Belongs to the glycosyltransferase group 1 family. Glycosyltransferase 4 subfamily.
Catalyzes the addition of a mannose residue from GDP-D-mannose to GlcAGroAc2 to generate 1,2-di-O-C16/C18:1-(alpha-D-mannopyranosyl)-(1-4)-(alpha-D-glucopyranosyluronic acid)-(1-3)-glycerol(ManGlcAGroAc2).
Forms a complex with cognate antitoxin MazE5.
Toxic component of a type II toxin-antitoxin (TA) system. Upon expression in M.smegmatis inhibits colony formation. Its toxic effect is neutralized by coexpression with cognate antitoxin MazE5 (PubMed:20011113). Probably an endoribonuclease (By similarity).
Belongs to the Pup ligase/Pup deamidase family. Pup-conjugating enzyme subfamily.
Catalyzes the covalent attachment of the prokaryotic ubiquitin-like protein modifier Pup to the proteasomal substrate proteins, thereby targeting them for proteasomal degradation. This tagging system is termed pupylation. The ligation reaction involves the side-chain carboxylate of the C-terminal glutamate of Pup and the side-chain amino group of a substrate lysine. PafA is required to confer resistance against the lethal effects of reactive nitrogen intermediates (RNI), antimicrobial molecules produced by activated macrophages and other cell types.
Cells lacking this gene have no detectable pupylated proteins and substrate proteins accumulate. These cells also become hypersensitive to reactive nitrogen intermediates (RNI) and fail to grow in both wild-type and nitric oxide synthase 2 deficient macrophages. Moreover, they display increased resistance to hydrogen peroxide.
The reaction mechanism probably proceeds via the activation of Pup by phosphorylation of its C-terminal glutamate, which is then subject to nucleophilic attack by the substrate lysine, resulting in an isopeptide bond and the release of phosphate as a good leaving group.
Grows normally in liquid culture, traffics into host (human and mouse) acidified compartments early after phagocytosis, suggesting it no longer arrests phagosome maturation as well as wild-type, impaired growth in mouse macrophages (PubMed:20844580). Decreased synthesis of 2,3-di-O-acyltrehaloses (DAT) and increased synthesis of sulfoglycolipids (SGL) (PubMed:20844580). Decreased colonization of mouse lung but not spleen 42 days after infection (PubMed:20844580).
Probably plays a role in host phagosome maturation arrest, as well as a role in the synthesis of acyltrehalose-containing glycolipids (PubMed:20844580).
Belongs to the CRISPR-associated Csm3 family.
This subunit has the target ssRNA endonuclease activity; it cleaves multiple sites in the target RNA at 6 nucleotide intervals.
Belongs to the dTDP-4-dehydrorhamnose 3,5-epimerase family.
Catalyzes the epimerization of the C3' and C5'positions of dTDP-6-deoxy-D-xylo-4-hexulose, forming dTDP-6-deoxy-L-lyxo-4-hexulose. Involved in the biosynthesis of the dTDP-L-rhamnose which is a component of the critical linker, D-N-acetylglucosamine-L-rhamnose disaccharide, which connects the galactan region of arabinogalactan to peptidoglycan via a phosphodiester linkage.
Double espI-eccD1 mutants abolish EsxA and EsxB secretion, but not their expression (PubMed:14557547). Disruption abolishes EsxA and EsxB secretion, but not their expression (PubMed:14557536). Results in a lack of antigen specific immunogenicity and leads to attenuated virulence (PubMed:16368961). Mutants exhibit defects in bacterial growth during the acute phase of C57BL/6 mouse infection, but survive for 140 days despite a wild-type bacterial load in the lungs at 100 days post-infection, suggesting the pathway is required for virulence (PubMed:14557536). Nearly wild-type levels of IL-12 p40 (IL12B) and TNF-alpha are produced by infected murine macrophages, while the nitric oxide response is about 50% reduced (PubMed:14557536). Mouse macrophages do not induce cGAMP production, and thus do not sense bacterial DNA correctly to induce the innate immune response (PubMed:26048137).
Possibly a homodimer (PubMed:26922638). Part of the ESX-1 / type VII secretion system (T7SS), which is composed of cytosolic and membrane components. The ESX-1 membrane complex is composed of EccB1, EccCa1, EccCb1, EccD1 and EccE1.
The structure in 4KV3 was determined for a fusion protein with E.coli maltose-binding protein.
Catalyzes the phosphorylation of the beta-carboxyl group of aspartic acid with ATP to yield 4-phospho-L-aspartate, which is involved in the branched biosynthetic pathway leading to the biosynthesis of amino acids lysine, threonine, isoleucine and methionine.
Heterotetramer consisting of 2 isoforms Alpha (catalytic and regulation) and of a homodimer of 2 isoforms Beta (regulation).
Belongs to the Mg-chelatase subunits D/I family.
Belongs to the class-II aminoacyl-tRNA synthetase family. Type-1 seryl-tRNA synthetase subfamily.
Catalyzes the attachment of serine to tRNA(Ser). Is also able to aminoacylate tRNA(Sec) with serine, to form the misacylated tRNA L-seryl-tRNA(Sec), which will be further converted into selenocysteinyl-tRNA(Sec).
Consists of two distinct domains, a catalytic core and a N-terminal extension that is involved in tRNA binding.
Homodimer. The tRNA molecule binds across the dimer.
Belongs to the class I-like SAM-binding methyltransferase superfamily.
Consists of two domains which are linked by a long alpha-helix. The N-terminal domain is essential for dimerization and the C-terminal domain has the class I MTase fold.
Homodimer (PubMed:26772148). Co-immunoprecipitates with DarG in the presence and absence of darT (PubMed:32634279).
Probable methyltransferase that may target bulky nonpolar molecules with aromatic rings.
Controls the expression level of the Mmps2-MmpL2, MmpS4-MmpL4, and MmpS5-MmpL5 transport systems. Also controls its own expression. Acts by binding directly to the promoter regions.
Mutations or insertions/deletions that inactivate MmpR5, or decrease its activity, lead to increased levels of MmpL5 and MmpS5, and to non-target based resistance to azoles, clofazimine and bedaquiline.
Belongs to the bacterial ribosomal protein bS16 family.
Probable S-adenosylmethionine-dependent methyltransferase required for the 6-O-methylation of the polysaccharide backbone of 6-O-methylglucosyl lipopolysaccharides (MGLP).
Toxic component of a type II toxin-antitoxin (TA) system. An RNase. The cognate antitoxin is VapB8 (By similarity).
Belongs to the bacterial ribosomal protein bL17 family.
Part of the 50S ribosomal subunit. Contacts protein L32.
Has strong T-cell and IFN-gamma inducing capacity in human tuberculin skin test positive patients, indicating this might be a good vaccine candidate.
Part of the ESX-3 / type VII secretion system (T7SS), which is composed of cytosolic and membrane components. The ESX-3 membrane complex is composed of EccB3, EccC3, EccD3 and EccE3.
Part of the ESX-3 specialized secretion system, which is important for iron and zinc uptake or homeostasis.
Repressed by IdeR in the presence of iron and by Zur in the presence of zinc.
Experiments to characterize enzymatic activity in (PubMed:21969609) and (PubMed:10564470) were performed with protein overexpressed in E.coli or M.smegmatis respectively; both papers use a protein that starts on Val-97 (PubMed:15939293, PubMed:18535356). Three start sites have been proposed for this protein, Met-1, Met-47 and Val-97, this is the longest translation. There is protein sequence that suggests Met-1 is the correct start. Antibodies detect a protein larger than 38 kDa in M.tuberculosis (PubMed:18535356).
Hydrolyzes short-chain esters. Shows maximal activity with triacetin and p-nitrophenyl acetate. Has no enzyme activity on triacylglycerides or p-nitrophenyl esters (p-NP) with long fatty acids (tricaprin, p-NP caprylate, or p-NP caprate); experiments performed with enzyme missing the first 97 residues (PubMed:15939293). Has phospholipase C activity, making 1,2-DAG phosphocholine; experiments performed with enzyme missing the first 97 residues (PubMed:18535356).
Mutants show reduced ability to grow in a mouse lung.
The antigen 85 proteins (FbpA, FbpB, FbpC) are responsible for the high affinity of mycobacteria for fibronectin, a large adhesive glycoprotein, which facilitates the attachment of M.tuberculosis to murine alveolar macrophages (AMs). They also help to maintain the integrity of the cell wall by catalyzing the transfer of mycolic acids to cell wall arabinogalactan and through the synthesis of alpha,alpha-trehalose dimycolate (TDM, cord factor). They catalyze the transfer of a mycoloyl residue from one molecule of alpha,alpha-trehalose monomycolate (TMM) to another TMM, leading to the formation of TDM.
Part of the ESX-1 / type VII secretion system (T7SS), which is composed of cytosolic and membrane components. The ESX-1 membrane complex is composed of EccB1, EccCa1, EccCb1, EccD1 and EccE1 (PubMed:19876390). Interacts with EspD (PubMed:16135231).
Belongs to the 3-oxoacid CoA-transferase subunit A family.
Heterotetramer composed of 2 IpdA subunits and 2 IpdB subunits.
Involved in the final steps of cholesterol and steroid degradation (PubMed:28377529). Opens the last steroid ring of cholesterol by catalyzing the hydrolysis of (3E)-2-(2-carboxylatoethyl)-3-methyl-6-oxocyclohex-1-ene-1-carboxyl-CoA (COCHEA-CoA) to 6-methyl-3,7-dioxodecanedioyl-CoA (MeDODA-CoA) (PubMed:29581275).
IpdAB double deletion mutant does not grow on cholesterol, but grows as the wild-type on glycerol. In the presence of cholesterol, ipdAB double deletion mutant accumulates COCHEA-CoA. Double mutant does not survive in macrophages and displays severely depleted CoASH levels that correlate with a cholesterol-dependent toxicity.
Belongs to the cyclophilin-type PPIase family.
PPIases accelerate the folding of proteins. It catalyzes the cis-trans isomerization of proline imidic peptide bonds in oligopeptides.
Belongs to the bacterial ribosomal protein bL28 family.
Catalyzes the reversible conversion of 2-phosphoglycerate into phosphoenolpyruvate. It is essential for the degradation of carbohydrates via glycolysis.
The covalent binding to the substrate causes inactivation of the enzyme, and possibly serves as a signal for the export of the protein.
Belongs to the class I-like SAM-binding methyltransferase superfamily. rRNA adenine N(6)-methyltransferase family.
Binds to RecA inhibiting ATP hydrolysis and the generation of heteroduplex DNA. It might act as an anti-recombinase to quell inappropriate recombinational repair during normal DNA metabolism. It is essential for cell survival.
Belongs to the TRAFAC class TrmE-Era-EngA-EngB-Septin-like GTPase superfamily. Era GTPase family.
Exhibits GTPase activity (PubMed:22578863). Binds RNA but is probably not involved in ribosome assembly in mycobacteria (By similarity).
The mRNA can be cleaved by the RV1102c mRNA interferase in E.coli.
A member of the dormancy regulon. Induced in response to reduced oxygen tension (hypoxia), low levels of nitric oxide (NO), carbon monoxide (CO) and carbon dioxide (CO(2)). Expression peaks in the late log phase of growth.
Could be involved in the biosynthesis, transport or localization of poly-alpha-L-glutamine (PLG), a cell wall component. Contributes to stress tolerance and virulence.
Disruption mutant shows reduced PLG content in the cell wall, increased sensitivity to chemical and mechanical agents, reduction of biofilm formation and attenuated virulence.
A possible member of the dormancy regulon. Induced in response to reduced oxygen tension (hypoxia), it is not induced by nitric oxide exposure.
Lacks the conserved His residue in position 138 suggested to serve as a proton acceptor for this family, however this protein still has diacyglycerol O-acyltransferase activity in E.coli.
Upon expression in E.coli functions as a triacylglycerol synthase, making triacylglycerol (TG) from diolein and long-chain fatty acyl-CoA. Has no wax synthase activity to produce wax esters.
100-fold induced in wild-type C57BL/6 mice 2 weeks after lung infection, RNA levels drop to 30X induced 8 weeks post-infection (PubMed:16923787). Similar but less dramatic induction is seen in immunocompromised mice (PubMed:16923787). Rapidly induced in resting mouse macrophages, remains up-regulated for at least 60 hours, continuing induction is repressed by interferon gamma (PubMed:16923787). Induced by growth at acidic pH (PubMed:26637353).
A redox-sensitive transcriptional regulator. Maintains intracellular redox homeostasis by regulating catabolic metabolism and polyketide biosynthesis (PubMed:17609386, PubMed:19680450). Regulates expression of the redox buffer ergothioneine (ERG) in a carbon-source-dependent manner; loss of ERG or mycothiol (MSH, the other major redox buffer in this bacteria) leads to respiratory alterations and bioenergetic deficiencies that negatively impact virulence (PubMed:26774486). In response to low external pH (like that found in host macrophage phagosomes) alters endogenous gene expression leading to acid resistance; MSH and WhiB3 are probably part of a regulatory circuit that mediates gene expression upon acid stress (PubMed:26637353). Regulates pathogenic lipid synthesis, coordinating proprionate flux (and other host-derived fatty acid oxidation intermediates) into methyl-branched fatty acids (polyacyltrehalose, phthiocerol dimycocerosates, sulfolipids) and the storage lipid triacylglycerol, functioning as reductive sink (PubMed:19680450). During intracellular growth M.tuberculosis uses host fatty acids as an energy source, generating large quantities of proprionate and NADH/NADPH, which are toxic and highly reducing respectively. WhiB3 is thought to help dissipate proprionate and NADH/NADPH by switching to the in vivo carbon source and via lipid anabolism (PubMed:19680450). Responds to NO and O(2) (PubMed:17609386). Regulates expression of genes encoding modular polyketide synthases such as pks2, pks3 and fbpA (PubMed:19680450). The oxidized apo-form of WhiB3 binds DNA (with 2 intramolecular disulfide bonds); holo-WhiB3 (with the 4Fe-4S cluster) binds DNA considerably less well (PubMed:19680450). Discriminates poorly between specific and non-specific DNA-binding. Plays a role in virulence and nutritional stress (PubMed:11880648, PubMed:17609386, PubMed:26637353). In its apo-form can act as a protein disulfide reductase (PubMed:18550384).
Binds 1 [4Fe-4S] cluster per subunit (PubMed:17609386). Following nitrosylation of the [4Fe-4S] cluster binds 1 [4Fe-8(NO)] cluster per subunit (PubMed:17609386).
Homodimer (Probable) (PubMed:18550384). Interacts with the C-terminal 54 residues of sigma factor SigA (RpoV) (PubMed:11880648).
May respond to mycothiol (MSH) redox potential (E-MSH) which decreases at pH 4.5 for up to 72 hours, indicative of cellular reductive stress; deletion of whiB3 leads to a lesser E-MSH at 72 hours, indicative of cellular oxidative stress (PubMed:26637353). Probably via its effects on production of polyketide lipids, regulates host gene expression, leading to blockage of phagosome maturation (PubMed:26637353). Equilibration of extra- and intracytoplasmic pH kills bacteria (PubMed:26637353).
Not essential for growth in culture, or growth in vivo in mouse and guinea pig infections (PubMed:11880648). Disruption significantly enhances survival of immunocompetent mice (PubMed:11880648). Decreased bacterial growth in guinea pig lungs, but not spleen (PubMed:26637353). Growth on minimal media, glucose or succinate is poor, suggesting WhiB3 is involved in starvation response (PubMed:17609386). Growth on acetate is better than wild-type (PubMed:17609386). 55-fold decreased survival at pH 4.5, no difference at pH 5.5 or 6.6 (PubMed:26637353). Altered expression of genes involved in cell wall lipid composition, the ESX-1 secretion system and redox balance, impairs the mycothiol-specific reductive response to acid stress (PubMed:26637353). Dysfunctional respiration when grown in pyruvate, increased intracellular ergothioneine (ERG) production when grown in a number of carbon sources (PubMed:26774486). Upon infection of human THP-1 macrophage-like cells bacteria are localized to acidified lysosomes (M.tuberculosis usually blocks lysosome acidification), do not reduce mycothiol (MSH) and have significantly decreased survival (PubMed:26637353). Leads to up-regulation of host innate immunity genes usually repressed by M.tuberculosis (such as phagosome maturation and TLR signaling) and down-regulation of genes that inhibit autophagy (such as mTOR) (PubMed:26637353). Cell size, shape and surface architecture are perturbed, as is synthesis of cell surface associated virulence lipids both in culture and in cultured macrophages, or in response to oxidizing or reducing agents (PubMed:19680450). Disrupted strains are more resistant to toxic levels of propionate (PubMed:19680450).
The 4Fe-4S cluster interacts with NO, forming a protein-bound dinitrosyliron dithiol complex (PubMed:17609386).
The 4Fe-4S cluster interacts with O(2), leading to its degradation. Cluster loss takes about 2 hours (PubMed:17609386). Once in the apo-form the cysteines oxidize to form 2 intramolecular disulfide bonds (PubMed:18550384).
Involved in the regulation of glutamine synthetase GlnA, a key enzyme in the process to assimilate ammonia. When cellular nitrogen levels are high, the C-terminal adenylyl transferase (AT) inactivates GlnA by covalent transfer of an adenylyl group from ATP to specific tyrosine residue of GlnA, thus reducing its activity. Conversely, when nitrogen levels are low, the N-terminal adenylyl removase (AR) activates GlnA by removing the adenylyl group by phosphorolysis, increasing its activity. The regulatory region of GlnE binds the signal transduction protein PII (GlnB) which indicates the nitrogen status of the cell.
Catalyzes the insertion of molybdate into adenylated molybdopterin with the concomitant release of AMP.
Digests double-stranded RNA. Involved in the processing of primary rRNA transcript to yield the immediate precursors to the large and small rRNAs (23S and 16S). Processes some mRNAs, and tRNAs when they are encoded in the rRNA operon. Processes pre-crRNA and tracrRNA of type II CRISPR loci if present in the organism (By similarity).
Belongs to the ABC transporter superfamily. Phosphate importer (TC 3.A.1.7) family.
Part of the ABC transporter complex PstSACB involved in phosphate import (Probable). Responsible for energy coupling to the transport system.
Transcription induced by phosphate starvation, no change in protein levels on phosphate starvation (at protein level). If bacteria are starved prior to growth in phosphate-free medium protein expression disappears.
Activity is stimulated by unphosphorylated GarA.
Belongs to the glutamate synthase family.
Involved in base excision repair of DNA damaged by oxidation or by mutagenic agents. Acts as DNA glycosylase that recognizes and removes damaged bases. Has AP (apurinic/apyrimidinic) lyase activity and introduces nicks in the DNA strand. Cleaves the DNA backbone by beta-delta elimination to generate a single-strand break at the site of the removed base with both 3'- and 5'-phosphates (By similarity). Complements an E.coli nei nth double mutant (PubMed:20031487).
There are 2 paralogs in M.tuberculosis, in a reference this gene is called nei1.
Belongs to the HPF/YfiA ribosome-associated protein family. Long HPF subfamily.
Required for dimerization of active 70S ribosomes into 100S ribosomes in stationary phase; 100S ribosomes are translationally inactive and sometimes present during exponential growth.
Belongs to the anti-sigma-factor antagonist family.
Bifunctional enzyme that catalyzes the GTP-dependent successive addition of multiple gamma-linked L-glutamates to the L-lactyl phosphodiester of 7,8-didemethyl-8-hydroxy-5-deazariboflavin (F420-0) to form polyglutamated F420 derivatives, and the FMNH2-dependent reduction of dehydro-F420-0 to form F420-0.
Binds 2 divalent metal cations per subunit. The ions could be magnesium and/or manganese.
In the N-terminal section; belongs to the CofE family.
Monovalent cation. The ion could be potassium.
Involved in the cellular defense against the biological effects of O6-methylguanine (O6-MeG) and O4-methylthymine (O4-MeT) in DNA. Repairs the methylated nucleobase in DNA by stoichiometrically transferring the methyl group to a cysteine residue in the enzyme. This is a suicide reaction: the enzyme is irreversibly inactivated.
This enzyme catalyzes only one turnover and therefore is not strictly catalytic. According to one definition, an enzyme is a biocatalyst that acts repeatedly and over many reaction cycles.
Part of the ESX-4 / type VII secretion system (T7SS), which is composed of cytosolic and membrane components.
Expressed during infection of macrophages. Down-regulated by the nucleoid-associated protein Lsr2.
Bidirectionally degrades single-stranded DNA into large acid-insoluble oligonucleotides, which are then degraded further into small acid-soluble oligonucleotides.
Heterooligomer composed of large and small subunits.
4'-phosphopantetheine is transferred from CoA to a specific serine of apo-ACP by PptT, leading to the activated holo-ACP form.
Acyl carrier protein involved in the formation of acyl-S-ACP intermediates within the mycobactin biosynthesis process. The aliphatic chains carried by ACP are subsequently transferred on to the mycobactin core by MbtK.
Induced by iron starvation conditions. Transcriptionally repressed by IdeR and iron.
Antitoxin component of a type II toxin-antitoxin (TA) system. Upon expression in M.smegmatis neutralizes the effect of cognate toxin VapC3.
Induced during infection of mouse macrophages (PubMed:20011113). Induced in persister cells in response to D-cycloserine (PubMed:21673191).
A member of the dormancy regulon. Induced in response to reduced oxygen tension (hypoxia) and low levels of nitric oxide (NO). It is hoped that this regulon will give insight into the latent, or dormant phase of infection.
Cells lacking both prpC and prpD genes are unable to grow on propionate or cholesterol as the sole carbon source.
Involved in the catabolism of short chain fatty acids (SCFA) via the tricarboxylic acid (TCA)(acetyl degradation route) and via the 2-methylcitrate cycle I (propionate degradation route). Catalyzes the Claisen condensation of propionyl-CoA and oxaloacetate (OAA) to yield 2-methylcitrate (2-MC) and CoA. Also catalyzes the condensation of oxaloacetate with acetyl-CoA.
The vitamin B12 restores growth of the prpDC mutant. It suggests the capacity of the MCM-dependent methylmalonyl pathway to support the metabolism of propionate independently of the methylcitrate cycle.
Alpha-ketoglutarate-dependent sulfate ester dioxygenase, which oxidizes medium-chain alkyl-sulfate esters (PubMed:23762287). Shows preference for 2-ethylhexyl sulfate (2-EHS) in vitro, leading to the formation of succinate and 2-ethylhexanal (PubMed:23762287, PubMed:25427196). Has likely a role in sulfate scavenging in vivo (PubMed:23762287).
Also causes the inactivation of the 2-carboxyquinoxaline Ty38c (an antitubercular compound that inhibits DprE1) via oxidative decarboxylation, using Ty38c instead of alpha-ketoglutarate as a substrate. Is thus responsible for primary resistance of M.tuberculosis to Ty38c in vitro. Overexpression of Rv3406 causes resistance to Ty38c.
Cells lacking this gene do not replicate in minimal media with 2-ethyl hexyl sulfate as the sole sulfur source, in contrast to wild-type.
Repressed by the transcriptional repressor Rv3405c.
Forms a U-shaped beta-half-barrel with a large hydrophobic cavity (2835 Angstroms(3)) which is large enough to hold a single phthiocerol dimycocerosate (PDIM) molecule.
Might be involved in translocating phthiocerol dimycocerosates (PDIM) from the cell membrane to the outer membrane; PDIM forms part of the cell wall.
Modified by Lgt on Cys-27 with an S-linked diacylglycerol with a mixture of C16 and C19 fatty acids (palmitic and tuberculostearic acid), signal peptide is removed by LspA, modified by Lnt with an amide-linked mixture of C16 and C19 fatty acids, expressed in M.bovis and M.smegmatis (PubMed:19661058, PubMed:24093492). Hexose glycosylated in N-terminus between residues 27 and 55; there may be 2 sugar moieties in this region, expressed in M.bovis (PubMed:24093492).
No growth phenotype when grown in culture, no release of phthiocerol dimycocerosates (PDIM) to the culture filtrate. Attenuated virulence, about 80-fold less recovery of bacteria from lungs of 3 week infected BALB/c mice.
Belongs to the nitronate monooxygenase family.
May play a role in DNA repair. It seems to be involved in an RecBC-independent recombinational process of DNA repair. It may act with RecF and RecO.
Inactivation does not abolish EsxA (ESAT-6) secretion, EsxA-specific immunogenicity and enhanced virulence.
May act as a chaperone that facilitates EspB secretion through an interaction with EccCb1.
Belongs to the cation diffusion facilitator (CDF) transporter (TC 2.A.4) family.
Transcription is repressed by KmtR. Induced by nickel and cobalt.
Catalyzes two activities which are involved in the cyclic version of arginine biosynthesis: the synthesis of N-acetylglutamate from glutamate and acetyl-CoA as the acetyl donor, and of ornithine by transacetylation between N(2)-acetylornithine and glutamate.
Heterotetramer of two alpha and two beta chains.
Some bacteria possess a monofunctional ArgJ, i.e. capable of catalyzing only the fifth step of the arginine biosynthetic pathway.
Belongs to the SIMIBI class G3E GTPase family. UreG subfamily.
Facilitates the functional incorporation of the urease nickel metallocenter. This process requires GTP hydrolysis, probably effectuated by UreG.
Homodimer; disulfide-linked (Probable). The physiological role of the disulfide bond has not been proven in vivo. UreD, UreF and UreG form a complex that acts as a GTP-hydrolysis-dependent molecular chaperone, activating the urease apoprotein by helping to assemble the nickel containing metallocenter of UreC. The UreE protein probably delivers the nickel (By similarity).
Belongs to the ChdC family. Type 2 subfamily.
Fe-coproporphyrin III acts as both substrate and redox cofactor (By similarity). Was originally thought to use heme as a cofactor (PubMed:20543190).
Involved in coproporphyrin-dependent heme b biosynthesis (PubMed:25646457). Catalyzes the decarboxylation of Fe-coproporphyrin III (coproheme) to heme b (protoheme IX), the last step of the pathway (PubMed:25646457). The reaction occurs in a stepwise manner with a three-propionate intermediate (By similarity).
Belongs to the homoserine dehydrogenase family.
Has 3 domains, the large (RuvB-L) and small ATPase (RuvB-S) domains and the C-terminal head (RuvB-H) domain. The head domain binds DNA, while the ATPase domains jointly bind ATP, ADP or are empty depending on the state of the subunit in the translocation cycle. During a single DNA translocation step the structure of each domain remains the same, but their relative positions change.
Homohexamer. Forms an RuvA(8)-RuvB(12)-Holliday junction (HJ) complex. HJ DNA is sandwiched between 2 RuvA tetramers; dsDNA enters through RuvA and exits via RuvB. An RuvB hexamer assembles on each DNA strand where it exits the tetramer. Each RuvB hexamer is contacted by two RuvA subunits (via domain III) on 2 adjacent RuvB subunits; this complex drives branch migration. In the full resolvosome a probable DNA-RuvA(4)-RuvB(12)-RuvC(2) complex forms which resolves the HJ.
The RuvA-RuvB-RuvC complex processes Holliday junction (HJ) DNA during genetic recombination and DNA repair, while the RuvA-RuvB complex plays an important role in the rescue of blocked DNA replication forks via replication fork reversal (RFR). RuvB binds Holliday junction (HJ) DNA in the presence of RuvA (PubMed:22094465). RuvA specifically binds to HJ cruciform DNA, conferring on it an open structure. The RuvB hexamer acts as an ATP-dependent pump, pulling dsDNA into and through the RuvAB complex. RuvB forms 2 homohexamers on either side of HJ DNA bound by 1 or 2 RuvA tetramers; 4 subunits per hexamer contact DNA at a time. Coordinated motions by a converter formed by DNA-disengaged RuvB subunits stimulates ATP hydrolysis and nucleotide exchange. Immobilization of the converter enables RuvB to convert the ATP-contained energy into a lever motion, pulling 2 nucleotides of DNA out of the RuvA tetramer per ATP hydrolyzed, thus driving DNA branch migration. The RuvB motors rotate together with the DNA substrate, which together with the progressing nucleotide cycle form the mechanistic basis for DNA recombination by continuous HJ branch migration. Branch migration allows RuvC to scan DNA until it finds its consensus sequence, where it cleaves and resolves cruciform DNA.
Generally found as a monomer; homodimer in culture fluids.
In the C-terminal section; belongs to the aminoglycoside phosphotransferase family.
Involved in resistance to gentamicin, tobramycin, and kanamycin. Tobramycin and kanamycin resistance is due to the ACC activity, specified by N-terminal region. The C-terminal region is a kinase that phosphorylates several 4,6-disubstituted aminoglycosides.
Contains a C-terminal ANTAR domain, which is a RNA binding domain.
Member of the two-component regulatory system PdtaR/PdtaS (PubMed:16026786, PubMed:33772870, PubMed:34003742). This two-component system plays an essential role in mycobacterial adaptation to poor nutrient conditions (PubMed:33772870). PdtaR probably acts at the level of transcriptional antitermination rather than transcriptional initiation (PubMed:15341725).
Monomer (PubMed:15341725). Dimer; when bound to its cognate DNA (Probable).
The NO arm of the pathway is further controlled by sequestration of PdtaR by PPE1-5', controlled by the Rip1 intramembrane protease (PubMed:34003742). PPE1-5' directly inhibits PdtaR and derepresses PdtaR targets, which are usually repressed by the PdtaR/PdtaS cascade (PubMed:34003742).
To M.tuberculosis Rv3630 and M.bovis Mb3654.
Belongs to the NiCoT transporter (TC 2.A.52) family.
Export of the fluoroquinolone antibiotic norfloxacin is inhibited by the proton ionophore carbonyl cyanide m-chlorophenylhydrazone (CCCP) (PubMed:36282241). Nickel may influence the extrusion of antibiotics possibly by facilitating the proton motive force-dependent efflux process (PubMed:36282241).
Involved in nickel uptake (PubMed:36282241). In addition, acts as a drug efflux pump and contributes to moderate tolerance towards different classes of antibiotics, including fluoroquinolones, aminoglycosides and the anti-TB drug isoniazid, with a preference for fluoroquinolones (PubMed:36282241). The drug efflux function is probably dependent on proton motive force (pmf) or ion gradient, and might be facilitated by the presence of Ni(2+) ions (PubMed:36282241).
Overexpression of NicT in E.coli and M.smegmatis enhances tolerance towards several antibiotics (norfloxacin, sparfloxacin, ofloxacin, gentamicin, nalidixic acid and isoniazid).
Belongs to the ABC-4 integral membrane protein family. FtsX subfamily.
Forms a membrane-associated complex with FtsE.
Part of the ABC transporter FtsEX involved in cellular division.
Functions as a ribosomal silencing factor. Interacts with ribosomal protein uL14 (rplN), blocking formation of intersubunit bridge B8. Prevents association of the 30S and 50S ribosomal subunits and the formation of functional ribosomes, thus repressing translation.
Interacts with ribosomal protein uL14 (rplN).
Belongs to the sugar phosphate cyclases superfamily. Dehydroquinate synthase family.
Binds 1 divalent metal cation per subunit. Can use either Co(2+) or Zn(2+).
Catalyzes the conversion of 3-deoxy-D-arabino-heptulosonate 7-phosphate (DAHP) to dehydroquinate (DHQ).
By glycerol supplementation as the sole carbon source in the minimal growth medium.
Plays a role in response to starvation and stress, likely environment within the host. Inhibits canonical autophagy in infected mouse RAW264.7 macrophages. Inhibits autophagy and enhances intracellular bacterial survival when expressed in human macrophage-like THP-1 cells. Inhibits Toll-like receptor 2 (TLR2)-dependent signaling leading to autophagy inhibition, increased intracellular bacterial survival, reduced phagocytosis and reduced secretion of interleukin 6 (IL-6) and IL-1 in infected mouse primary bone marrow-derived macrophage (BMDM) cells. Required for virulence and persistence in the lungs and spleens of intranasally infected C57BL/6J mice. Blocks the antibacterial effects of TLR2 activation, suppresses MHC class II-dependent antigen presentation, and reduces IFN-gamma and TNF-alpha-producing CD4(+) T cells during infection in C57BL/6J mice.
Small molecule-selective channel required for the uptake of nutrients across the outer mycomembrane (PubMed:32138343, PubMed:32139546). Transports glycerol and glucose. Involved in sensitivity to M.tuberculosis growth inhibitory agrichemical 3,3-bis-di(methylsulfonyl)propionamide (3bMP1) (PubMed:32139546). Transports maltose and lactose disaccharides. Involved in sensitivity to bactericidal thio-disaccharide T-6 compound (1,6-anhydro-3-deoxy-4-S-(2,3,4,6-tetra-O-acetyl-beta-D-glucopyranosyl)-D-glycero-hexopyranos-2-ulose) (PubMed:32138343). Transports extracellular trehalose, a component of the cell envelope, and trehalose analog, 6-azido trehalose (6-TreAz), which has antimycobacterial activity (PubMed:35136132).
Unable to grow on minimal medium with trehalose or glucose as the sole carbon sources or in limited medium containing trehalose (PubMed:35136132). Resistant to trehalose analog 6-TreAz (PubMed:35136132). Slow growth on minimal medium supplemented with maltose or lactose as the sole carbon and energy sources at both neutral pH and acidic pH 5.7 (PubMed:32138343). The supplementation of glycerol or glucose promotes growth at acidic pH, but reduces growth significantly at neutral pH in minimal medium and on solid agar (PubMed:32138343, PubMed:32139546, PubMed:35467412, PubMed:35136132). Mutants grow normally in rich medium at either neutral or acidic pH, and in media containing oleic acid or hexanamide as the sole carbon sources (PubMed:32138343, PubMed:32139546, PubMed:35467412). Cell envelope-associated glycolipid phthiocerol dimycocerosate (PDIM)-positive mutants are resistant to 3bMP1 compound (PubMed:32139546). Deletion mutant-infected mouse RAW264.7 macrophages have increased canonical autophagy and decreased intracellular bacterial burden 24 hours postinfection (PubMed:35467412). They have significantly higher reactive oxygen species (ROS) levels and increased MAP kinase Erk1/2 phosphorylation compared to macrophages infected with wild-type bacteria, but no increase in JNK mitogen-activated protein kinase (MAPK) or p38 MAPK expression or phosphorylation (PubMed:35467412). Primary murine bone marrow-derived macrophages (BMDMs) and dendritic cells (BMDDCs) have improved internalization of the deletion mutant, increased autophagy and reduced intracellular survival of the mutant during infection, compared to infection with wild-type (PubMed:35467412). Mutant-infected primary murine BMDMs secrete increased interleukin 6 (IL-6) and IL-1, and accumulate ROS (PubMed:35467412). These effects are not seen in mutant-infected BMDMs of the TLR2-deficient (tlr2(-/-)) mice (PubMed:35467412). Deletion mutant-infected human macrophage-like THP-1 cells have increased induction of autophagy and reduced intracellular bacterial burden compared to THP-1 cells infected with the wild-type (PubMed:35467412). At 72 hours postinfection, significantly more necrotic cell deaths occur in the mutant-infected THP-1 cells (PubMed:35467412). Significantly attenuated infection in lungs and spleens by deletion mutant delivered to the lungs of C57BL/6J mice by intranasal inoculation, but no attenuation in TLR2-deficient mice (PubMed:35467412). Increased autophagy in lungs, enhanced MHC class II antigen presentation and recognition, and significantly increased IFN-gamma and TNF-alpha-producing CD4(+) T cells in spleen, in response to tubercular antigens compared with wild-type in mutant-infected C57BL/6J mice (PubMed:35467412).
Belongs to the succinate dehydrogenase/fumarate reductase iron-sulfur protein family.
Belongs to the ketopantoate reductase family.
Catalyzes the NADPH-dependent reduction of ketopantoate into pantoic acid.
Controls the expression of a small regulon that may play a role in the utilization of cholesterol.
Possibly the antitoxic component of a type II toxin-antitoxin (TA) system. Its cognate toxin is VapC29.
Belongs to the pyridoxal phosphate-binding protein YggS/PROSC family.
Pyridoxal 5'-phosphate (PLP)-binding protein, which is involved in PLP homeostasis.
Toxic component of a type II toxin-antitoxin (TA) system. An RNase. The cognate antitoxin is VapB17 (By similarity).
Required for formate dehydrogenase (FDH) activity. Acts as a sulfur carrier protein that transfers sulfur from IscS to the molybdenum cofactor prior to its insertion into FDH.
Belongs to the flavin monoamine oxidase family.
Belongs to the transposase IS21/IS408/IS1162 family.
Inhibited by sulfonamides and sulfamates. The best inhibitors are 3-bromosulfanilamide and indisulam.
Belongs to the universal ribosomal protein uL18 family.
Part of the 50S ribosomal subunit; part of the 5S rRNA/L5/L18/L25 subcomplex. Contacts the 5S and 23S rRNAs.
This is one of the proteins that bind and probably mediate the attachment of the 5S RNA into the large ribosomal subunit, where it forms part of the central protuberance.
Cells lacking this gene display impaired growth and abnormal cell morphology, since they are shorter and more swollen than wild-type cells. This phenotype likely stems from the decreased incorporation of arabinose into arabinogalactan observed in the disruption mutant. The mutant also accumulates decaprenyl-phospho-arabinose (DPA), the arabinose donor required for the synthesis of cell-wall arabinans. The lipoglycan fraction comprising LAM (lipoarabinomannan) and LM (lipomannan) is not affected.
Interacts with the priming arabinosyltransferase AftA (PubMed:26369580). Also interacts with the galactosyltransferase GlfT1, which initiates the polymerization of the galactan domain of AG (PubMed:23038254). Is thus probably part of an AG biosynthetic complex (PubMed:23038254, PubMed:26369580).
Is cotranscribed with dprE1, dprE2 and aftA.
Required for arabinosylation of arabinogalactan (AG), an essential component of the mycobacterial cell wall. Probably acts as an anchor protein recruiting AftA, the first arabinosyl transferase involved in AG biosynthesis.
Was originally thought to be a lipid-linked sugar translocase involved in the reorientation and export of decaprenyl-phospho-arabinose (DPA) across the plasma membrane to the site of AG (arabinogalactan) and LAM (lipoarabinomannan) synthesis (PubMed:23038254). It was later shown that synthesis of DPA takes place in the periplasm and it was suggested that Rv3789 does not act as a DPA flippase but, rather, recruits AftA for arabinogalactan biosynthesis (PubMed:25906160, PubMed:26369580).
Belongs to the MsrA Met sulfoxide reductase family.
Has an important function as a repair enzyme for proteins that have been inactivated by oxidation. Catalyzes the reversible oxidation-reduction of methionine sulfoxide in proteins to methionine.
Belongs to the glycosyltransferase group 1 family. MshA subfamily.
Catalyzes the transfer of an N-acetyl-glucosamine moiety to 1D-myo-inositol 3-phosphate to produce 1D-myo-inositol 2-acetamido-2-deoxy-glucopyranoside 3-phosphate in the mycothiol (MSH) biosynthesis pathway (PubMed:12754249). MSH and WhiB3 are probably part of a regulatory circuit that mediates gene expression upon acid stress (like that found in host macrophage phagosomes) (PubMed:26637353). MSH is one of the major redox buffers which protects bacteria against redox stressors and antibiotics; loss of MSH or ergothioneine (ERG, the other major redox buffer in this bacteria) leads to respiratory alterations and bioenergetic deficiencies that negatively impact virulence (PubMed:26774486).
Increased intracellular levels of ergothioneine, 8-fold increase in reactive oxygen species-producing cells, decreased resistance to the antibiotics rifampicin, isoniazid, bedaquiline and clofazimine (PubMed:26774486). Increased oxygen consumption and extracellular acidification rates, which are further increased by membrane uncoupler CCCP, indicative of electron chain dysfunction in the absence of MSH (PubMed:26774486). Absence leads to alteration of transcript levels for 139 genes which probably compensate for loss of redox control (PubMed:26774486). Loss of induction of some pH-inducible genes at pH 4.5, including the redox-sensor whiB3 (PubMed:26637353).
Belongs to the HpaH/HsaA monooxygenase family.
Catalyzes the o-hydroxylation of 3-hydroxy-9,10-secoandrosta-1,3,5(10)-triene-9,17-dione (3-HSA) to 3,4-dihydroxy-9,10-secoandrosta-1,3,5(10)-triene-9,17-dione (3,4-DHSA) in the catabolism of cholesterol. Can also use 3,17-dihydroxy-9,10-seconandrost-1,3,5(10)-triene-9-one (3,17-DHSA), but it has higher specificity for 3-HSA than for 3,17-DHSA. Can use either FADH(2) or FMNH(2) as flavin cosubstrate. Also catalyzes the o-hydroxylation of a range of p-substituted phenols to generate the corresponding catechols.
Homotetramer under anaerobic conditions. HsaAB monooxygenase consists of an oxygenase component HsaA and a reductase component HsaB.
Activated by CRP. Essentially constitutive over all growth phases. 2-fold induced by ethanol, repressed by SDS and heat shock. Not induced by hypoxia, slightly induced by NO and in macrophage and mouse infection, 10-fold induced by cAMP. There are 2 CRP-binding sites in the promoter of whiB1, at low concentrations of CRP with or without cAMP transcription of whiB1 is enhanced via site CRP1, then repressed as site CRP2 is filled.
Acts as a transcriptional repressor, inhibiting expression in vitro. Probably redox-responsive. The apo- but not holo-form binds to its own promoter as well as that of groEL2. Oxidized apo-form and nitrosylated holo-form also bind DNA. The apo-form has been shown to act as a protein disulfide reductase (PubMed:17157031) (PubMed:19016840), but also not to act as a protein disulfide reductase (PubMed:20929442).
Binds 1 [4Fe-4S] cluster per subunit. This cluster is stable to O(2) but very reactive to nitric oxide (NO). Following nitrosylation of the [4Fe-4S] cluster binds 1 [4Fe-8(NO)] cluster per subunit.
Can be nitrosylated by NO, 8 NO react per cluster leading to the formation of 2 dinitrosyliron thiol complexes (DNIC). These complexes are quite stable in the presence of air.
Homodimer. Interacts with GlgB via an intermolecular disulfide bond.
Upon aerobic 4Fe-4S cluster removal intramolecular disulfide bonds are formed.
Component of a biotin-dependent acyl-CoA carboxylase complex. This subunit transfers the CO2 from carboxybiotin to the CoA ester substrate (PubMed:16354663, PubMed:28222482). When associated with the alpha3 subunit AccA3, the beta5 subunit AccD5 and the epsilon subunit AccE5, forms the LCC complex, which is involved in the carboxylation of long chain acyl-CoA (PubMed:16354663, PubMed:28222482). The LCC complex can use C16-C24 substrates, the highest specific activity is obtained with carboxy-C20-CoA (PubMed:28222482). Has low activity with acetyl-CoA and propionyl-CoA (PubMed:16354663).
Expressed at higher levels during the exponential growth phase.
The biotin-dependent long-chain acyl-CoA carboxylase (LCC) complex is composed of AccA3, which contains the biotin carboxylase (BC) and biotin carboxyl carrier protein (BCCP) domains, and AccD4, which contains the carboxyl transferase (CT) domain (PubMed:16354663, PubMed:28222482). The complex also contains the beta5 subunit AccD5 and the epsilon subunit AccE5. The four subunits are essential for activity, but AccD5, together with AccE5, probably plays a structural role rather than a catalytic one (PubMed:28222482).
Belongs to the dTDP-Qui4N formyltransferase family.
Mice infected with M.tuberculosis H37Rv mutants for Rv3404c present a highly significant increase in their survival time as compared with mice infected with the parental strain.
Sugar N-formyltransferase that catalyzes the conversion of dTDP-4-amino-4,6-dideoxyglucose into dTDP-4-formamido-4,6-dideoxyglucose using N(10)-formyltetrahydrofolate as the carbon source (PubMed:28665588). Plays a role in virulence (PubMed:12368431). Has no activity on dTDP-3-amino-3,6-dideoxyglucose, dTDP-3-amino-3,6-dideoxygalactose, UDP-4-amino-4-deoxyarabinose, and GDP-4-amino-4,6-dideoxymannose (PubMed:28665588).
Acts as a host evasion factor, that significantly contributes to the pathogenesis of M.tuberculosis by modulating adaptive immune responses by inhibiting host-protective Th1 and Th17 cytokine responses as well as autophagy (PubMed:25847237). Catalyzes the 2'-O-methylation at nucleotides C1409 in 16S rRNA and C1920 in 23S rRNA (PubMed:16857584, PubMed:20854656). Is likely involved in ribosomal biogenesis (PubMed:21443791). Also exhibits hemolytic activity in vitro, by binding with and oligomerizing into host cell membranes (PubMed:20854656, PubMed:9611795).
Can form oligomers on macrophage phagosomal membranes.
Cells lacking this gene induce increased IL-12 and reduced IL-1beta and IL-10 cytokine responses, which sharply contrasts with the immune responses induced by wild-type M.tuberculosis (PubMed:25847237). They are also more susceptible to autophagy in macrophages (PubMed:25847237). Consequently, animals infected with the TlyA-deficient mutant M.tuberculosis organisms exhibit increased host-protective immune responses, reduced bacillary load, and increased survival compared with animals infected with wild-type M.tuberculosis (PubMed:25847237). Disruption of this gene leads to capreomycin resistance (PubMed:15673735).
Toxic component of a type II toxin-antitoxin (TA) system. An RNase (By similarity). Upon expression in M.smegmatis inhibits colony formation. Its toxic effect is neutralized by coexpression with cognate antitoxin VapB25.
Contains two ACAD domains separated by a short linker. The two domains interact to form a single active site.
Involved in the second cycle of side chain dehydrogenation in the beta-oxidation of cholesterol catabolism. It contributes partly to the virulence by increasing the efficiency of beta-oxidation (PubMed:26161441). Catalyzes the dehydrogenation of the five-carbon steroid side chain of 3-oxo-chol-4-en-24-oyl-CoA (3-OCO-CoA) to yield 3-oxochol-4,22-dien-24-oyl-CoA (PubMed:26161441). Can also use 3beta-hydroxy-chol-5-ene-24-oyl-CoA, and shows weak activity with cholyl-CoA and deoxycholyl-CoA (PubMed:25645564).
Inhibited by salicyl-AMS, an acyl-AMP analog (PubMed:16407990, PubMed:17181146). Also inhibited by 5'-O-[(N-acyl)sulfamoyl]adenosines (PubMed:17967002).
Involved in the initial steps of the mycobactin biosynthetic pathway. Catalyzes the salicylation of the aryl carrier protein (ArCP) domain of MbtB through a two-step reaction. The first step is the ATP-dependent adenylation of salicylate to generate a salicyl-AMP intermediate. The second step is the transfer of this activated salicylate to MbtB to form a salicyl-ArCP domain thioester.
Antitoxin component of a type II toxin-antitoxin (TA) system. Cognate toxin is VapC27. Upon expression in E.coli partially counteracts the ribonuclease activity of non-cognate toxins MazF6 and MazF9.
Interacts with cognate toxin VapC27 and non-cognate toxins MazF6 and VapC40. Interaction with MazF6 and MazF9 partially neutralizes the toxins.
Forms a complex with cognate antitoxin MazE1.
Toxic component of a type II toxin-antitoxin (TA) system, its cognate antitoxin is MazE1 (Probable). Probably an endoribonuclease (By similarity).
Belongs to the metallo-beta-lactamase superfamily. Type III sulfatase family.
A member of the dormancy regulon. Induced in response to reduced oxygen tension (hypoxia), low levels of nitric oxide (NO) and carbon monoxide (CO). It is hoped that this regulon will give insight into the latent, or dormant phase of infection. Induced in C57BL/6 mouse lungs 3 weeks after low dose aerosol infection with H37Rv bacteria.
DNA-binding ability is not susceptible to zinc, nickel, cobalt, cadmium, lead, copper and manganese ions.
Involved in the regulation of lipid metabolism and hypoxic response. Positively regulates transcription of various genes, such as phoP, groEL2 and dosR. Negatively regulates its own transcription. Acts by binding to a specific palindromic sequence motif in promoter regions.
To M.leprae L518_C2_147 and M.tuberculosis Rv1524.
Interacts with anti-sigma-F factor RsbW (UsfX). Its phosphorylation may prevent this interaction.
Positive regulator of sigma-F (SigF) activity. Binds to anti-sigma-F factor RsbW (UsfX) preventing its binding to SigF, thus activating transcription.
Putative phosphorylation on Ser-61 may prevent interaction with RsbW.
Forms a tight 1:1 complex with EsxE (PubMed:20085764).
Belongs to the glycosyl hydrolase 38 family.
Belongs to the NAD(P)-dependent epimerase/dehydratase family. SDR39U1 subfamily.
Belongs to the glycosyltransferase 87 family.
Catalyzes the alpha-1,2 addition of a mannose residue from polyprenol-phosphate-mannose (PPM) to a monoacyl phosphatidylinositol tetramannoside (AcPIM4) to generate a monoacyl phosphatidylinositol pentamannoside (AcPIM5).
Belongs to the thiamine-monophosphate kinase family.
Catalyzes the ATP-dependent phosphorylation of thiamine-monophosphate (TMP) to form thiamine-pyrophosphate (TPP), the active form of vitamin B1.
Reaction mechanism of ThiL seems to utilize a direct, inline transfer of the gamma-phosphate of ATP to TMP rather than a phosphorylated enzyme intermediate.
Confers a high level of resistance to isoniazid (INH) when overexpressed in M.smegmatis.
Disruption causes altered colony morphology (PubMed:10573420). Inactivation increases mouse survival (PubMed:15908378). Mutants are unable to liberate PDIM into the culture medium and are compromised for growth in mouse lungs, but not in the liver or spleen (PubMed:10573420). DIM are found mostly in the cytosol and plasma membrane, and mutants exhibit higher cell wall permeability and are more sensitive to detergent (PubMed:11279114).
Phosphorylated by PknD in vitro. Phosphorylation could regulate the formation of the cell wall.
Required for export of phthiocerol dimycocerosate (PDIM) to the cell wall (PubMed:10573420, PubMed:11279114). Essential for normal replication during the active-growth phase of the murine tuberculosis model (PubMed:15908378).
Forms a heterotetramer with cognate antitoxin Rv3188.
Probable toxic component of a type II toxin-antitoxin (TA) system. Degrades NAD(+) by phosphorolysis. Neutralized by its cognate antitoxin Rv3188.
Toxic component of a type II toxin-antitoxin (TA) system (PubMed:19016878, PubMed:24225902). An endoribonuclease that cleaves both E.coli and M.smegmatis 23S rRNA between G2661 and A2662 in the sarcin-ricin loop (SRL, E.coli 23S rRNA numbering). The SRL sequence is highly conserved and is implicated in GTP hydrolysis by EF-Tu and EF-G. Acts on purified ribosomes but not on isolated RNA in E.coli, nor on a shortened artificial substrate (PubMed:24225902). Upon expression in E.coli inhibits cell growth, colony formation and translation. Its toxic effect is neutralized by coexpression, or subsequent expression (tested over 2 hours) with cognate antitoxin VapB20 (PubMed:19016878, PubMed:24225902).
This protein specifically catalyzes the removal of signal peptides from prolipoproteins.
Belongs to the PNP/MTAP phosphorylase family.
The purine nucleoside phosphorylases catalyze the phosphorolytic breakdown of the N-glycosidic bond in the beta-(deoxy)ribonucleoside molecules, with the formation of the corresponding free purine bases and pentose-1-phosphate. Cleaves guanosine, inosine, 2'-deoxyguanosine and 2'-deoxyinosine.
Binds 2 [4Fe-4S] clusters. The clusters are coordinated with 3 cysteines and an exchangeable S-adenosyl-L-methionine.
Catalyzes the radical-mediated synthesis of 7,8-didemethyl-8-hydroxy-5-deazariboflavin (FO) from 5-amino-6-(D-ribitylamino)uracil and L-tyrosine.
In the C-terminal section; belongs to the radical SAM superfamily. CofH family.
In the N-terminal section; belongs to the radical SAM superfamily. CofG family.
Involved in the biosynthesis of phosphatidyl-myo-inositol mannosides (PIM) which are early precursors in the biosynthesis of lipomannans (LM) and lipoarabinomannans (LAM) (PubMed:19395496). Catalyzes the addition of a mannosyl residue from GDP-D-mannose (GDP-Man) to the position 6 of a phosphatidyl-myo-inositol bearing an alpha-1,2-linked mannose residue (PIM1) to generate phosphatidyl-myo-inositol bearing alpha-1,2- and alpha-1,6-linked mannose residues (Ac1PIM2) (PubMed:19395496). PimB also catalyzes the addition of a mannosyl residue from GDP-Man to the position 6 of phosphatidyl-myo-inositol bearing an acylated alpha-1,2-linked mannose residue (Ac1PIM1) to generate monoacylated phosphatidyl-myo-inositol bearing alpha-1,2- and alpha-1,6-linked mannose residues (Ac1PIM2) (By similarity). The addition of the second mannosyl residue by PimB preferentially occurs before the acylation of the mannosyl residue transferred by PimA (By similarity). Also able to transfer a mannosyl residue from GDP-Man to the position 6 of a phosphatidyl-myo-inositol (PI), but this reaction is very slow (By similarity).
The alpha subunit is responsible for the aldol cleavage of indoleglycerol phosphate to indole and glyceraldehyde 3-phosphate.
Belongs to the carbohydrate kinase PfkB family.
Catalyzes the phosphorylation of adenosine to adenosine monophosphate (AMP) (PubMed:14594827, PubMed:16511094). Can also catalyze the phosphorylation of the adenosine analog 2-methyladenosine (methyl-Ado) to methyl-AMP, the first step in the metabolism of this compound to an active form that displays antitubercular activity. Is not active on guanosine, inosine, deoxyadenosine, cytidine, uridine, or thymidine. Prefers dGTP and GTP to ATP as phosphate donors in vitro (PubMed:14594827).
The enzyme is subject to substrate inhibition by adenosine and is competitively inhibited by the adenosine analog iodotubercidin. Unlike other adenosine kinases it is not stimulated by inorganic phosphate. Activity is stimulated in the presence of potassium (PubMed:14594827). Is inhibited by a series of 7-(het)aryl-7-deazaadenine ribonucleosides bearing small and bulky substituents in position 7; some of them display micromolar antimycobacterial activity and low cytotoxicity (PubMed:25259627).
Belongs to the SEDS family. FtsW subfamily.
Forms a complex with FtsZ and PbpB (PBP3, FtsI).
Interacts with FtsZ via its C-terminal region, and with PbpB via two extracytoplasmic loops.
Peptidoglycan polymerase that is essential for cell division.
Deletion mutant does not synthesize SMK and shows a hypervirulent phenotype in the mouse model of infection (PubMed:16537518, PubMed:27933784). Mutant has significantly higher levels of menaquinone-9 (MK-9), an essential component in the electron-transport chain in M.tuberculosis (PubMed:27933784).
Involved in the biosynthesis of sulfomenaquinone (SMK, initially named S881 on the basis of its mass), which is localized in the outer envelope of M.tuberculosis and negatively regulates its virulence (PubMed:16537518, PubMed:27933784). Catalyzes the transfer of a sulfonate group from 3'-phosphoadenosine-5'-phosphosulfate (PAPS) to omega-hydroxy-beta-dihydromenaquinone-9, generating omega-sulfo-beta-dihydromenaquinone-9 (sulfomenaquinone) (PubMed:16537518, PubMed:18928249).
Belongs to the FtsK/SpoIIIE/SftA family.
Consists of an N-terminal domain, which is sufficient for the localization to the septal ring and is required for cell division, followed by a linker domain, and a C-terminal domain, which forms the translocation motor involved in chromosome segregation. The C-terminal domain can be further subdivided into alpha, beta and gamma subdomains. The alpha and beta subdomains form the DNA pump, and the gamma subdomain is a regulatory subdomain (By similarity).
Essential cell division protein that coordinates cell division and chromosome segregation. The N-terminus is involved in assembly of the cell-division machinery. The C-terminus functions as a DNA motor that moves dsDNA in an ATP-dependent manner towards the dif recombination site, which is located within the replication terminus region. Required for activation of the Xer recombinase, allowing activation of chromosome unlinking by recombination (By similarity).
Homohexamer. Forms a ring that surrounds DNA (By similarity).
An anti-sigma factor for extracytoplasmic function (ECF) sigma factor SigL. ECF sigma factors are held in an inactive form by an anti-sigma factor until released by regulated intramembrane proteolysis (RIP). RIP occurs when an extracytoplasmic signal triggers a concerted proteolytic cascade to transmit information and elicit cellular responses. The membrane-spanning regulatory substrate protein is first cut extracytoplasmically (site-1 protease, S1P), then within the membrane itself (site-2 protease, S2P, Rip1), while cytoplasmic proteases finish degrading the regulatory protein, liberating the sigma factor.
Belongs to the zinc-associated anti-sigma factor (ZAS) superfamily.
Constitutively expressed from a very weak SigL-independent promoter during growth in culture. Also weakly autoregulated. Forms an operon with sigL.
In a double sigL-rslA disruption mutant, no visible phenotype; not more susceptible than the parental strain to several oxidative and nitrosative stresses. Infected DBA/2 mice showed a significantly prolonged survival time relative to mice infected with wild-type bacteria, although bacteria proliferate normally.
Interacts with ECF RNA polymerase sigma factor SigL; this should inhibit the interaction of SigL with the RNA polymerase catalytic core.
The cytosolic domain interacts with sigma factor SigL.
Cells lacking this gene are unable to produce PIM and show an increase of phosphatidyl-myo-inositol (PI).
Involved in the biosynthesis of phosphatidyl-myo-inositol mannosides (PIM) which are early precursors in the biosynthesis of lipomannans (LM) and lipoarabinomannans (LAM). Catalyzes the addition of a mannosyl residue from GDP-D-mannose (GDP-Man) to the position 2 of the carrier lipid phosphatidyl-myo-inositol (PI) to generate a phosphatidyl-myo-inositol bearing an alpha-1,2-linked mannose residue (PIM1) (PubMed:15939292). PimA plays an essential role for growth in macrophages and during both the acute and chronic phases of infection (PubMed:25049093).
Belongs to the DNA polymerase HolA subunit family.
DNA polymerase III is a complex, multichain enzyme responsible for most of the replicative synthesis in bacteria. Pol III also exhibits 3'-5' exonuclease activity. The delta subunit interacts with the gamma/tau subunit to load the beta sliding clamp (dnaN) onto the DNA (By similarity).
Pol III contains a core (composed of alpha, epsilon and theta chains) that associates with a tau subunit. This core dimerizes and associates with the clamp-loading complex (or gamma) complex (composed of gamma/tau, delta, delta', psi and chi subunits) which binds Pol III cores each with a beta sliding clamp dimer (By similarity). Interacts with beta sliding clamp (dnaN) (PubMed:21219854).
Could be used in vaccine production; both recombinant protein and DNA vaccines stimulate antigen-specific T cell responses in mice (PubMed:22567094).
Highly expressed and immunogenic during infection of mice with live bacteria (at protein level).
Interacts with host TLR2 (tested in mouse) (PubMed:22174456).
O-glycosylated. Contains 0-3 mannose residues attached to residues 48-49 in various configurations; the dominant glycoform is Thr-48(Man)/Thr-49(Man2) with an unusual Man(1->3)Man linkage, but Thr48(Man3)/Thr49(Man0) through to Thr48(Man0/)Thr49(Man3) are also seen (By similarity).
Recombinant, non-modified protein stimulates secretion of cytokines (TNF-alpha, IL-6 and IL-12p40) by mouse macrophage cell lines in a TLR2-dependent fashion, which leads to increased host innate immunity responses against the bacterium (PubMed:22174456). Serves as a strong human and mouse antigen T cell antigen during M.tuberculosis infection, inducing strong IFN-gamma expression (PubMed:22567094).
Belongs to the AIR carboxylase family. Class I subfamily.
Catalyzes the conversion of N5-carboxyaminoimidazole ribonucleotide (N5-CAIR) to 4-carboxy-5-aminoimidazole ribonucleotide (CAIR).
Belongs to the SecD/SecF family. SecD subfamily.
Forms a complex with SecF. Part of the essential Sec protein translocation apparatus which comprises SecA, SecYEG and auxiliary proteins SecDF. Other proteins may also be involved.
Part of the Sec protein translocase complex. Interacts with the SecYEG preprotein conducting channel. SecDF uses the proton motive force (PMF) to complete protein translocation after the ATP-dependent function of SecA.
Antitoxin component of a type II toxin-antitoxin (TA) system. Upon expression in M.smegmatis neutralizes the effect of cognate toxin VapC2. The C-terminal helix of the antitoxin may obstruct the toxin's RNA-binding groove, blocking access to the active sites. Additionally, the C-terminal arginine of the antitoxin may remove Mg(2+) ions from the toxin active sites.
Forms a homodimer, which binds to a toxin homodimer, which then oligomerizes further to a hetero-octamer. When bound to toxin VapC2 the toxin activity is inhibited; 1 antitoxin may suffice to inhibit toxin.
Consists of two domains connected by a short loop, which form a bent shape. The N-terminal domain (residues 32-122) resembles a c-type immunoglobulin (Ig) domain, and the C-terminal contains the catalytic site that is located in a tiny tunnel.
Generates 3->3 cross-links in peptidoglycan, catalyzing the cleavage of the mDap(3)-D-Ala(4) bond of a tetrapeptide donor stem and the formation of a bond between the carbonyl of mDap(3) of the donor stem and the side chain of mDap(3) of the acceptor stem. Is specific for donor substrates containing a stem tetrapeptide since it cannot use pentapeptide stems. Is thought to play a role in adaptation to the nonreplicative state of M.tuberculosis.
Is irreversibly inactivated by the beta-lactams carbapenems via the formation of a covalent adduct resulting from acylation of the catalytic Cys; ertapenem and imipenem are the most efficient drugs for in vitro LdtMt1 inactivation. Cephalosporins (cefotaxime, cephalothin, and ceftriaxone) also form covalent adducts with LdtMt1, although the acylation reaction was 7- to 1,000-fold slower and leads to elimination of one of the drug side chains. A high drug concentration (360 uM) of ceftriaxone is required for full inhibition of enzyme activity. Is not inhibited by ampicillin.
The peptidoglycan structure of stationary-phase M.tuberculosis is atypical since it contains a majority (80%) of 3->3 cross-links synthesized by L,D-transpeptidases that predominate over the 4->3 cross-links formed by the D,D-transpeptidase activity of classical penicillin-binding proteins (PubMed:18408028). In fact, 3-3 cross-linkages predominate throughout all growth phases and the ratio of 4-3/3-3 linkages does not vary significantly under any growth condition (PubMed:22906310).
Up-regulated 17-fold under nutrient starvation.
Belongs to the aconitase/IPM isomerase family. LeuC type 1 subfamily.
Catalyzes the isomerization between 2-isopropylmalate and 3-isopropylmalate, via the formation of 2-isopropylmaleate.
Accumulates the precursor SL1278. Can produce SL-1, albeit at reduced levels.
Belongs to the peptidoglycolipid addressing protein (GAP) (TC 2.A.116) family.
Required for the transport across the inner membrane of sulfolipid-1 (SL-1), which is a major cell wall lipid of pathogenic mycobacteria. Could also transport SL1278 (2-palmitoyl-3-(C43)-phthioceranyl-alpha, alpha'-D-trehalose-2'-sulfate), which is the precursor of SL-1. May potentiate SL-1 levels and confer specificity for sulfolipids over structurally similar glycolipids.
Belongs to the metallo-dependent hydrolases superfamily. N-acyl-D-amino-acid deacylase family.
Alpha-ketoglutarate dehydrogenase and decarboxylase activities are inhibited by unphosphorylated GarA, and allosterically activated by acetyl-CoA, the main substrate of the TCA cycle.
Attempts to disrupt Rv1248c in M.tuberculosis H37Rv and Erdman strains by homologous recombination were unsuccessful, raising the possibility that Rv1248c may be essential (PubMed:20416504). However, deletion mutants were readily obtained in a strain derived from H37Rv in PubMed:19936047. The mutant strain grows as well as wild-type in medium containing both carbohydrates (dextrose and glycerol) and fatty acids, under a CO(2) enriched atmosphere, but shows a marked growth defect when grown in medium containing carbohydrates as the sole carbon source in the presence of CO(2). Simultaneous disruption of korAB and kgd results in strict dependence upon the glyoxylate shunt for growth. Growth of the kgd mutant strain on fatty acids as the sole carbon source is similar to that of the wild type strain regardless of the presence of CO(2). But cells lacking both korAB and kgd is significantly more retarded for growth on fatty acids than is either korAB or kgd deleted mutant alone.
Belongs to the 2-oxoacid dehydrogenase family. Kgd subfamily.
Homodimer (By similarity). The 2-oxoglutarate dehydrogenase (ODH) complex contains multiple copies of three enzymatic components: 2-oxoglutarate dehydrogenase (E1), dihydrolipoamide succinyltransferase (E2) and lipoamide dehydrogenase (E3) (By similarity). Interacts with the FHA domain of unphosphorylated GarA.
Is a fusion protein with two major domains exhibiting structural features of an E1 and E2 protein, and a short sequence stretch of E1 localized at the N-terminus, which is connected by a linker region to the rest of the protein.
Shows three enzymatic activities that share a first common step, the attack of thiamine-PP on 2-oxoglutarate (alpha-ketoglutarate, KG), leading to the formation of an enamine-thiamine-PP intermediate upon decarboxylation. Thus, displays KGD activity, catalyzing the decarboxylation from five-carbon 2-oxoglutarate to four-carbon succinate semialdehyde (SSA). Also catalyzes C-C bond formation between the activated aldehyde formed after decarboxylation of alpha-ketoglutarate and the carbonyl of glyoxylate (GLX), to yield 2-hydroxy-3-oxoadipate (HOA), which spontaneously decarboxylates to form 5-hydroxylevulinate (HLA). And is also a component of the 2-oxoglutarate dehydrogenase (ODH) complex, that catalyzes the overall conversion of 2-oxoglutarate to succinyl-CoA and CO(2). The KG decarboxylase and KG dehydrogenase reactions provide two alternative, tightly regulated, pathways connecting the oxidative and reductive branches of the TCA cycle, which can endow M.tuberculosis with the metabolic plasticity required for growth on diverse host-derived carbon sources. Appears to play a predominant role in growth on carbohydrates as the sole carbon source, and only a minimal role during growth on fatty acids.
Was originally annotated as sucA because of sequence similarity(PubMed:9634230, PubMed:12218036). But this protein was shown not to be able to serve as the E1 component of 2-oxoglutarate dehydrogenase (ODH) (PubMed:16045627). However, it was later shown that this protein does in fact sustain ODH activity, and requires specific activation by acetyl-CoA (PubMed:21867916).
Contains an N-terminal DNA-binding domain, a linker region and a C-terminal effector binding domain. Dimerization is mediated via the C-terminal domain.
Transcriptional regulator that binds to its own promoter and thus may play a role in the regulation of the cotranscribed genes Rv1827 and Rv1828. Can also bind several promoter regions of genes that are essential, including ftsZ. Binds to the imperfect everted repeat sequence CTCAA through its winged-HTH motif.
Pupylated at Lys-189 by the prokaryotic ubiquitin-like protein Pup, which probably leads to its degradation by the proteasome.
Belongs to the type-B carboxylesterase/lipase family.
Belongs to the mycobacterial serine protease inhibitor Rv3364c family.
Component of the signal transduction operon Rv3361c-Rv3365c that is highly up-regulated during M.tuberculosis infection of macrophages.
Effector protein that binds to the host serine protease cathepsin G on the macrophage cell membrane, inhibiting its enzymatic activity and the downstream activation of caspase-1-dependent apoptosis. Thus prevents macrophage pyroptosis and helps M.tuberculosis survival within host cells.
Interacts with human cathepsin G protein.
Cells lacking this gene result in a significant increase in the expression of mce3 either in vitro or in a murine cell macrophages line.
Mce3R represses the transcription of mce3 operon and down-regulates its own expression, but does not affect the transcription of mce1, mce2 and mce4 operons.
ATP-dependent carboxylate-amine ligase which exhibits weak glutamate--cysteine ligase activity.
Belongs to the glutamate--cysteine ligase type 2 family. YbdK subfamily.
May be involved in the GO system responsible for removing an oxidatively damaged form of guanine (7,8-dihydro-8-oxoguanine, 8-oxo-dGTP) from DNA and the nucleotide pool (By similarity). In vitro has dATPase rather than 8-oxo-dGTPase activity.
There are 4 mutT paralogs in M.tuberculosis; the exact function of each is unknown.
A triple higB1-higA1-Rv1957 disruption mutant has no visible phenotype.
Belongs to the mycobacterial HigB family.
Induced by hypoxia and by DNA damaging agent mitomycin C. Part of the Rv1954A-higB1-higA1-Rv1957 operon, as well as the higB1-higA1-Rv1957 operon, which is probably the mitomycin-induced operon; the former but not latter operon is autorepressed by HigA1 (PubMed:20585061). Induced in persister cells in response to D-cycloserine (PubMed:21673191).
Toxic component of an atypical, type II toxin-antitoxin chaperone (TAC) system. Upon expression in M.smegmatis inhibits colony formation and cell growth (PubMed:20011113, PubMed:23927792). Ectopic expression in wild-type M.tuberculosis has no effect on cell growth; ectopic expression in a triple higB1-higA1-Rv1957 (delta TAC) disruption mutant causes growth arrest, killing a considerable proportion of the cells. Increased ectopic expression leads to decreased levels of IdeR- and Zur-regulated genes as well as cleavage within the mRNA region of tmRNA (transfer-mRNA), strongly suggesting it is an endoribonuclease; also degrades E.coli and M-smegmatis tmRNA (PubMed:23927792). Its toxic effect is neutralized by coexpression with antitoxin HigA. Neutralization of HigB1 toxin in E.coli or M.marinum also requires SecB-like chaperone Rv1957, making this the first toxin-antitoxin chaperone (TAC) system (PubMed:21536872).
Upon expression in E.coli, Rv1955 has been shown to function as an antitoxin against Rv1956 (PubMed:19016878). It is not clear if these conflicting results are due to expression in a heterologous system. The gene names higA and higB have been assigned to both Rv1955 and Rv1956; we have chosen to call Rv1955 higB1 after consulting the authors.
Activity is inhibited by the serine modifier phenylmethylsulfonyl fluoride (PMSF).
Belongs to the 'GDSL' lipolytic enzyme family.
Expression in M.smegmatis alters colony morphology and growth kinetics, provides resistance to SDS, lysozyme and anti-TB drugs, increases the total lipid content and trehalose dimycolates, and enhances infection ability and intracellular survival capability of M.smegmatis.
Expression is up-regulated under nutrient starvation (in strain H37Ra).
GDSL lipase that catalyzes the hydrolysis of p-nitrophenyl (pNP) esters. pNP-decanoate (C10) is the preferred substrate. It can also use pNP-octanoate (C8), pNP-dodecanoate (C12) and pNP-tetradecanoate (C14). Has lower activity with pNP-butyrate (C4), pNP-palmitate (C16) and pNP-stearate (C18) (PubMed:31125644). Does not show phospholipase A1 activity (PubMed:31125644). Might help bacteria to utilize available lipids for its growth as well as provide resistance to various intracellular stresses by cell wall modulation resulting in enhanced intracellular survival (PubMed:31125644).
Belongs to the universal ribosomal protein uL22 family.
The globular domain of the protein is located near the polypeptide exit tunnel on the outside of the subunit, while an extended beta-hairpin is found that lines the wall of the exit tunnel in the center of the 70S ribosome.
This protein binds specifically to 23S rRNA; its binding is stimulated by other ribosomal proteins, e.g. L4, L17, and L20. It is important during the early stages of 50S assembly. It makes multiple contacts with different domains of the 23S rRNA in the assembled 50S subunit and ribosome (By similarity).
Belongs to the EPSP synthase family. MurA subfamily.
Cell wall formation. Adds enolpyruvyl to UDP-N-acetylglucosamine.
Autophosphorylated (PubMed:16739134) (PubMed:25665034) (PubMed:25586004). Phosphorylation of Thr-180 in the activation loop is critical for the functionality of PknA (PubMed:25665034). Autophosphorylation level increases in the presence of H(2)O(2) suggesting that PknA is activated by H(2)O(2) (PubMed:25224505). Phosphorylation of the activation loop at Thr-172 of PknA is critical for bacterial growth; PknA autophosphorylates its activation loop independent of PknB (PubMed:25713147). Dephosphorylated by PstP (PubMed:16817899).
Expressed predominantly in exponential phase.
Is activated by autophosphorylation of activation loop threonine residues, which results in conformational change and allows substrate binding. It seems that following ATP binding, phosphate is first transferred to Thr-180 via a cis mechanism to activate the kinase activity; phosphorylation of Thr-180 triggers PknA to phosphorylate Thr-172/Thr-174 via a trans mechanism. Phosphorylation of all of the activation loop threonines is necessary for efficient catalytic activity.
Overexpression causes major growth and morphological changes that indicate defects in cell wall synthesis and possibly in cell division.
PknA depletion in M.tuberculosis results in cell death and aberrant cell morphology, and leads to complete clearance of the pathogen from the host tissues using the murine infection model.
Protein kinase that regulates many aspects of mycobacterial physiology, and is critical for growth in vitro and survival of the pathogen in the host (PubMed:25713147). Is a key component of a signal transduction pathway that regulates cell growth, cell shape and cell division via phosphorylation of target proteins such as FtsZ, Wag31, GlmU, PstP, EmbR and Rv1422 (PubMed:15985609, PubMed:16817899, PubMed:19121323, PubMed:21190553, PubMed:21423706). Also catalyzes the phosphorylation of the proteasome alpha-subunit (PrcA) and unprocessed proteasome beta-subunit (pre-PrcB), which results in the inhibition of processing of pre-PrcB and assembly of the proteasome complex, and thereby enhances the mycobacterial resistance to H(2)O(2); PknA thus plays an important role in the oxidative stress response by impeding the formation of holo-proteasome in M.tuberculosis under H(2)O(2) stress (PubMed:25224505). Shows a strong preference for Thr versus Ser as the phosphoacceptor.
The article by Sureka et al was retracted by the editors after publication. Concerns were raised regarding the results presented in multiple figure panels. The raw data or replacement panels that were available did not satisfactorily address all the issues, thus questioning the integrity of the data.
The extracellular domain is dispensable for cell growth and survival in vitro (PubMed:25713147). The catalytic activity of PknA is confined within the N-terminal 283 amino acids (PubMed:25665034).
Belongs to the glycosyl hydrolase family 6.
Catalyzes the conversion of inosine 5'-phosphate (IMP) to xanthosine 5'-phosphate (XMP), the first committed and rate-limiting step in the de novo synthesis of guanine nucleotides, and therefore plays an important role in the regulation of cell growth (PubMed:20491506, PubMed:21081761). Does not catalyze the reverse reaction, i.e. the conversion of XMP to IMP (PubMed:21081761). Appears to be essential for the optimal growth of M.tuberculosis (PubMed:12657046).
Mycophenolic acid (MPA) is a non-competitive inhibitor that prevents formation of the closed enzyme conformation by binding to the same site as the amobile flap. In contrast, mizoribine monophosphate (MZP) is a competitive inhibitor that induces the closed conformation. MPA is a potent inhibitor of mammalian IMPDHs but a poor inhibitor of the bacterial enzymes. MZP is a more potent inhibitor of bacterial IMPDH (By similarity). Inhibited by the products XMP and NADH. Significantly inhibited in vitro by a panel of diphenyl urea-based derivatives and a series of novel classes of inhibitors, which are also potent anti-mycobacterial agents against M.tuberculosis and M.smegmatis (PubMed:21081761) (PubMed:22479467). Is also inhibited by a mycophenolic adenine dinucleotide (MAD) derivative in which a 1,2,3-triazole linker was incorporated as isosteric replacement of the pyrophosphate linker, thereby mimicking NAD (PubMed:20491506). Other inhibitors with modular structures consisting of two aromatic moieties connected by different linkers (such as urea and amide) have been identified and shown to exhibit antitubercular activity (PubMed:26440283).
Toxic component of a type II toxin-antitoxin (TA) system. An RNase (By similarity). Upon expression in M.smegmatis inhibits colony formation. Its toxic effect is neutralized by coexpression with cognate antitoxin VapB46.
Belongs to the drug/metabolite transporter (DMT) superfamily. Small multidrug resistance (SMR) (TC 2.A.7.1) family. Mmr subfamily.
Multidrug efflux pump. Confers resistance to tetraphenylphosphonium (TPP), erythromycin, ethidium bromide, acriflavine, safranin O, pyronin Y and methyl viologen.
Belongs to the glycosyl hydrolase 57 family.
Catalyzes the formation of branch points in alpha-glucans by cleavage of an alpha-1,4 glycosidic bond and subsequent transfer of the cleaved-off oligosaccharide to a new alpha-1,6 position (Probable). Is probably involved in the biosynthesis of 6-O-methylglucosyl lipopolysaccharides (MGLP).
Belongs to the enoyl-CoA hydratase/isomerase family. MenB subfamily.
Converts o-succinylbenzoyl-CoA (OSB-CoA) to 1,4-dihydroxy-2-naphthoyl-CoA (DHNA-CoA).
Belongs to the bacterial ribosomal protein bL9 family.
Belongs to the class-IV pyridoxal-phosphate-dependent aminotransferase family.
Catalyzes the reversible transfers of an amino group from glutamate to the alpha-ketoacid of the respective amino acid in the final step in the biosynthesis of branchedchain amino acids. The amino acids can be ranked in the following order with respect to their efficiency as amino donor: Leu > Ile > Val.
Inbibited by ammonium sulfate at millimolar concentrations and by O-benzylhydroxylamine (Obe).
Contains a conserved PPE N-terminal domain and a variable C-terminal domain (PubMed:31375544). The C-terminal region includes a SH3-like region, a leucine zipper DNA-binding motif and a functional nuclear localization signal (NLS) (PubMed:28071726, PubMed:31375544).
Inhibits nitric oxide (NO) production in activated macrophages (PubMed:23448669, PubMed:28071726). Acts by inhibiting expression of the host inducible nitric oxide synthase (iNOS) (PubMed:28071726). PPE2 is translocated into the host macrophage nucleus, where it interacts with a GATA-binding site overlapping with the TATA box of NOS2 (iNOS) promoter, and strongly inhibits NOS2 gene transcription (PubMed:28071726). Reduction in NO production in turn facilitates intracellular survival of the bacilli inside the macrophage (PubMed:28071726). In addition, disrupts the assembly of NADPH oxidase complex, which inhibits NADPH oxidase-mediated reactive oxygen species (ROS) generation in macrophages and favors M.tuberculosis survival (PubMed:31375544). Acts by interacting with NCF2, the cytosolic subunit of NADPH oxidase, and preventing translocation of NCF2 and NCF1 to the membrane, which causes a reduction of the functional assembly of NADPH oxidase complex and a decrease in NADPH oxidase activity (PubMed:31375544).
Shows a strong immunoreactivity toward tuberculosis patient sera compared to that of BCG-vaccinated controls. Could be an attractive candidate for serodiagnosis to discriminate patients with active tuberculosis from BCG-vaccinated individuals (PubMed:23827809, PubMed:26364913). Could diagnose both pulmonary and extrapulmonary tuberculosis cases (PubMed:23827809). However, it has lower sensitivity to detect smear negative and extrapulmonary cases as compared to PPE17/Rv1168c (PubMed:26364913).
Antitoxin component of a type II toxin-antitoxin (TA) system. Upon expression in E.coli neutralizes the toxic effect of cognate toxin VapC20.
Belongs to the DyP-type peroxidase family.
Cargo of a type 1 encapsulin nanocompartment in situ; this cargo protects against oxidative stress at low pH. When expressed in the cytoplasm (absence of the encapsulin shell gene) it is almost as protective as the intact nanocompartment; its encapsulation has a modest yet significant effect on protection against oxidative stress at low pH (PubMed:34751132). A heme-dependent peroxidase, it probably does not have deferrochelatase activity. Converts guaiacol and H2O2 to tetraguaiacol, also acts on 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS). Retains peroxidase activity when encapsulated but has a reduced set of substrates; acts on ABTS but not guaiacol (PubMed:24855650, PubMed:34751132).
Homotetramer, presumably also in the encapsulin nanocompartment.
No change in ability to grow on an exogenous siderophore (mycobactin), suggesting it does not have an iron-chelating function (PubMed:24855650). A double dyp-enc deletion mutant cannot produce encapsulin nanocompartments, cells are highly sensitive to H2O2 at pH 4.5 (mimics growth in the phagolysosome), mutants exhibit significant dysregulation of redox homeostasis, survive less well in C57BL/6 mouse-derived bone marrow cells and are more sensitive to pyrazinamide treatment in infected BALB/C mice (PubMed:34751132).
Tetramer binds heme in a 1:1 ratio (PubMed:24855650). Addition of hemin to purified protein yields a tetrameric protein (Probable).
The C-terminus (residues 312-335) targets the protein to the encapsulin nanocompartment.
The initiator methionine may be further upstream making the sequence a precursor.
Constitutes a host TLR2 agonist (toll-like receptor), shown experimentally for human and mouse (PubMed:19362712). In host cells full-length (acylated) protein acts as a TLR2 agonist, inducing human and murine macrophages to produce cytokines, inducing murine dendritic cell maturation and cytokine production and inhibiting antibody processing in murine macrophages (PubMed:16785538). Binds diacylated phosphatidyl-myo-inositol mannosides (PIMs) (PubMed:20694006). Does not induce murine macrophage apoptosis or necrosis (PubMed:16785538). Non-acylated protein does not act as a TLR2 agonist (PubMed:20694006). Requires only host TLR2 as receptors to elicit host response in mouse, although TLR6 may play a redundant role, also requires CD14 and CD16 as accessory receptors (PubMed:19362712).
Modified by Lgt on Cys-25 with an S-linked diacylglycerol, signal peptide is removed by LspA, Cys-25 is further modifed with an amide group on the amino group by Lnt yielding a triacylated protein (PubMed:20694006). Upon expression in M.smegmatis non-glycosylated form and glycosylated forms are detected (by concanavalin A binding); when only the mature sequence is expressed from mutated protein only the non-glycosylated form is detected (PubMed:16785538).
Expressed in log phase cells (at protein level). Induced by rifampicin treatment. Expressed in human macrophages 110 hours after infection. Induced in the lungs of mice infected for 4 weeks. A member of the relBE operon.
In combination with RelB represses its own promoter. Has been seen to bind DNA in complex with cognate antitoxin RelB but not alone.
Interacts with cognate antitoxin RelB, which neutralizes the toxin. Also interacts with non-cognate antitoxin RelF in vitro, in M.smegmatis coexpression of these 2 genes increases the toxicity of RelE.
No visible phenotype in culture or upon infection of mice.
Toxic component of a type II toxin-antitoxin (TA) system. Has RNase activity (By similarity). Overexpression in M.tuberculosis or M.smegmatis inhibits colony formation in a bacteriostatic rather than bacteriocidal fashion. Its toxic effect is neutralized by coexpression with cognate antitoxin RelB (shown only for M.smegmatis).
Belongs to the ribonucleoside diphosphate reductase large chain family.
Provides the precursors necessary for DNA synthesis. Catalyzes the biosynthesis of deoxyribonucleotides from the corresponding ribonucleotides. When coexpressed in E.coli with nrdF2 the 2 proteins complement a temperature-sensitive E.coli mutant, however coexpression with nrdF1 does not complement.
Tetramer of two alpha and two beta subunits (Probable). Co-immunoprecipitates with DarG in the presence and absence of darT (PubMed:32634279).
Under complex allosteric control mediated by deoxynucleoside triphosphates and ATP binding. The type of nucleotide bound at the specificity site determines substrate preference. It seems probable that ATP makes the enzyme reduce CDP and UDP, dGTP favors ADP reduction and dTTP favors GDP reduction (By similarity). CDP reduction is stimulated by dATP.
Catalyzes the reversible oxidation of 3-phospho-D-glycerate to 3-phosphonooxypyruvate, the first step of the phosphorylated L-serine biosynthesis pathway. Also catalyzes the reversible oxidation of 2-hydroxyglutarate to 2-oxoglutarate.
Belongs to the succinate/malate CoA ligase alpha subunit family.
Heterotetramer of two alpha and two beta subunits.
Succinyl-CoA synthetase functions in the citric acid cycle (TCA), coupling the hydrolysis of succinyl-CoA to the synthesis of either ATP or GTP and thus represents the only step of substrate-level phosphorylation in the TCA. The alpha subunit of the enzyme binds the substrates coenzyme A and phosphate, while succinate binding and nucleotide specificity is provided by the beta subunit.
Contains an N-terminal DNA-binding domain and a C-terminal ligand binding pocket.
Negatively regulates the expression of sulfate ester dioxygenase Rv3406 and its own expression (PubMed:25427196, PubMed:29395080). Binds specifically to the inverted repeat sequence of the intergenic region between Rv3405c and Rv3406 (PubMed:29395080).
Specifically binds to tetracycline, which leads to a conformational change in the structure of the protein and inhibits the DNA binding activity.
Catalyzes the conversion of a double bond to a cyclopropane ring at the distal position of an alpha mycolic acid via the transfer of a methylene group from S-adenosyl-L-methionine. Cyclopropanated mycolic acids are key factors participating in cell envelope permeability, host immunomodulation and persistence.
Essential for cell growth and peptidoglycan synthesis.
Homodimer. Interacts with the FHA domain of FhaA.
In the N-terminal section; belongs to the MurJ/MviN family.
Phosphorylated by PknB. Phosphorylation recruits FhaA.
Probably regulated via interaction with FhaA.
The extendend C-terminal region contains a kinase-like region, which encodes a catalytically inactive pseudokinase, and an extracellular region reminiscent of carbohydrate-binding proteins.
Cells lacking this gene result in an increased permeability and an altered cell wall.
Involved in the biosynthesis of the arabinogalactan (AG) region of the mycolylarabinogalactan-peptidoglycan (mAGP) complex, an essential component of the mycobacterial cell wall. Catalyzes the addition of an arabinofuranosyl (Araf) residue from the sugar donor decaprenyl-phospho-arabinose (DPA) on the C-3 of an alpha-(1->5)-linked Araf from the arabinan backbone of AG. It can also use (Z,Z)-farnesylphosphoryl D-arabinose (Z-FPA), and to a lesser extent (E,E,Z,Z,Z,Z)-heptaprenylphosphoryl D-arabinose (Z-HPA) and (Z)-nerylphosphoryl D-arabinose (Z-NPA) as sugar donors.
Belongs to the oxygen-dependent FAD-linked oxidoreductase family.
In contrast to mammalian L-gulono-1,4-lactone oxidases, the ortholog in M.tuberculosis is not a flavoenzyme.
Is completely inhibited by EDTA, N-ethylmaleimide, Cu(2+), Zn(2+), and potassium cyanide in vitro. Mg(2+) and Ca(2+) have no effect on the dehydrogenase activity, and 1 mm Mn(2+) slightly inhibit the enzyme (21% inhibition).
Oxidizes L-gulono-1,4-lactone to L-xylo-hexulonolactone which spontaneously isomerizes to L-ascorbate. Can use both cytochrome c and phenazine methosulfate as exogenous electron acceptors, but molecular oxygen does not serve as a substrate. Is very specific for the L-gulono-1,4-lactone substrate, since it cannot oxidize L-galactono-1,4-lactone, D-glucurono-3,6-lactone, D-glucuronate, D-arabinose, or D-xylose.
Belongs to the dihydrofolate reductase family.
Inhibited by isoniazid metabolites. The prodrug isoniazid is metabolized to isoniazid-NADP adducts that inhibit the enzyme at subnanomolar concentration.
Key enzyme in folate metabolism. Catalyzes an essential reaction for de novo glycine and purine synthesis, and for DNA precursor synthesis.
Belongs to the class-II pyridoxal-phosphate-dependent aminotransferase family. Histidinol-phosphate aminotransferase subfamily.
Belongs to the adenylyl cyclase class-4/guanylyl cyclase family.
Catalyzes the activation of medium/long-chain fatty acids as acyl-coenzyme A (acyl-CoA) (PubMed:15984864, PubMed:19182784, PubMed:25490545). May play a role in the uptake of fatty acids by trapping them metabolically as CoA esters (PubMed:25490545). May also play an important role in the channeling of fatty acids into triacylglycerol (TAG) for use by Mycobacterium during its dormancy (PubMed:25490545).
Deletion mutant displays a diminished ability to synthesize acyl-coenzyme A in cell-free extracts. Deletion of the gene results in a significant decrease in the accumulation of intracellular triacylglycerol (TAG) in Mycobacterium under dormancy-inducing conditions in vitro.
Expression is significantly increased during in vitro dormancy (at protein level).
Stimulates fatty acid uptake in E.coli cells.
Induced in response to low levels of nitric oxide (NO).
Member of the two-component regulatory system PrrB/PrrA that is involved specifically in early intracellular multiplication of Mycobacterium and is essential for its viability (PubMed:11953357, PubMed:22081401). Functions as a sensor protein kinase which is autophosphorylated at a histidine residue and transfers its phosphate group to the conserved aspartic acid residue in the regulatory domain of PrrA (PubMed:14702417, PubMed:29101285). In turn, PrrA binds to the upstream promoter regions of target genes including itself to positively regulate their expression (PubMed:14702417).
Could be involved in fluoroquinolones efflux.
Belongs to the Cob(I)alamin adenosyltransferase family.
Exonuclease that cleaves single-stranded 3' overhangs of double-stranded RNA. Has no activity with 5' overhangs. Has negligible endonuclease activity. Can bind ATP, dATP and AMP (in vitro); the nucleotide occupies the predicted substrate binding site.
Member of the DEDD group of RNAses that are characterized by the presence of four acidic residues in the active site. These residues are conserved even when the proteins have highly divergent sequences. Has high structural similarity to RNase T despite very low sequence identity.
Autophosphorylated (PubMed:15967413, PubMed:16739134, PubMed:17242402). Dephosphorylated by PstP (PubMed:15967413).
Dimerization activates the kinase domain of unphosphorylated PknD via an allosteric mechanism, triggering autophosphorylation and phosphorylation of target proteins. Phosphorylated PknD is fully active even in the absence of dimerization.
Increased expression after 3 hours of phosphate starvation, no protein detected after 24 hours phosphate starvation (at protein level). Part of the pstS2-pknD operon.
Key microbial factor required for central nervous system tuberculosis. Required for invasion of host brain endothelia, but not macrophages, lung epithelia or other endothelia.
No growth phenotype in phosphate-rich medium (3.6 mM Pi), in restricted medium (Sauton) grows better than wild-type but in phosphate-free Sauton medium dies faster than wild-type when pre-exposed to starvation.
Part of a signaling pathway that enables adaptation to osmotic stress through cell wall remodeling and virulence factor production (PubMed:24309377). Phosphorylates the osmosensory protein OprA, which inhibits binding of OprA to Rv2638, leading to the regulation of osmotically regulated genes, including the ESX-1-associated virulence factor espA (PubMed:17411339, PubMed:17242402, PubMed:24309377). In addition, directly phosphorylates the alternative sigma factor SigF and its regulator, Rv1364c, which regulates the SigF-Rv1364c interaction (PubMed:30642988). Can also phosphorylate the FHA domain of Rv1747 (PubMed:15987910).
Belongs to the class-II pyridoxal-phosphate-dependent aminotransferase family.
May catalyze the transamination reaction in phenylalanine biosynthesis.
Catalyzes the conjugation of the 1'-hydroxyl group of D-myo-inositol-3-phosphate (also named L-myo-inositol-1-phosphate) with a lipid tail of cytidine diphosphate diacylglycerol (CDP-DAG), forming phosphatidylinositol phosphate (PIP) and CMP. PIP is a precursor of phosphatidylinositol (PI) which is an essential lipid for mycobacteria required for formation of their cell wall.
Contains a di-nuclear catalytic Mg(2+) center.
M.tuberculosis PgsA1 has been identified as a promising candidate for drug development because of its vital role in growth and proliferation of the pathogen as well as the differences between eukaryotic and mycobacterial PI biosynthesis pathways.
Was orginally thought to be a phosphatidylinositol (PI) synthase.
Belongs to the class II aldolase/RraA-like family.
Catalyzes the aldol cleavage of 4-hydroxy-4-methyl-2-oxoglutarate (HMG) into 2 molecules of pyruvate. Also contains a secondary oxaloacetate (OAA) decarboxylase activity due to the common pyruvate enolate transition state formed following C-C bond cleavage in the retro-aldol and decarboxylation reactions (By similarity).
Originally described as a SAM-dependent methyltransferase (PubMed:9634230), the crystal structure does not resemble other known SAM-dependent methyltransferases. The structure does resemble the phosphohistidine domain of several phosphotransfer system proteins. The protein does not bind S-adenosylmethionine cofactor or potential methyltransferase substrate molecules.
Inhibited by econazole, clotrimazole and miconazole.
Involved in the utilization of cholesterol as the sole carbon and energy source by degrading the side chain during infection (PubMed:20843794). Primarily catalyzes the sequential oxidation of the terminal methyl of cholest-4-en-3-one into (25R)-26-hydroxycholest-4-en-3-one (alcohol), (25R)-26-oxocholest-4-en-3-one (aldehyde), to finally yield the carboxylic acid (25R)-3-oxocholest-4-en-26-oate (PubMed:20843794, PubMed:20889498). In vitro, Cyp142 catalyzes with equal preference the oxidation of both (25R)- and (25S)-26-hydroxycholest-4-en-3-one diastereomers to the corresponding carboxylic acid which is a prerequisite for entry into the beta-oxidation pathway (PubMed:20843794). Also able to sequentially oxidize cholesterol itself, not only cholest-4-en-3-one (PubMed:20843794).
Catalyzes the ATP-dependent amidation of the two carboxylate groups at positions a and c of hydrogenobyrinate, using either L-glutamine or ammonia as the nitrogen source.
Comprises of two domains. The C-terminal domain contains the binding site for glutamine and catalyzes the hydrolysis of this substrate to glutamate and ammonia. The N-terminal domain is anticipated to bind ATP and hydrogenobyrinate and catalyzes the ultimate synthesis of the diamide product. The ammonia produced via the glutaminase domain is probably translocated to the adjacent domain via a molecular tunnel, where it reacts with an activated intermediate.
The a and c carboxylates of hydrogenobyrinate are activated for nucleophilic attack via formation of a phosphorylated intermediate by ATP. CobB catalyzes first the amidation of the c-carboxylate, and then that of the a-carboxylate.
Belongs to the anthranilate synthase component I family. Salicylate synthase subfamily.
Cells lacking this gene display a reduction in salicylic acid biosynthesis and a drastic decrease in production of mycobactin compared with the wild-type strain.
Induced by iron starvation conditions and during infection of human THP-1 macrophages. Transcriptionally repressed by IdeR and iron.
Inhibited by (E)-3-(1-carboxyprop-1-enyloxy)-2-hydroxybenzoic acid (AMT), 3-(1-carboxy-2-phenylvinyloxy)-2-hydroxybenzoic acid (phenyl-AMT), 3-(1-carboxy-3-methylbut-1-enyloxy)-2-hydroxybenzoic acid, 3-(1-carboxybut-1-enyloxy)-2-hydroxybenzoic acid (ethyl-AMT), 3-(1-carboxyprop-1-enyloxy)-2-hydroxybenzoic acid (methyl-AMT), 3-(1-carboxy-2-cyclopropylethenyloxy)-2-hydroxybenzoic acid (cyclopropyl-AMT) and 3-(1-carboxy-3-methylbut-1-enyloxy)-2-hydroxybenzoic acid (isopropyl-AMT).
Involved in the incorporation of salicylate into the virulence-conferring salicylate-based siderophore mycobactin. Catalyzes the initial conversion of chorismate to yield the intermediate isochorismate (isochorismate synthase activity), and the subsequent elimination of the enolpyruvyl side chain to give salicylate (isochorismate pyruvate-lyase activity). In the absence of magnesium, MbtI displays a chorismate mutase activity and converts chorismate to prephenate.
Consists of a catalytic RNA component (M1 or rnpB) and a protein subunit.
RNaseP catalyzes the removal of the 5'-leader sequence from pre-tRNA to produce the mature 5'-terminus. It can also cleave other RNA substrates such as 4.5S RNA. The protein component plays an auxiliary but essential role in vivo by binding to the 5'-leader sequence and broadening the substrate specificity of the ribozyme.
Belongs to the outer membrane OOP (TC 1.B.6) superfamily. ArfA family.
Controversial; may form oligomers (PubMed:17573469, PubMed:21117233), or not (PubMed:20199110, PubMed:21117233).
Induced at low pH (at protein level), upon infecting a human monocytic cell line and in murine bone marrow macrophages. Part of the arfA-arfB-arfC operon. Maximal expression of ArfA requires the full operon.
May bind Zn(2+) via residues in the BON domain.
Probably plays a role in ammonia secretion that neutralizes the medium at pH 5.5, although it does not play a direct role in ammonia transport. The OmpA-like domain (196-326) binds M.tuberculosis peptidoglycan. Overexpression in M.bovis or M.smegmatis gives channels with average conductance value of 1,600 +/- 100 pS, but this may not be physiologically relevant.
Significantly impaired growth at pH 5.5, reduced uptake of serine at both pH 7.2 and 5.5. Reduces growth in macrophages and in intravenously infected mice (PubMed:12366842). But the same mutant has very little effect when studied by another group (PubMed:21410778). Upon operon disruption no reduction of serine uptake at pH 6.9, no visible effect on outer membrane permeability, however severe delays in ammonia secretion, medium pH neutralization and growth also occur at pH 5.5 (PubMed:21410778).
Acyl-carrier protein (ACP) involved in the biosynthesis of a unique class of isonitrile lipopeptides (INLPs) that seem to function as virulence factors in M.tuberculosis and to play a role in metal acquisition (PubMed:28634299). Is the dedicated ACP for the loading of activated acyl groups catalyzed by FadD10 (PubMed:22451903, PubMed:23625916, PubMed:28634299).
Autophosphorylated. Thr-173 is required for autophosphorylation and transphosphorylation activities. Thr-175 is not necessary for autophosphorylation activity, but is required for full kinase activity.
Phosphorylates the DNA-binding protein Rv2175c. May be involved in the regulation of cell division and cell envelope biosynthesis.
Required for regulated cell division, cell wall synthesis and the maintenance of cell shape.
Deletion mutant does not show any difference in intracellular survival and oxidative stress responses.
Plays an important role in mycobacterial pathogenesis in the context of innate immunity. Aids host cell invasion and intracellular bacillary persistence. Increases host oxidative stress response, leading to genomic instability and decrease in macrophage viability. Also induces autophagy and modulates the immune function of macrophages.
Deletion mutant does not grow on cholesterol, but grows as the wild-type on glycerol. In the presence of cholesterol, disruption mutant accumulates 5OH-HIC-CoA.
Involved in the final steps of cholesterol and steroid degradation (PubMed:28377529). Probably catalyzes the introduction of a double bound into the C ring of 5OH-HIC-CoA, leading to the formation of (5R,7aS)-5-hydroxy-7a-methyl-1-oxo-3,5,6,7-tetrahydro-2H-indene-4-carboxyl-CoA (Probable).
Belongs to the bacterial phospholipase C family.
Expression is induced in vitro in the presence of phosphatidylcholine. Also induced upon infection of THP-1 macrophages.
Involved in virulence (PubMed:20736081). Induces cytotoxic effects on mouse macrophage cell lines, via direct or indirect enzymatic hydrolysis of cell membrane phospholipids (PubMed:20736081). Hydrolyzes phosphatidylcholine and sphingomyelin (PubMed:8757862, PubMed:20736081). Does not have hemolytic activity (PubMed:20736081).
Polymorphism was discovered in the phospholipase plcA/B/C region.
Predicted to be exported by the Tat system. The position of the signal peptide cleavage has not been experimentally proven.
An RNA-guided dsDNA endonuclease. When guided by an RNA derived from the right-end element of its insertion sequence element (IS), cleaves DNA downstream of the transposon-associated motif (TAM). Cleaves supercoiled and linear DNA in a staggered manner 15-21 bases from the TAM yielding 5'-overhangs. Binds reRNA, an approximately 150 nucleotide base sRNA derived from the 3' end of its own gene, the right end (RE) of the insertion sequence (IS) plus sequence downstream of the IS.
In the C-terminal section; belongs to the transposase 35 family.
In the N-terminal section; belongs to the transposase 2 family.
Can complement rsmD-deleted E.coli cells.
Forms a two-domain structure with a short hairpin domain at the N-terminus and a large C-terminal domain with the S-adenosylmethionine-MT fold (PubMed:21474448). The N-terminal domain helps target recognition and is important for binding RNA and DNA substrates (PubMed:21474448). The C-terminal residues dictate the nuclear localization (PubMed:25824946).
Monomer (PubMed:21474448, PubMed:32888991). Within host cells, interacts with histones H3 and H4 (PubMed:25824946).
Phosphorylated (PubMed:25824946). In vitro, is phosphorylated by multiple mycobacterial kinases (PknA, PknB, PknD, PknH, PknJ and PknL) and by mammalian kinases (PubMed:25824946).
Phosphorylation stimulates DNA binding and DNA methyltransferase activity, but does not influence secretion (PubMed:25824946). Exists in a compact, folded state at both pH 7.5 and pH 4.0, the acidic pH that mycobacterial proteins may encounter in the host lysosomal or endosomal compartments (PubMed:32888991). The protein is more compact and stable at pH 4.0 than pH 7.5 (PubMed:32888991).
SAM-dependent methyltransferase that binds both to RNA and DNA (PubMed:21474448). Specifically methylates the guanine in position 966 of 16S rRNA in the 30S particle (PubMed:21474448). In addition, can methylate and modulate host cellular DNA within an infected mammalian cell, altering the host epigenetic machinery (PubMed:25824946). Binds to specific host DNA sequences and methylates cytosines predominantly in a non-CpG context (PubMed:25824946).
Binds fibronectin. May contribute to pathogenicity.
Belongs to the bacterial ribosomal protein bL33 family.
Antitoxin component of a type II toxin-antitoxin (TA) system. Upon expression in M.smegmatis neutralizes the effect of cognate toxin VapC22.
Putative antitoxin component of a type II toxin-antitoxin (TA) system; however the expected toxin coding sequence is not found adjacent to this gene.
Belongs to the gamma-glutamyltransferase family.
Cleaved by autocatalysis into a large and a small subunit.
This enzyme consists of two polypeptide chains, which are synthesized in precursor form from a single polypeptide.
Binds calcium ions. May play a role in sequestering additional small ligands.
Dodecin family members from different organisms have non-identical ligand binding specificity.
Homododecamer; 12 subunits assemble to form a hollow sphere with a diameter of about 75 Angstroms. Calcium ions are bound at the interface between three subunits.
Up-regulated 12-fold 7 days after infection of human macrophages.
Part of the twin-arginine translocation (Tat) system that transports large folded proteins containing a characteristic twin-arginine motif in their signal peptide across membranes. TatA could form the protein-conducting channel of the Tat system.
ATPase that binds to both the 70S ribosome and the 50S ribosomal subunit in a nucleotide-independent manner.
Belongs to the TRAFAC class OBG-HflX-like GTPase superfamily. OBG GTPase family. YchF/OLA1 subfamily.
Belongs to the mycobacterial Pra family.
Belongs to the vitamin-B12 dependent methionine synthase family.
Catalyzes the transfer of a methyl group from methyl-cobalamin to homocysteine, yielding enzyme-bound cob(I)alamin and methionine. Subsequently, remethylates the cofactor using methyltetrahydrofolate (By similarity).
L-homocysteine is bound via the zinc atom.
Modular enzyme with four functionally distinct domains. The isolated Hcy-binding domain catalyzes methyl transfer from free methylcobalamin to homocysteine. The Hcy-binding domain in association with the pterin-binding domain catalyzes the methylation of cob(I)alamin by methyltetrahydrofolate and the methylation of homocysteine. The B12-binding domain binds the cofactor. The AdoMet activation domain binds S-adenosyl-L-methionine. Under aerobic conditions cob(I)alamin can be converted to inactive cob(II)alamin. Reductive methylation by S-adenosyl-L-methionine and flavodoxin regenerates methylcobalamin (By similarity).
Forms a tight 1:1 complex with EsxV. The complex is destabilized at low pH. Unfolding of the proteins is required for dissociation of the complex and membrane binding.
Factor that stimulates resuscitation of dormant cells. Has peptidoglycan (PG) hydrolytic activity. Active in the pM concentration range. Has little to no effect on actively-growing cells. PG fragments could either directly activate the resuscitation pathway of dormant bacteria or serve as a substrate for endogenous Rpf, resulting in low molecular weight products with resuscitation activity.
Not essential, disruption of rpfE alone has no effect on growth or survival in liquid culture, nor in mouse infection models, although colony size is reduced. Alterations in gene expression are seen. All 5 genes in this family can be deleted without affecting growth in culture, however quadruple deletion mutants (rpfA-rpfC-rpfB-rpfE or rpfA-rpfC-rpfD-rpfE) are not able to resuscitate spontaneously in the presence or absence of O(2), and are attenuated in a mouse infection model.
Stimulates growth of stationary phase M.bovis (a slow-growing Mycobacterium), reduces the lag phase of diluted fast-growers M.smegmatis and Micrococcus luteus. Sequential gene disruption indicates RpfB and RpfE are higher than RpfD and RpfC in functional hierarchy.
Catalyzes a 2-step reaction, involving the ATP-dependent carboxylation of the covalently attached biotin in the first step and the transfer of the carboxyl group to pyruvate in the second.
Belongs to the AAA ATPase family. RarA/MGS1/WRNIP1 subfamily.
Belongs to the pterin-4-alpha-carbinolamine dehydratase family.
Catalyzes the phosphorylation of hydroxymethylpyrimidine phosphate (HMP-P) to HMP-PP, and of HMP to HMP-P.
A helicase/nuclease that prepares dsDNA breaks (DSB) for recombinational DNA repair. Binds to DSBs and unwinds DNA via a highly rapid and processive ATP-dependent bidirectional helicase activity. Unwinds dsDNA until it encounters a Chi (crossover hotspot instigator) sequence from the 3' direction. Cuts ssDNA a few nucleotides 3' to the Chi site. The properties and activities of the enzyme are changed at Chi. The Chi-altered holoenzyme produces a long 3'-ssDNA overhang and facilitates RecA-binding to the ssDNA for homologous DNA recombination and repair. Holoenzyme degrades any linearized DNA that is unable to undergo homologous recombination. In the holoenzyme this subunit recognizes the wild-type Chi sequence, and when added to isolated RecB increases its ATP-dependent helicase processivity.
Heterotrimer of RecB, RecC and RecD. All subunits contribute to DNA-binding.
Associates with the EF-Tu.GDP complex and induces the exchange of GDP to GTP. It remains bound to the aminoacyl-tRNA.EF-Tu.GTP complex up to the GTP hydrolysis stage on the ribosome (By similarity).
Belongs to the peroxiredoxin family. Tpx subfamily.
The active site is a conserved redox-active cysteine residue, the peroxidatic cysteine (C(P)), which makes the nucleophilic attack on the peroxide substrate. The peroxide oxidizes the C(P)-SH to cysteine sulfenic acid (C(P)-SOH), which then reacts with another cysteine residue, the resolving cysteine (C(R)), to form a disulfide bridge. The disulfide is subsequently reduced by an appropriate electron donor to complete the catalytic cycle. In this atypical 2-Cys peroxiredoxin, C(R) is present in the same subunit to form an intramolecular disulfide. The disulfide is subsequently reduced by thioredoxin (TrxB and TrxC).
Thiol-specific peroxidase that catalyzes the reduction of hydrogen peroxide and organic hydroperoxides to water and alcohols, respectively. Plays a role in cell protection against oxidative stress by detoxifying peroxides.
Binds 1 divalent metal ion per subunit. Mn(2+) is the most efficient metal, but can also use Co(2+), Ca(2+) and Mg(2+).
Catabolizes diadenosine 5',5'''-P1,P4-tetraphosphate (Ap4A) into ADP and ATP. It does not catalyze the reverse phosphorolysis reaction. The optimum substrates are dinucleoside polyphosphates containing four or five phosphate residues.
Rv2613c is a unique Ap4A phosphorylase with a primary structure homologous to that of Ap4A hydrolase rather than typical Ap4A phosphorylases. Was identified as a high-confidence drug target.
Belongs to the lyase 1 family. Adenylosuccinate lyase subfamily.
Binding to DNA is inhibited by nickel and cobalt ions.
KmtR has tighter affinities for nickel and cobalt than NmtR.
Represses expression of Rv2025c and its own expression. Acts by binding to the promoter regions.
Belongs to the glutamine synthetase family.
Catalyzes the hydrolysis of both intracellular and extracellular triacylglycerol (TAG) (PubMed:16354661, PubMed:17938218, PubMed:21471225, PubMed:29986895, PubMed:31034693). In vitro, can also hydrolyze p-nitrophenyl (pNP) esters with various chain lengths, including pNP-acetate (C2), pNP-butyrate (C4), pNP-caproate (C6), pNP-caprylate (C8), pNP-laurate (C12), pNP-myristate (C14), pNP-palmitate (C16) and pNP-stearate (C18) (PubMed:23684389, PubMed:26398213). Also hydrolyzes monobutyrin, tributyrin and trioctanoin (PubMed:29986895). Overexpression results in increase of virulence characterized by reduced survival of infected mouse and increased burden of bacilli in the lungs (PubMed:24631199). Hydrolyzes internal or host-derived TAG depending on its localization (PubMed:29986895).
Cells lacking this gene show a drastically diminished ability to hydrolyze stored long-chain triacylglycerol.
Cleavage by PecA does not affect surface localization and lipase activity.
Contains an N-terminal PE domain and a C-terminal catalytic domain, which are connected by a linker region (PubMed:17938218). The PE domain is involved in aggregation and activity regulation (PubMed:26270534). It is also required for ESX-5-dependent secretion (PubMed:21471225). After transport, the PE domain is removed by proteolytic cleavage (PubMed:21471225).
Hydrolyzes TAG that accumulates within mycobacterial intracytosolic lipid inclusions (ILI) (PubMed:29986895). Probably responsible for the utilization of stored long-chain TAG during the dormancy and reactivation stages of the pathogen (PubMed:16354661).
In the C-terminal section; belongs to the 'GDXG' lipolytic enzyme family.
In the N-terminal section; belongs to the mycobacterial PE family. PGRS subfamily.
Inhibited by diethyl-p-nitrophenyl phosphate (E-600) at 0.5 uM, by phenylmethanesulfonyl fluoride at 5 mM and by polyethylene glycol sorbitan monolaurate (Tween 20). Also inhibited by CaCl(2), CoCl(2), MnCl(2), ZnCl(2) and MgCl(2) (PubMed:16354661). Inhibited by several hydrazides compounds (PubMed:23684389). Stimulated slightly by SDS at concentrations up to 2 mM, above which the activity is severely inhibited (PubMed:16354661).
PE domain down-regulates lipase activity.
Upon export, the PE domain is removed by proteolytic cleavage (PubMed:21471225, PubMed:31662454). Cleavage occurs at the cell surface and is not required for secretion (PubMed:31662454). Cleaved after Gly-149 by the aspartic protease PecA. May also be cleaved before Leu-98 and after Ala-136 (PubMed:31662454).
Toxic component of a type II toxin-antitoxin (TA) system. An RNase (By similarity). Upon expression in M.smegmatis inhibits colony formation. Its toxic effect is neutralized by coexpression with cognate antitoxin VapB28.
Belongs to the UbiA prenyltransferase family.
Divalent metal cations such as Mg(2+), Mn(2+) or Ca(2+).
Involved in the biosynthesis of decaprenylphosphoryl arabinose (DPA) a precursor for arabinan synthesis in mycobacterial cell wall biosynthesis. Catalyzes the transfer of a 5-phosphoribosyl residue from phosphoribose diphosphate (pRpp) to decaprenyl phosphate (DP) to form decaprenylphosphoryl-5-phosphoribose (DPPR). The enzyme favors polyprenyl phosphate with 50-60 carbon atoms uses C-75 polyprenyl phosphate less efficiently than C-50 or C-60.
Involved in the final steps of cholesterol and steroid degradation (PubMed:28377529). Catalyzes the hydrolytic ring D opening of (7aS)-7a-methyl-1,5-dioxo-2,3,5,6,7,7a-hexahydro-1H-indene-carboxyl-CoA (HIEC-CoA) to (3E)-2-(2-carboxylatoethyl)-3-methyl-6-oxocyclohex-1-ene-1-carboxyl-CoA (COCHEA-CoA) (By similarity).
Belongs to the CobB/CobQ family. CobQ subfamily.
Catalyzes amidations at positions B, D, E, and G on adenosylcobyrinic A,C-diamide. NH(2) groups are provided by glutamine, and one molecule of ATP is hydrogenolyzed for each amidation (By similarity).
Belongs to the universal ribosomal protein uL10 family.
Forms part of the ribosomal stalk, playing a central role in the interaction of the ribosome with GTP-bound translation factors.
Part of the ribosomal stalk of the 50S ribosomal subunit. The N-terminus interacts with L11 and the large rRNA to form the base of the stalk. The C-terminus forms an elongated spine to which L12 dimers bind in a sequential fashion forming a multimeric L10(L12)X complex (By similarity).
Possibly the antitoxin component of a type II toxin-antitoxin (TA) system. Its cognate toxin is VapC44.
Seems to contain an N-terminal exonuclease domain and a C-terminal UvrC-like endonuclease domain.
Deletion mutant shows reduced growth in Sauton's minimal media and is highly sensitive to SDS and copper when grown on solid media (PubMed:23562345). Reduced growth in acidic media (pH 5.5) and under hypoxic conditions, with decreased survival in hypoxia (PubMed:26768127). In vitro, the mutant is attenuated for growth in PMA-activated THP-1 (human) cells (PubMed:23562345). Mutant is extremely resistant to copper and shows increased growth in vivo (PubMed:24549843). In vivo infected guinea pigs exhibited a considerably attenuated infection, and a few animals cleared the infection (PubMed:26768127).
May play an essential role in M.tuberculosis replication and survival inside the host cell.
Belongs to the GMC oxidoreductase family.
Belongs to the PA-phosphatase related phosphoesterase family.
Involved in the biosynthesis of decaprenylphosphoryl arabinose (DPA) a precursor for arabinan synthesis in mycobacterial cell wall biosynthesis. Could be involved in the dephosphorylation of decaprenylphosphoryl-5-phosphoribose (DPPR) to decaprenyl-phospho-ribose (DPR) (By similarity).
Belongs to the RNA methyltransferase TrmD family.
Specifically methylates guanosine-37 in various tRNAs.
Probable antitoxin component of a type II toxin-antitoxin (TA) system. Its putative cognate toxin is VapC38.
Component of the Sec protein translocase complex. Heterotrimer consisting of SecY, SecE and SecG subunits. The heterotrimers can form oligomers, although 1 heterotrimer is thought to be able to translocate proteins. Interacts with the ribosome. Interacts with SecDF, and other proteins may be involved. Interacts with SecA.
Essential subunit of the Sec protein translocation channel SecYEG. Clamps together the 2 halves of SecY. May contact the channel plug during translocation.
Possibly the antitoxin component of a type II toxin-antitoxin (TA) system. Its cognate toxin is VapC45.
Belongs to the ETF alpha-subunit/FixB family.
Belongs to the AB hydrolase superfamily. MetX family.
Transfers an acetyl group from acetyl-CoA to L-homoserine, forming acetyl-L-homoserine.
Belongs to the alpha-IPM synthase/homocitrate synthase family. LeuA type 2 subfamily.
Catalyzes the condensation of the acetyl group of acetyl-CoA with 3-methyl-2-oxobutanoate (alpha-ketoisovalerate) to form 3-carboxy-3-hydroxy-4-methylpentanoate (2-isopropylmalate) (PubMed:11914056, PubMed:16846242). Active on small alpha-keto acids such as 3-methyl-2-oxobutanoate, pyruvate, alpha-ketovalerate, and alpha-ketobutyrate; only uses acetyl-CoA (PubMed:16846242). Complements an E.coli deletion (PubMed:22352945).
Has two major domains which are separated by two small subdomains, that are themselves joined by a flexible hinge. The N-terminal catalytic domain forms an (alpha/beta)8 TIM barrel and binds substrate (3-methyl-2-oxobutanoate) and Zn(2+). Subdomains I and II (separated by a flexible linker) make a three-helix bundle that packs against the C-terminal domain. The C-terminal regulatory domain includes two variable number tandem repeats (VNTR) in this strain. The regulatory domain binds L-Leu (the pathway end product) in the dimer interface. The individual domains of the monomers swap between monomers (PubMed:15159544). The C-terminus (residues 426-644) is required for condensation of the 2 substrates (PubMed:22352945).
Homodimer (PubMed:11914056, PubMed:16846242, PubMed:15159544). Remains a homodimer in the presence of L-leucine (PubMed:16846242, PubMed:15159544, PubMed:22352945).
In Mycobacteria this gene has a variable number tandem repeat (VNTR); in H37Rv there are 2 repeats, other strains can have up to 6 repeats.
In the different crystal structures Zn(2+), Ni(2+) and Mn(2+) have been detected (PubMed:15159544, Ref.7, PubMed:22352945). The divalent cation used in Chanchaem is not stated (PubMed:11914056). Mg(2+) was used in de Carvalho (PubMed:16846242). A fourth metal ligand is only seen in the truncated enzyme in the absence of substrate (PubMed:22352945).
Antitoxin component of a type II toxin-antitoxin (TA) system. Upon expression in M.smegmatis neutralizes the effect of cognate toxin VapC41.
Belongs to the mandelate racemase/muconate lactonizing enzyme family. MenC type 1 subfamily.
Converts 2-succinyl-6-hydroxy-2,4-cyclohexadiene-1-carboxylate (SHCHC) to 2-succinylbenzoate (OSB).
Catalyzes the sequential condensations of isopentenyl pyrophosphate (IPP) with geranyl diphosphate (GPP) to yield (2E,6E)-farnesyl diphosphate (E,E-FPP), with E,E-FPP to yield geranylgeranyl diphosphate (GGPP) and with GGPP to yield nonaprenyl diphosphate (PubMed:23091471, PubMed:30301210, PubMed:32495977). May also have weak activity with dimethylallyl diphosphate (DMAPP) (PubMed:23091471).
Contains the canonical two aspartate-rich DDxxD motifs, designated as FARM (the first aspartate-rich motif) and SARM (the second aspartate-rich motif). The primary role of the FARM and SARM is the chelation of the divalent magnesium ion cofactors that assist substrate binding and catalysis, but it may also play a role in determining product chain length.
Catalyzes two sequential steps in the biosynthesis of coenzyme A. In the first step cysteine is conjugated to 4'-phosphopantothenate to form 4-phosphopantothenoylcysteine. In the second step the latter compound is decarboxylated to form 4'-phosphopantotheine (By similarity). Required for growth and persistence in mice (PubMed:27676316).
In the C-terminal section; belongs to the PPC synthetase family.
In the N-terminal section; belongs to the HFCD (homo-oligomeric flavin containing Cys decarboxylase) superfamily.
Inhibited by coenzyme A (CoA) and CoA thioesthers (PubMed:33420031). Two related chemical scaffolds that potently inhibit the activity of the CoaB moiety of CoaBC through a cryptic allosteric site that sits in the dimer interface region of the CoaB enzyme were identified (PubMed:33420031).
Transcriptional silencing of this gene leads to growth attenuation and results in a bactericidal phenotype in vitro and in vivo, whether initiated at infection or during either the acute or chronic stages of infection.
Belongs to the class-III pyridoxal-phosphate-dependent aminotransferase family.
Toxic component of a type II toxin-antitoxin (TA) system. An RNase. The cognate antitoxin is VapB23 (By similarity).
Belongs to the ABC-2 integral membrane protein family.
Belongs to the RNA polymerase alpha chain family.
Homodimer. The RNAP catalytic core consists of 2 alpha, 1 beta, 1 beta' and 1 omega subunit. When a sigma factor is associated with the core the holoenzyme is formed, which can initiate transcription.
The N-terminal domain is essential for RNAP assembly and basal transcription, whereas the C-terminal domain is involved in interaction with transcriptional regulators and with upstream promoter elements.
Catalyzes hydrolysis of the D-alanyl-D-alanine dipeptide.
Catalyzes the formation of S-adenosylmethionine (AdoMet) from methionine and ATP. The overall synthetic reaction is composed of two sequential steps, AdoMet formation and the subsequent tripolyphosphate hydrolysis which occurs prior to release of AdoMet from the enzyme.
Involved in transcription antitermination. Required for transcription of ribosomal RNA (rRNA) genes. Binds specifically to the boxA antiterminator sequence of the ribosomal RNA (rrn) operons.
Antitoxin component of a possible type II toxin-antitoxin (TA) system. The cognate toxin is VapC6.
Belongs to the prokaryotic/mitochondrial release factor family.
Methylated by PrmC. Methylation increases the termination efficiency of RF2 (By similarity).
Peptide chain release factor 2 directs the termination of translation in response to the peptide chain termination codons UGA and UAA.
Belongs to the glycogen phosphorylase family.
Phosphorylase is an important allosteric enzyme in carbohydrate metabolism. Enzymes from different sources differ in their regulatory mechanisms and in their natural substrates. However, all known phosphorylases share catalytic and structural properties (By similarity).
Belongs to the CRISPR-associated endonuclease Cas1 family.
Homodimer, forms a heterotetramer with a Cas2 homodimer.
Antitoxin component of a type II toxin-antitoxin (TA) system. Upon expression in M.smegmatis neutralizes the effect of cognate toxin VapC47.
Essential cell division protein that forms a contractile ring structure (Z ring) at the future cell division site. The regulation of the ring assembly controls the timing and the location of cell division. One of the functions of the FtsZ ring is to recruit other cell division proteins to the septum to produce a new cell wall between the dividing cells. Binds GTP and shows GTPase activity.
Homodimer (PubMed:15342249, PubMed:23888039). Polymerizes to form a dynamic ring structure in a strictly GTP-dependent manner. Interacts directly with several other division proteins (By similarity).
Component of the branched-chain alpha-ketoacid dehydrogenase (BCKADH) complex, that catalyzes the overall conversion of branched-chain alpha-ketoacids to acyl-CoA and CO(2).
Heteromer of E1 alpha (BkdA) and beta (BkdB) subunits. Part of the BCKADH complex, consisting of multiple copies of BkdA/BkdB (E1), BkdC (E2) and Lpd (E3).
Up-regulated upon nutrient starvation. Is also highly up-regulated in a DlaT-deficient strain. Part of the bkdABC operon.
Null mutant does not produce SL-1 (PubMed:17259623, PubMed:17592143). Disruption of the gene does not alter the virulence of M.tuberculosis in mice (PubMed:17592143).
Required for the biosynthesis of sulfolipid-1 (SL-1), a major mycobacterial cell wall lipid (PubMed:17259623, PubMed:17592143, PubMed:22194604). Catalyzes the acylation of trehalose-2-sulfate-2'-palmitate (SL659) by adding the (hydroxy)phthioceranoyl group at the 3'-position to yield the diacylated intermediate 2-palmitoyl-3-(C43)-phthioceranyl-alpha, alpha'-D-trehalose-2'-sulfate (SL1278) (PubMed:17592143, PubMed:22194604).
Up-regulated by the PhoP/PhoR two-component system.
Putative monooygenase that might be involved in antibiotic biosynthesis, or may act as reactive oxygen species scavenger that could help in evading host defenses.
Belongs to the methyltransferase superfamily. Tam family.
Catalyzes the S-adenosylmethionine monomethyl esterification of trans-aconitate.
May play a role in the development of protective immune responses.
Zinc phosphodiesterase, which displays some tRNA 3'-processing endonuclease activity. Probably involved in tRNA maturation, by removing a 3'-trailer from precursor tRNA.
To S.violaceus chloramphenicol 3-O phosphotransferase.
Belongs to the aminoglycoside phosphotransferase family.
Catalyzes the ATP-dependent phosphorylation of maltose to maltose 1-phosphate (By similarity). Is involved in a branched alpha-glucan biosynthetic pathway from trehalose, together with TreS, GlgE and GlgB.
An aminopeptidase; acts on free N-terminal amino groups with a very strong preference for Leu in the first position.
Belongs to the peptidase M28 family. M28A subfamily.
Modified by Lgt on Cys-25 with an S-linked diacylglycerol with a mixture of C16 and C19 fatty acids (palmitic and tuberculostearic acid), signal peptide is removed by LspA, modified by Lnt with an amide-linked mixture of C16 and C19 fatty acids, expressed in M.bovis (PubMed:24093492).
In the C-terminal section; belongs to the phosphate acetyltransferase and butyryltransferase family.
In the N-terminal section; belongs to the CobB/CobQ family.
The N-terminal region seems to be important for proper quaternary structure. The C-terminal region contains the substrate-binding site (By similarity).
Contains 12 catalytic domains constituting two modules. Both modules contain a complete set of catalytic and auxiliary domains.
Deletion of the gene completely abolishes the ability of the strain to activate CD1c-restricted T cells (PubMed:15611286). Growth of the mutant is attenuated in mouse alveolar macrophage cell line, and the virulence of the mutant in vivo is highly attenuated in a murine model (PubMed:12819062). Sirakova et al. showed that disruption of the gene causes a drastic decrease in the synthesis of dimycocerosyl phthiocerol (DIM), but Matsunaga et al. demonstrated later that DIM is produced by the disruption mutant (PubMed:12819062, PubMed:15611286).
Forms a large supramolecular assembly mediated through specific interactions between the N- and C-terminus linkers.
Involved in the synthesis of beta-D-mannosyl phosphomycoketide (MPM), an antigenic mycobacterial polyketide (PubMed:15611286, PubMed:18613748). Binds a fatty acyl-CoA as a starter unit, and extends it by five rounds of alternative additions of malonyl-CoA and methylmalonyl-CoA extender units. Depending on the starter unit, the enzyme forms mycoketide-CoAs of different lengths (PubMed:15611286, PubMed:18613748). Shows preference for small-/medium-chain starter fatty acyl substrates (PubMed:18613748). Uses a hybrid modularly iterative mechanism, by forming a supramolecular assembly to perform repetitive cycles of iterations (PubMed:18613748).
The alkane moiety distinguishes these mycobacterial lipid antigens from mammalian mannosyl beta-1-phosphodolichol (MPD) and is necessary for activation of CD1c-restricted T cells.
Conversion of NADPH, generated by peripheral catabolic pathways, to NADH, which can enter the respiratory chain for energy generation.
Belongs to the PNP/UDP phosphorylase family. MtnN subfamily.
Catalyzes the irreversible cleavage of the glycosidic bond in both 5'-methylthioadenosine (MTA) and S-adenosylhomocysteine (SAH/AdoHcy) to adenine and the corresponding thioribose, 5'-methylthioribose and S-ribosylhomocysteine, respectively. Also cleaves 5'-deoxyadenosine, a toxic by-product of radical S-adenosylmethionine (SAM) enzymes, into 5-deoxyribose and adenine.
Belongs to the tetrahydrofolate dehydrogenase/cyclohydrolase family.
Catalyzes the oxidation of 5,10-methylenetetrahydrofolate to 5,10-methenyltetrahydrofolate and then the hydrolysis of 5,10-methenyltetrahydrofolate to 10-formyltetrahydrofolate.
Binds 1 [4Fe-4S] cluster. The cluster is coordinated with 3 cysteines and an exchangeable S-adenosyl-L-methionine.
Belongs to the SAICAR synthetase family.
Toxic component of a type II toxin-antitoxin (TA) system. An RNase. The cognate antitoxin is VapB45.
Able to catalyze the elimination of the C-1 and C-2 hydrogen atoms of the A-ring from the polycyclic ring structure of 3-ketosteroids.
Belongs to the FAD-dependent oxidoreductase 2 family.
Involved in a F420-dependent anti-oxidant mechanism that protects M.tuberculosis against oxidative stress and bactericidal agents. Catalyzes the F420H(2)-dependent two-electron reduction of quinones to dihydroquinones, thereby preventing the formation of cytotoxic semiquinones obtained by the one-electron reduction pathway. In vitro, catalyzes the reduction of menadione to menadiol; since menaquinone is the sole quinone electron carrier in the respiratory chain in M.tuberculosis, the physiological electron acceptor for Fqr-mediated F420H(2) oxidation is therefore likely to be the endogenous menaquinone found in the membrane fraction of M.tuberculosis.
Channel that opens in response to stretch forces in the membrane lipid bilayer. The force required to trigger channel opening depends on the nature of the membrane lipids; the presence of phosphatidylinositol enhances mechanosensitivity of the channel. May participate in the regulation of osmotic pressure changes within the cell.
E.coli inner membranes are often used to measure the activity of heterologously expressed channels, but the lipid composition of E.coli membranes differs considerably from that of M.tuberculosis. Phosphatidylinositol is one of the major constituents of M.tuberculosis membranes, but not of E.coli membranes, and this affects channel activity.
Not essential for aerobic growth in vitro, has a 20% decrease in tmRNA levels. Increased sensitivity to antibiotics that inhibit translation (chloramphenicol and erythromycin) but not transcription (rifampicin). No change in sensitivity to pyrazinamide (PZA). Unlike smpB, the gene for tmRNA (ssr, 10Sa RNA) is essential. Strains with ssr or smpB disruptions are not more sensitive to pyrazinamide, suggesting the prodrug does not directly target either of these components of trans-translation.
Required for rescue of stalled ribosomes mediated by trans-translation. Binds to transfer-messenger RNA (tmRNA), required for stable association of tmRNA with ribosomes. tmRNA and SmpB together mimic tRNA shape, replacing the anticodon stem-loop with SmpB. tmRNA is encoded by the ssrA gene; the 2 termini fold to resemble tRNA(Ala) and it encodes a 'tag peptide', a short internal open reading frame. During trans-translation Ala-aminoacylated tmRNA acts like a tRNA, entering the A-site of stalled ribosomes, displacing the stalled mRNA. The ribosome then switches to translate the ORF on the tmRNA; the nascent peptide is terminated with the 'tag peptide' encoded by the tmRNA and targeted for degradation. The ribosome is freed to recommence translation, which seems to be the essential function of trans-translation.
Belongs to the purine/pyrimidine phosphoribosyltransferase family. PyrE subfamily.
Catalyzes the transfer of a ribosyl phosphate group from 5-phosphoribose 1-diphosphate to orotate, leading to the formation of orotidine monophosphate (OMP).
Toxic component of a type II toxin-antitoxin (TA) system. An RNase. The cognate antitoxin is VapB18 (By similarity).
Belongs to the ribonucleoside diphosphate reductase small chain family. R2-like ligand binding oxidase subfamily.
Binds 1 manganese ion per subunit. The iron and manganese ions form a dinuclear manganese-iron cluster.
Deletion of the gene does not have a major impact on sensitivity to frontline tuberculosis drugs such as rifampicin, isoniazid or ethambutol, and does not affect susceptibility to hydrogen peroxide (PubMed:36149732). The deletion mutant survives equally well under nutrient starvation or in hypoxia and is not attenuated for growth in macrophages (PubMed:36149732).
Probable oxidase that might be involved in lipid metabolism (PubMed:19321420). Is not essential for the survival of M.tuberculosis in stress conditions (PubMed:36149732).
The C-terminal segment can alternate between an ordered and disordered state (PubMed:22976985). Ordering of the C-terminal helix shields a large positively charged patch on the protein surface, potentially used for interaction with other cellular components (PubMed:22976985).
Active efflux pump that plays an important role in chloramphenicol resistance (PubMed:31054279). Overexpression causes pyrazinamide resistance (PubMed:28584158).
Expression is negatively regulated by the transcriptional repressor Rv1353c.
Inhibited by the drug efflux pump inhibitors verapamil, resperine, piperine, chlorpromazine and carbonyl cyanide m-chlorophenylhydrazone (CCCP).
Could be a crucial virulence factor for intracellular survival of M.tuberculosis (PubMed:23300718). Favors development of Th2-type response, and down-regulates the pro-inflammatory and Th1-type response (PubMed:19880448, PubMed:21451109). Specifically interacts with the human Toll-like receptor 2 (TLR2), leading to an early and sustained activation of p38 MAPK, which induces IL-10 production and activates Th2-type immune response (PubMed:19880448). Also inhibits pro-inflammatory cytokines IL-12p40 and TNF-alpha production. Acts by up-regulating the expression as well as tyrosine phosphorylation of suppressor of cytokine signaling 3 (SOCS-3), leading to the inhibition of phosphorylation of I-kappa-B-alpha, thereby preventing nuclear translocation of the NF-kappa-B/REL subunits and expression of NF-kappa-B regulated genes like IL-12 and TNF-alpha. Induction of SOCS-3 probably depends on the activation of p38 MAPK (PubMed:21451109).
Expression is positively regulated by Rv0485.
Mice infected with the ppe18 deleted strain have reduced infection burden in lung, liver and spleen and have better survival rates compared to mice infected with the wild-type train.
The N-terminal region is responsible for interaction with TLR2 (PubMed:19880448). It is also important in mediating tyrosine phosphorylation of SOCS-3 (PubMed:21451109).
Inactivation of treZ does not affect the production of both capsular alpha-D-glucan and glycogen. Cells lacking this gene are not affected in their multiplication or persistence in the BALB/c mouse infection model.
Is involved in the biosynthesis of trehalose but not in that of capsular glucan and glycogen.
Belongs to the universal ribosomal protein uL3 family.
One of the primary rRNA binding proteins, it binds directly near the 3'-end of the 23S rRNA, where it nucleates assembly of the 50S subunit.
Part of the 50S ribosomal subunit. Forms a cluster with proteins L14 and L19.
A type II topoisomerase that negatively supercoils closed circular double-stranded (ds) DNA in an ATP-dependent manner to maintain chromosomes in an underwound state, while in the absence of ATP it relaxes supercoiled dsDNA (PubMed:15047530, PubMed:16377674, PubMed:16876125, PubMed:17015625, PubMed:18426901, PubMed:19060136, PubMed:22844097, PubMed:20805881). Also catalyzes the interconversion of other topological isomers of dsDNA rings, including catenanes (PubMed:16876125, PubMed:19060136, PubMed:22457352). Gyrase from M.tuberculosis has higher decatenation than supercoiling activity compared to E.coli; as M.tuberculosis only has 1 type II topoisomerase, gyrase has to fulfill the decatenation function of topoisomerase IV as well (PubMed:16876125, PubMed:22457352, PubMed:23869946). At comparable concentrations M.tuberculosis gyrase cannot introduce as many negative supercoils into DNA as the E.coli enzyme, and its ATPase activity is lower, perhaps because it does not couple DNA wrapping and ATP binding as well as E.coli (PubMed:22457352).
Belongs to the type II topoisomerase GyrA/ParC subunit family.
DNA supercoiling inhibited by (fluoro)quinoline antibiotics such as sparfloxacin and levofloxacin, which usually act on GyrA (PubMed:15047530, PubMed:17015625). DNA supercoiling inhibited by the coumarin antibiotic novobiocin which acts on GyrB (PubMed:16876125). Quinolones lead to gyrase-mediated dsDNA cleavage while preventing reclosure (PubMed:15047530, PubMed:16876125, PubMed:23869946). DNA supercoiling activity inhibited by aminopyrazinamide and pyrrolamide derivatives, probably via effects on the GyrB subunit (PubMed:23268609, PubMed:24126580). DNA relaxation inhibited by ATP and its analogs (PubMed:16876125). DNA supercoiling, relaxation, decatenation and quinolone-promoted DNA cleavage are inhibited by MfpA (50% inhibition occurs at 2 uM), inhibition of gyrase activities is enhanced in a concentration-dependent manner by MfpA (PubMed:19060136).
Gyrase from M.tuberculosis is usually assayed in the presence of potassium glutamate (KGlu); KGlu stimulates supercoiling but inhibits DNA relaxation activity, and has concentration-dependent effects on GyrA-box mutants (PubMed:16876125, PubMed:23869946).
Heterotetramer, composed of two GyrA and two GyrB chains. In the heterotetramer, GyrA contains the active site tyrosine that forms a transient covalent intermediate with DNA, while GyrB binds cofactors and catalyzes ATP hydrolysis (PubMed:15047530).
May bind up to 2 Ca(2+) per subunit, Ca(2+) does not substitute for supercoiling activity, but is required for relaxation, probably by an interaction with this subunit (PubMed:22844097). This subunit has altered protease sensitivity in the presence of Ca(2+), which might reflect regulation (PubMed:22844097).
Negative supercoiling favors strand separation, and DNA replication, transcription, recombination and repair, all of which involve strand separation. Type II topoisomerases break and join 2 DNA strands simultaneously in an ATP-dependent manner.
The N-terminal domain (residues 1-502, also called GA57BK) forms a dimer; when reconstituted with intact GyrB or the C-terminus of GyrB (residues 448-675) can catalyze quinolone-mediated DNA breaks (PubMed:20805881). The C-terminal domain (CTD, residues 514-838) contains 6 tandemly repeated subdomains known as blades, each of which is composed of a 4-stranded antiparallel beta-sheet (PubMed:22457352, PubMed:23869946). The blades form a circular-shaped beta-pinwheel fold arranged in a spiral around a screw axis, which binds DNA (PubMed:22457352, PubMed:23869946). Unlike in E.coli, isolated CTD both binds and wraps DNA and is able to introduce writhe into DNA, but the holoenzyme in M.tuberculosis is missing the GyrA acidic tail found in E.coli and thus does not couple DNA wrapping and ATP binding as well as E.coli (PubMed:22457352). There are 2 GyrA-boxes in the CTD; mutations in GyrA-box (residues 537-543, the canonical box) affect supercoiling but not decatenation, those in GyrA-box-1 (residues 743-749, conserved in some Actinobacteria) affect both, suggesting there is a novel DNA-binding pathway in M.tuberculosis compared to E.coli (PubMed:23869946).
When the enzyme transiently cleaves DNA a phosphotyrosine bond is formed between GyrA and DNA (PubMed:15047530). In the presence of quinolones this intermediate can be trapped and is used as an indicator of drug toxicity (PubMed:16377674, PubMed:23869946). DNA gyrase is intrinsically more resistant to fluoroquinolone drugs than in E.coli, mutating it to resemble E.coli increases its susceptibility to fluoroquinolones (most quinolone-resistant mutations are in this subunit) (PubMed:18426901).
Part of the ABC transporter complex DrrABC involved in doxorubicin resistance. Probably responsible for the translocation of the substrate across the membrane.
The complex is composed of two ATP-binding proteins (DrrA) and two transmembrane proteins (DrrB and DrrC).
Extracytoplasmic function sigma factors (ECF) are held in an inactive form by an anti-sigma factor until released by regulated intramembrane proteolysis (RIP). RIP occurs when an extracytoplasmic signal triggers a concerted proteolytic cascade to transmit information and elicit cellular responses. The membrane-spanning anti-sigma factor is first cut extracytoplasmically (site-1 protease, S1P), then within the membrane itself (site-2 protease, S2P), while cytoplasmic proteases finish degrading the regulatory protein, liberating SigD (Probable).
Interacts transiently with the RNA polymerase catalytic core formed by RpoA, RpoB, RpoC and RpoZ (2 alpha, 1 beta, 1 beta' and 1 omega subunit) to form the RNA polymerase holoenzyme that can initiate transcription. Interacts (via sigma-70 factor domain 4) with RsdA.
Not essential for growth in culture. Upon disruption about 260 genes show significantly decreased expression while about 200 showed increased expression. BALB/c mice infected with the disruption mutant showed a moderate but significant decrease in virulence, surviving about 30% longer than wild-type.
Positively autoregulates, probably directly, expressed at a relatively high level throughout exponential growth and during stationary phase. Expression decreases during O(2) depletion (hypoxia) (PubMed:15375142) and after heat shock (5-fold, 45 degrees Celsius) (PubMed:10027986).
Sigma factors are initiation factors that promote the attachment of RNA polymerase to specific initiation sites and are then released. Extracytoplasmic function (ECF) sigma factors are held in an inactive form by an anti-sigma factor until released by regulated intramembrane proteolysis.
Disruption abolishes EsxA and EsxB secretion, but not their expression. It results in a lack of antigen specific immunogenicity and leads to attenuated virulence.
Part of the ESX-1 / type VII secretion system (T7SS), which is composed of cytosolic and membrane components (PubMed:16368961, PubMed:19876390). Homohexamer (PubMed:18974091). Interacts with Ppe68, EspF and the C-terminus of EspC (PubMed:17433643, PubMed:19682254).
Part of the ESX-1 specialized secretion system, which delivers several virulence factors to host cells during infection, including the key virulence factors EsxA (ESAT-6) and EsxB (CFP-10) (PubMed:18974091, PubMed:16368961). EccA1 exhibits ATPase activity and may provide energy for the export of ESX-1 substrates (PubMed:18974091).
The N-terminal region is compact and probably functions to regulate the ATPase activity and the oligomerization. The C-terminal region contains the ATPase activity and the oligomerization domain.
Catalyzes ATP-dependent phosphorylation of adenosylcobinamide and addition of GMP to adenosylcobinamide phosphate.
ATPase activity is inhibited by EDTA, N-ethylmaleimide (NEM) and sodium azide.
ATPase which is responsible for recognizing, binding, unfolding and translocation of pupylated proteins into the bacterial 20S proteasome core particle. May be essential for opening the gate of the 20S proteasome via an interaction with its C-terminus, thereby allowing substrate entry and access to the site of proteolysis. Thus, the C-termini of the proteasomal ATPase may function like a 'key in a lock' to induce gate opening and therefore regulate proteolysis. Is required but not sufficient to confer resistance against the lethal effects of reactive nitrogen intermediates (RNI), antimicrobial molecules produced by activated macrophages and other cell types.
Cells lacking this gene accumulate pupylated proteins. These cells also become hypersensitive to reactive nitrogen intermediates (RNI) and are severely attenuated in both wild-type and nitric oxide synthase 2 deficient mice. Moreover, they display increased resistance to hydrogen peroxide.
Consists of three main regions, an N-terminal coiled-coil domain (residues 1-96) that binds to protein Pup and functions as a docking station, an interdomain (residues 97-245) involved in Mpa hexamerization, and a C-terminal ATPase domain of the AAA type (residues 246-609).
Homohexamer. Assembles into a hexameric ring structure that caps the 20S proteasome core. Strongly interacts with the prokaryotic ubiquitin-like protein Pup through a hydrophobic interface; the interacting region of Mpa lies in its N-terminal coiled-coil domain. There is one Pup binding site per Mpa hexamer ring; the K(D) measured is about 3.8 uM. Upon ATP-binding, the C-terminus of Mpa interacts with the alpha-rings of the proteasome core, possibly by binding to the intersubunit pockets.
Mpa is a target of RNI, thereby is S-nitrosylated in the phagosome of immunologically activated host macrophages, which causes enzyme inhibition.
Pupylated at Lys-591 by the prokaryotic ubiquitin-like protein Pup, which leads to its degradation by the proteasome. Mpa thus promotes its own turnover.
Catalyzes the formation of acetyl phosphate from acetate and ATP. Can also catalyze the reverse reaction.
Disruption mutant does not synthesize sulfolipids (PubMed:11278910, PubMed:24028583). Mutant is incapable of producing hepta- and octamethyl phthioceranic acids and hydroxyphthioceranic acids, which are the major acyl constituents of sulfolipids (PubMed:11278910).
Involved in sulfolipid-1 biosynthesis (PubMed:11278910, PubMed:12724526). Catalyzes the synthesis of the hepta- and octamethyl phthioceranic and hydroxyphthioceranic acids, the methyl-branched acyl constituents of sulfolipids (PubMed:11278910).
Up-regulated by the PhoP/PhoR two-component system (PubMed:16573683). Expressed in response to phagocytosis by human macrophages (PubMed:10500215).
Disruption of the gene reduces the ability of M.tuberculosis to bind to host cells. Disruption does not reduce virulence in a mouse model of infection.
Probably part of an ABC transporter complex involved in host cell binding either through secretion of an adherence factor or through maintaining the architecture and integrity of the mycobacterial cell envelope.
The complex is probably composed of two ATP-binding proteins (Rv0986) and two transmembrane proteins (Rv0987).
Belongs to the pentapeptide repeat protein family.
Each subunit forms a right-handed beta-helix with 8 complete coils that stack upon each other.
Homodimer. Probably interacts with DNA gyrase.
Might be involved in fluoroquinolone resistance (PubMed:15933203). Inhibits ATP-independent DNA relaxation, ATP-dependent DNA supercoiling and ATP-dependent decatenation by endogenous gyrase, 50% inhibition occurs at 2 uM; inhibition is abolished if GyrA is mutated (Asp-87 to Gly or His) (PubMed:19060136). Also inhibits fluoroquinolone-promoted dsDNA cleavage (PubMed:19060136). Increases fluoroquinolone (ciprofloxacin or moxifloxacin) inhibition of gyrase supercoiling activity in a concentration-dependent manner (PubMed:19060136). Inhibits DNA relaxation and supercoiling by E.coli gyrase (PubMed:15933203). Forms a structure that exhibits size, shape and electrostatic similarity to B-form DNA; it may bind to DNA gyrase which is postulated to protect it from fluoroquinolones (PubMed:15933203).
Has three domains with a flexible linker between the domains II and III, and assumes an 'L' shape. The position of domain III with respect to the tetramer is variable.
Homotetramer; forms a dimer of tetramers with an internal space large enough to bind the Holliday junction DNA (PubMed:16880543, PubMed:19374958). Forms an RuvA(8)-RuvB(12)-Holliday junction (HJ) complex. HJ DNA is sandwiched between 2 RuvA tetramers; dsDNA enters through RuvA and exits via RuvB. An RuvB hexamer assembles on each DNA strand where it exits the tetramer. Each RuvB hexamer is contacted by two RuvA subunits (via domain III) on 2 adjacent RuvB subunits; this complex drives branch migration. In the full resolvosome a probable DNA-RuvA(4)-RuvB(12)-RuvC(2) complex forms which resolves the HJ.
The RuvA-RuvB-RuvC complex processes Holliday junction (HJ) DNA during genetic recombination and DNA repair, while the RuvA-RuvB complex plays an important role in the rescue of blocked DNA replication forks via replication fork reversal (RFR). Binds HJ DNA (PubMed:22094465). RuvA specifically binds to HJ cruciform DNA, conferring on it an open structure. The RuvB hexamer acts as an ATP-dependent pump, pulling dsDNA into and through the RuvAB complex. HJ branch migration allows RuvC to scan DNA until it finds its consensus sequence, where it cleaves and resolves the cruciform DNA.
The expression is up-regulated in the mid-exponential and extended stationary phase.
Belongs to the major facilitator superfamily. Nitrate/nitrite porter (TC 2.A.1.8) family.
Belongs to the FAD-dependent oxidoreductase 2 family. NadB subfamily.
Catalyzes the oxidation of L-aspartate to iminoaspartate, the first step in the de novo biosynthesis of NAD(+).
Catalyzes the methylation of C-11 in precorrin-4 to form precorrin-5.
Catalyzes the attachment of threonine to tRNA(Thr) in a two-step reaction: L-threonine is first activated by ATP to form Thr-AMP and then transferred to the acceptor end of tRNA(Thr). Also edits incorrectly charged L-seryl-tRNA(Thr).
Expressed at a higher level in a phoP disruption mutant than in the wild type.
Not essential, disruption of rpfC alone has no effect on growth or survival in liquid culture, nor in mouse infection models,although colony size is reduced. Alterations in gene expression are seen. All 5 genes in this family can be deleted without affecting growth in culture, however triple deletion mutants (rpfA-rpfC-rpfB or rpfA-rpfC-rpfD) are not able to resuscitate spontaneously in the presence or absence of O(2), and are attenuated in a mouse infection model.
Belongs to the autoinducer-2 exporter (AI-2E) (TC 2.A.86) family.
APS kinase catalyzes the synthesis of activated sulfate.
Heterodimer composed of CysD, the smaller subunit, and CysNC.
In the C-terminal section; belongs to the APS kinase family.
In the N-terminal section; belongs to the TRAFAC class translation factor GTPase superfamily. Classic translation factor GTPase family. CysN/NodQ subfamily.
Induced by sulfur limitation and oxidative stress. Repressed by the presence of cysteine.
With CysD forms the ATP sulfurylase (ATPS) that catalyzes the adenylation of sulfate producing adenosine 5'-phosphosulfate (APS) and diphosphate, the first enzymatic step in sulfur assimilation pathway. APS synthesis involves the formation of a high-energy phosphoric-sulfuric acid anhydride bond driven by GTP hydrolysis by CysN coupled to ATP hydrolysis by CysD.
Inhibited by the antitubercular drug SQ109. Also inhibited by several other compounds such as the pyrrole derivative BM212, the adamantyl urea derivative AU1235, the benzimidazole C215, indoleamides, tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide (THPP) and N-benzyl-6',7'-dihydrospiro[piperidine-4,4'-thieno[3,2-c]pyran] (Spiro) analogs. Inhibitory effects of these compounds, including SQ109, are most likely due to their ability to dissipate the transmembrane electrochemical proton gradient.
Is the target of the antitubercular drug SQ109.
Monomer. Interacts with TtfA (via N-terminus); active trehalose monomycolate (TMM) biosynthesis is not required for the complex formation.
Transports trehalose monomycolate (TMM) to the cell wall. Flips TMM across the inner membrane (PubMed:22252828, PubMed:22344175). Membrane potential is not required for this function. Transports probably phosphatidylethanolamine (PE) as well. Binds specifically both TMM and PE, but not trehalose dimycolate (TDM). Binds also diacylglycerol (DAG) and other phospholipids, including phosphatidylglycerol (PG), phosphatidylinositol (PI), and cardiolipin (CDL). Contributes to membrane potential, cell wall composition, antibiotic susceptibility and fitness (By similarity). Could also be part of a heme-iron acquisition system (PubMed:21383189).
Cells lacking this gene are not severely sensitized to RNI and display no accumulation of the proteasome substrates Mpa, FabD and PanB.
Interacts with PafB; with which it probably forms a heterocomplex.
Part of the pafABC operon, but PafC does not seem to be involved in pupylation or substrate degradation. Appears to play at least a small role in resistance to reactive nitrogen intermediates (RNI) in vitro.
Belongs to the glutamate 5-kinase family.
Catalyzes the transfer of a phosphate group to glutamate to form L-glutamate 5-phosphate.
Belongs to the uracil-DNA glycosylase (UDG) superfamily. Type 5 (UDGb) family.
DNA glycosylase with broad substrate specificity. Can remove uracil from double-stranded DNA containing either a U/G, U/A, U/C or U/T base pair. Can also excise ethenocytosine and hypoxanthine from double-stranded DNA.
Product inhibited by AP-site containing dsDNA but not by uracil.
Catalyzes C-C bond formation between the carbons ortho to the phenolic hydroxyl of cyclo(L-tyr-L-tyr) (cYY) producing mycocyclosin. Can also use cyclo(L-Tyr-L-Phe) (cYF), cyclo(L-Tyr-L-Trp) (cYW) and cyclo(L-Tyr-L-3,4-dihydroxyphenylalanine) (cY-DOPA) as substrate.
Inhibited by clotrimazole, econazole, ketoconazole, and miconazole.
Expression is controlled by VirS. Induced at acidic pH and in macrophages.
Required for maintaining the appropriate mycolic acid composition and permeability of the envelope on its exposure to acidic pH.
Catalyzes the NADPH-dependent rearrangement and reduction of 1-deoxy-D-xylulose-5-phosphate (DXP) to 2-C-methyl-D-erythritol 4-phosphate (MEP).
Belongs to the adenylosuccinate synthetase family.
Plays an important role in the de novo pathway of purine nucleotide biosynthesis. Catalyzes the first committed step in the biosynthesis of AMP from IMP.
In this enzyme the conserved residue Asp-4 binds Mg(2+) via H(2)O.
Toxic component of a type II toxin-antitoxin (TA) system. Degrades total E.coli RNA, which is partially inhibited by cognate antitoxin VapB15 (PubMed:25450593). Upon expression in M.smegmatis inhibits colony formation, which is neutralized by coexpression with VapB15 (PubMed:20011113).
Hydrolyzes ester substrates carbon chain lengths ranging from C2 to C14 (PubMed:25224799). In vitro, acetate (C2), butyrate (C4) and caprylate (C6) are hydrolyzed with high efficiency. Has lower activity against laurate (C12), myristate (C14) and caproate (C8), and weak activity against palmitate (C16) (PubMed:25224799).
Belongs to the aldo/keto reductase family. Aldo/keto reductase 2 subfamily.
Belongs to the universal ribosomal protein uL30 family.
Binds 1 Mg(2+) ion per monomer; in the crystal structure only 1 toxin is bound to Mg(2+).
Probably active as a homodimer, which binds to a VapB2 antitoxin homodimer, which then oligomerizes further to a hetero-octamer. When in complex with antitoxin VapB2 the toxin activity is inhibited; 1 VapB2 may suffice to inhibit toxin.
Toxic component of a type II toxin-antitoxin (TA) system. Acts as an RNase. Upon expression in M.smegmatis inhibits translation, growth and colony formation. All its toxic effects are neutralized by coexpression with cognate antitoxin VapB2.
Antitoxin component of a type II toxin-antitoxin (TA) system. Upon expression in M.smegmatis neutralizes the effect of toxin RelE2.
Expressed in log phase cells. Also expressed in human macrophages 110 hours after infection. A member of the relFG operon.
Induces its own promoter, in combination with RelG represses its own promoter. Has been seen to bind DNA in complex with toxin RelG but not alone.
Interacts with toxin RelG, which neutralizes the toxin. Also interacts with toxins RelE and RelK in vitro, in M.smegmatis coexpression with non-cognate toxins increases the toxicity of RelE but not of RelK.
Catalyzes the deamination of adenosine to inosine at the wobble position 34 of tRNA(Arg2).
The N-terminal domain determines nucleotide recognition and specific binding, while the C-terminal domain determines the specific binding to the target protein.
Transfers a GMP moiety from GTP to Mo-molybdopterin (Mo-MPT) cofactor (Moco or molybdenum cofactor) to form Mo-molybdopterin guanine dinucleotide (Mo-MGD) cofactor.
Possibly the antitoxin component of a type II toxin-antitoxin (TA) system. Its cognate toxin is VapC42.
Belongs to the class I-like SAM-binding methyltransferase superfamily. TRM61 family.
Catalyzes the S-adenosyl-L-methionine-dependent formation of N(1)-methyladenine at position 58 (m1A58) in tRNA.
Contains a large catalytic C-terminal domain that binds S-adenosyl-L-methionine and a smaller N-terminal domain that may play a role in tRNA recognition. Domains are connected by a linker region.
Homotetramer composed of a dimer of dimers.
Catalyzes the reversible phosphorylation of UMP to UDP.
Modified by Lgt on Cys-35 with an S-linked diacylglycerol, signal peptide is removed by LspA, modified by Lnt with amide-linked fatty acid (By similarity).
Overexpression induces expression of sensor protein kdpD gene at low K(+) concentrations (0 and 250 uM, tested in M.smegatis).
May be involved in the final steps of cholesterol and steroid degradation (PubMed:28377529). Catalyzes the formation of 4-methyl-5-oxo-octanedioyl-CoA (MOODA-CoA) and acetyl-CoA from 6-methyl-3,7-dioxodecanedioyl-CoA (MeDODA-CoA) and coenzyme A (Probable).
Turnover of MeDODA-CoA is low and FadA6 may not be the physiological thiolase responsible for MOODA-CoA formation.
Contains an N-terminal zinc-binding domain, a central core domain that contains the primase activity, and a C-terminal DnaB-binding domain.
Monomer. Interacts with DnaB (By similarity). Co-immunoprecipitates with DarG in the presence and absence of darT (PubMed:32634279).
RNA polymerase that catalyzes the synthesis of short RNA molecules used as primers for DNA polymerase during DNA replication.
Belongs to the complex I 75 kDa subunit family.
Deletion of nuoG in M.tuberculosis reduces its ability to inhibit apoptosis of infected human or mouse macrophages and significantly decreases its virulence in mice (PubMed:17658950). The apoptogenic phenotype of the mutant strain is significantly reduced in human macrophages treated with caspase-3 and -8 inhibitors, TNF-alpha-neutralizing antibodies, and also after infection of murine TNF(-/-) macrophages. Moreover, incubation of macrophages with inhibitors of reactive oxygen species (ROS) reduces not only the apoptosis induced by the nuoG deletion mutant, but also its capacity to increase macrophage TNF-alpha secretion. The phagosomes infected with the mutant show increased ROS levels compared to M.tuberculosis phagosomes in primary murine and human alveolar macrophages. The increase in nuoG deletion mutant induced ROS and apoptosis is abolished in NOX-2 deficient (gp91(-/-)) macrophages (PubMed:20421951). Compared to wild-type, the nuoG deletion mutant spreads to a larger number of lung phagocytic cells. Consistent with the shorter lifespan of infected neutrophils, infection with the nuoG mutant results in fewer bacteria per infected neutrophil, accelerated bacterial acquisition by dendritic cells, earlier trafficking of these dendritic cells to lymph nodes, and faster CD4 T cell priming. Neutrophil depletion abrogates accelerated CD4 T cell priming by the nuoG mutant, suggesting that inhibiting neutrophil apoptosis delays adaptive immunity in tuberculosis (PubMed:22264515).
Plays a critical role in M.tuberculosis ability to inhibit apoptosis of infected macrophages; thus helps the bacterium in its struggle to resist the host immune response (PubMed:17658950). In fact, via a NuoG-dependent mechanism, M.tuberculosis can neutralize NOX2-derived reactive oxygen species (ROS) in order to inhibit TNF-alpha-mediated host cell apoptosis (PubMed:20421951). Also mediates inhibition of neutrophil apoptosis, leading to delayed activation of naive CD4 T cells (PubMed:22264515).
The type I NADH dehydrogenase consists of 14 different subunits.
Constitutively low in all growth stages; repressed by detergent (3.5-fold). Induced by WhiB5.
Extracytoplasmic function (ECF) sigma factors are held in an inactive form by an anti-sigma factor until released by regulated intramembrane proteolysis (RIP). RIP occurs when an extracytoplasmic signal triggers a concerted proteolytic cascade to transmit information and elicit cellular responses. The membrane-spanning anti-sigma factor is first cut extracytoplasmically (site-1 protease, S1P), then within the membrane itself (site-2 protease, S2P, Rip1), while cytoplasmic proteases finish degrading the regulatory protein, liberating SigM (Probable).
Interacts transiently with the RNA polymerase catalytic core formed by RpoA, RpoB, RpoC and RpoZ (2 alpha, 1 beta, 1 beta' and 1 omega subunit) to form the RNA polymerase holoenzyme that can initiate transcription. Interacts (via sigma-70 factor domain-4) with anti-sigma-M factor RsmA (AC L7N5D7) (By similarity).
No effect on growth in culture, or in isolated macrophages; infected guinea pigs have a partially attenuated lung infection.
Sigma factors are initiation factors that promote the attachment of RNA polymerase to specific initiation sites and are then released. Extracytoplasmic function (ECF) sigma factors are held in an inactive form by an anti-sigma factor (RsaM, AC L7N5D7) until released by regulated intramembrane proteolysis (Probable). This sigma factor is required for the synthesis of surface or secreted molecules.
Binds 1 Mg(2+) ion per subunit. Can also use Co(2+), Zn(2+), Ni(2+) and Ca(2+) to a lesser extent.
Catalyzes the reversible reaction in which hydroxymethyl group from 5,10-methylenetetrahydrofolate is transferred onto alpha-ketoisovalerate to form ketopantoate.
Pupylated at an undetermined lysine residue by the prokaryotic ubiquitin-like protein Pup with the help of the ligase PafA, which leads to its degradation by the proteasome. The cross-link involves the side-chain carboxylate of the C-terminal glutamate of Pup and the side-chain amino group of a lysine in PanB.
Belongs to the polypeptide deformylase family.
Removes the formyl group from the N-terminal Met of newly synthesized proteins. Requires at least a dipeptide for an efficient rate of reaction. N-terminal L-methionine is a prerequisite for activity but the enzyme has broad specificity at other positions (By similarity).
Antitoxin component of a type II toxin-antitoxin (TA) system. Upon expression in E.coli but not in M.smegmatis neutralizes the effect of cognate toxin MazF7.
Forms a complex with cognate toxin MazF7.
Homodimer (By similarity). Interacts with RNase J.
Participates actively in the response to hyperosmotic and heat shock by preventing the aggregation of stress-denatured proteins and by disaggregating proteins, also in an autonomous, DnaK-independent fashion. Unfolded proteins bind initially to DnaJ; upon interaction with the DnaJ-bound protein, DnaK hydrolyzes its bound ATP, resulting in the formation of a stable complex. GrpE releases ADP from DnaK; ATP binding to DnaK triggers the release of the substrate protein, thus completing the reaction cycle. Several rounds of ATP-dependent interactions between DnaJ, DnaK and GrpE are required for fully efficient folding. Also involved, together with DnaK and GrpE, in the DNA replication of plasmids through activation of initiation proteins (By similarity). Inhibits the beta-lactamase and RNase activity of RNase J.
The J domain is necessary and sufficient to stimulate DnaK ATPase activity. Zinc center 1 plays an important role in the autonomous, DnaK-independent chaperone activity of DnaJ. Zinc center 2 is essential for interaction with DnaK and for DnaJ activity.
Belongs to the Rieske iron-sulfur protein family.
Iron-sulfur subunit of the cytochrome bc1 complex, an essential component of the respiratory electron transport chain required for ATP synthesis. The bc1 complex catalyzes the oxidation of menaquinol and the reduction of cytochrome c in the respiratory chain. The bc1 complex operates through a Q-cycle mechanism that couples electron transfer to generation of the proton gradient that drives ATP synthesis.
Shows trans-enoyl-CoA hydratase/3-hydroxyacyl-CoA dehydratase activity. In vitro, can hydrate (2E)-butenoyl-CoA, (2E)-hexenoyl-CoA and (2E)-decenoyl-CoA.
Catalyzes the conversion of a double bond to a cis cyclopropane ring at the distal position of an alpha mycolic acid via the transfer of a methylene group from S-adenosyl-L-methionine. MmaA2 also catalyzes the biosynthesis of the cis-cyclopropanated methoxymycolates. Cyclopropanated mycolic acids are key factors participating in cell envelope permeability, host immunomodulation and persistence.
Disruption of this gene suppresses a cyclopropane group at the distal position of alpha mycolic acid. Mutant produces fully cyclopropanated methoxymycolates, but the efficiency of cis-methoxymycolate cyclopropanation is reduced, leading to accumulation of unsaturated methoxymycolate derivatives. Cis/trans ratios in purified ketomycolates are unchanged (PubMed:12502719). Cells lacking both cmaA2 and mmaA2 genes cannot cis cyclopropanate methoxymycolates or ketomycolates (PubMed:20472794).
Inhibited by S-adenosyl-N-decyl-aminoethyl (SADAE) and thiacetazone (TAC).
A cleavage of the protein removes the N-terminal 120-150 residues, immediately upstream the PGRS domain (PubMed:33757409). The exact position of the cleavage site could not be identified (PubMed:33757409).
Expression in M.smegmatis enhances adhesion of M.smegmatis to murine macrophages and human alveolar epithelial cells and improves bacterial persistence in spleen tissue following infection in mice (PubMed:30192424). Overexpression in M.tuberculosis improves adhesion to pneumocytes, but not to phagocytic cells (PubMed:33757409).
Specifically expressed under low phosphate concentrations (PubMed:30192424). Expression is very low and undetectable under classical growth conditions but long-term exposure to low phosphate triggers its expression (PubMed:30192424). Administration of free phosphate, cardiolipin and phosphatidylinositol to phosphate-starved culture turns off expression of the gene (PubMed:33757409).
The 77 amino acids long, arginine-rich C-terminal domain plays a critical role in tuberculosis pathogenesis (PubMed:30192424, PubMed:33757409). This positively charged helical domain specifically binds phosphorylated phosphatidylinositols and cardiolipin, whereas it is unable to bind other phospholipids (PubMed:33757409).
The arginine-rich C-terminal region protrudes from the mycobacterial membrane and mediates M.tuberculosis entry into host epithelial cells (PubMed:33757409). May serve as a bridge between mycobacteria and host cells by interacting with specific host phospholipids and extracting them from host cells, for their direct integration or as a source of phosphate, during phases of TB pathogenesis when M.tuberculosis is short of phosphate supply (PubMed:33757409).
Contains a winged helix-turn-helix domain connected to an alpha-helical dimerization domain.
Elicits a strong B-cell humoral response among different clinical categories of both adult and child tuberculosis patients.
Expression in non-pathogenic M.smegmatis (Msmeg) strain induces necrotic cell death of macrophage after infection and significantly decreased IL-6 production compared to controls (PubMed:26157429). Msmeg-PE11 bacilli exhibit altered colony morphology and cell wall lipid composition leading to a marked increase in resistance against various environmental stressors and antibiotics (PubMed:26902658). Mice infected with Msmeg-PE11 have higher bacterial load, show exacerbated organ pathology and mortality. The liver and lung of Msmeg-PE11-infected mice have higher levels of IL-10, IL-4 and TNF-alpha cytokines (PubMed:26902658).
Involved in cell wall lipids remodeling and in virulence (PubMed:26157429, PubMed:26902658, PubMed:28198348). Restricts the biofilm growth and is essential for the optimal intracellular survival of M.tuberculosis (PubMed:28198348). Shows esterase activity with a preference for short-chain esters, particularly pNP-acetate (C2) and pNP-butyrate (C4) (PubMed:26902658). Has weaker activity with pNP-octanoate (C8), pNP-laurate (C12) and pNP-myristate (C14) (PubMed:26902658). Shows weak long-chain triacylglycerol (TAG) hydrolase activity in vitro (PubMed:16354661). Not necessary for PPE17 stability or for its localization on the mycobacterial surface (PubMed:23469198).
Knock-down of the gene alters the colony morphology and slows down growth. Knock-down induces aggregation, early biofilm formation and changes in cell wall lipid composition. It also results in decreased survival of Mycobacterium inside macrophages and reduced necrotic death of THP-1 macrophages.
Electron transport system for the ribonucleotide reductase system NrdEF.
Catalyzes the acyloin condensation reaction between C atoms 2 and 3 of pyruvate and glyceraldehyde 3-phosphate to yield 1-deoxy-D-xylulose-5-phosphate (DXP).
Belongs to the quinolinate synthase family. Type 2 subfamily.
Catalyzes the condensation of iminoaspartate with dihydroxyacetone phosphate to form quinolinate.
Belongs to the FMN-dependent alpha-hydroxy acid dehydrogenase family.
Involved in the biosynthesis of the enzyme cofactor mycofactocin (MFT). Catalyzes the oxidative deamination of AHDP (3-amino-5-[(4-hydroxyphenyl)methyl]-4,4-dimethyl-2-pyrrolidin-2-one), forming an alpha-keto amide moiety on the resulting molecule, which is called pre-mycofactocin (PMFT). This reaction occurs via a 5-[(4-hydroxyphenyl)methyl]-3-imino-4,4-dimethylpyrrolidin-2-one intermediate, which converts to PMFT. The alpha-keto amide moiety is the redox-active center for the redox activity of mycofactocin.
Homotetramer (PubMed:12524453). Homodimer (PubMed:11807257).
Probably involved in steroid metabolism. Catalyzes the oxidation of androsterone (3alpha-hydroxy-5alpha-androstan-17-one) and 20beta-hydroxyprogesterone (4-pregnen-20beta-ol-3-one), and the reduction of progesterone (4-pregnen-3,20-dione). Shows a preference for NADH. Has no detectable activity for oxidation of L-3-hydroxybutyric acid and only an insignificant activity for reduction of acetoacetyl-CoA.
Contains a eukaryotic-like ubiquitin-associated (UBA) domain that mediates interaction with host ubiquitin.
Deletion mutant shows enhanced viability, reduced p62 aggregation and reduced colocalization with LC3 and LAMP1 in bone marrow-derived murine macrophages (BMDMs).
Interacts directly with host polyubiquitin in a UBA-dependent manner.
Mediates direct binding of host ubiquitin (Ub) to the mycobacterial surface, which triggers host xenophagy. Interaction between Rv1468c and ubiquitin recruits autophagy receptor p62 to deliver mycobacteria into LC3-associated autophagosomes. It could be a viable evolutionary strategy adopted by M.tuberculosis to maintain long-term intracellular survival through self-controlling its intracellular bacterial loads to avoid excessive host inflammatory immune responses.
Up-regulated after infection of macrophages.
Toxic component of a type II toxin-antitoxin (TA) system. An RNase. The cognate antitoxin is VapB16 (By similarity).
Inhibited by 1-(2,5-dichlorophenyl)-3-(dimethylamino)propan-1-one (MD3).
Belongs to the universal ribosomal protein uL2 family.
One of the primary rRNA binding proteins. Required for association of the 30S and 50S subunits to form the 70S ribosome, for tRNA binding and peptide bond formation. It has been suggested to have peptidyltransferase activity; this is somewhat controversial. Makes several contacts with the 16S rRNA in the 70S ribosome.
Part of the 50S ribosomal subunit. Forms a bridge to the 30S subunit in the 70S ribosome.
Cells show attenuated virulence in murine survival studies although initial replication rates and containment of this replication in the lung and spleen are identical to the wild-type. Inactivation of the mmpL8 gene interrupts the normal biosynthesis of SL-1 and leads to the accumulation of the precursor SL1278.
Required for the biosynthesis and the transport across the inner membrane of sulfolipid-1 (SL-1), which is a major cell wall lipid of pathogenic mycobacteria. Could also transport SL1278 (2-palmitoyl-3-(C43)-phthioceranyl-alpha, alpha'-D-trehalose-2'-sulfate), which is the precursor of SL-1. Required for virulence.
Belongs to the iron-sulfur dependent L-serine dehydratase family.
Belongs to the acetylglutamate kinase family. ArgB subfamily.
Catalyzes the ATP-dependent phosphorylation of N-acetyl-L-glutamate.
Putative toxic component of a type II toxin-antitoxin (TA) system. Its cognate antitoxin would be HigA2.
Belongs to the imidazoleglycerol-phosphate dehydratase family.
Competitive inhibition by 3-amino-1,2,4-triazole (e.g. ATZ).
IF-3 binds to the 30S ribosomal subunit and shifts the equilibrum between 70S ribosomes and their 50S and 30S subunits in favor of the free subunits, thus enhancing the availability of 30S subunits on which protein synthesis initiation begins.
Belongs to the class-II pyridoxal-phosphate-dependent aminotransferase family. MalY/PatB cystathionine beta-lyase subfamily.
Belongs to the NAD(P)-dependent epimerase/dehydratase family. dTDP-glucose dehydratase subfamily.
Catalyzes the dehydration of dTDP-D-glucose to form dTDP-6-deoxy-D-xylo-4-hexulose via a three-step process involving oxidation, dehydration and reduction (By similarity). Involved in the biosynthesis of the dTDP-L-rhamnose which is a component of the critical linker, D-N-acetylglucosamine-L-rhamnose disaccharide, which connects the galactan region of arabinogalactan to peptidoglycan via a phosphodiester linkage (PubMed:16472764).
Catalyzes the reversible reductive amination of pyruvate to L-alanine. However, since the physiological environment of M.tuberculosis has a neutral pH, it can be assumed that the enzyme catalyzes exclusively the formation of L-alanine. May play a role in cell wall synthesis as L-alanine is an important constituent of the peptidoglycan layer.
L-alanine dehydrogenase activity increases when the M.tuberculosis is shifted from aerobic to anaerobic growth conditions.
Belongs to the complex I subunit 4 family.
Pupylated at Lys-528 by the prokaryotic ubiquitin-like protein Pup, which probably leads to its degradation by the proteasome.
Belongs to the RNA methyltransferase RsmE family.
Specifically methylates the N3 position of the uracil ring of uridine 1498 (m3U1498) in 16S rRNA. Acts on the fully assembled 30S ribosomal subunit (By similarity).
In the C-terminal section; belongs to the alkylbase DNA glycosidase AlkA family.
Is involved in the adaptive response to alkylation damage in DNA caused by alkylating agents. Repairs the Sp diastereomer of DNA methylphosphotriester lesions by a direct and irreversible transfer of the methyl group to one of its own cysteine residues. Also catalyzes the hydrolysis of the deoxyribose N-glycosidic bond to excise 3-methyladenine, 3-methylguanine, 7-methylguanine, O2-methylthymine, and O2-methylcytosine from the damaged DNA polymer formed by alkylation lesions (By similarity).
The methylation of Alka by methylphosphotriesters in DNA leads to its activation as a transcriptional regulator that activates the transcription of its own gene and other alkylation resistance genes.
Belongs to the SIS family. GmhA subfamily.
Catalyzes the isomerization of sedoheptulose 7-phosphate in D-glycero-D-manno-heptose 7-phosphate.
Homotetramer (PubMed:33257730). Interacts wit HddA and GmhB (PubMed:33257730).
The reaction produces a racemic mixture of D-glycero-alpha-D-manno-heptose 7-phosphate and D-glycero-beta-D-manno-heptose 7-phosphate.
Catalyzes the activation of medium/long-chain fatty acids as acyl-coenzyme A (acyl-CoA), which are then transferred to the multifunctional polyketide synthase (PKS) type III for further chain extension (PubMed:15042094, PubMed:19182784). Also involved in steroid side-chain degradation. Activates cholesterol metabolites with a C5 side chain, including cholate and chenodeoxycholate (PubMed:24244004).
Belongs to the bacterial ribosomal protein bL19 family.
This protein is located at the 30S-50S ribosomal subunit interface and may play a role in the structure and function of the aminoacyl-tRNA binding site.
Belongs to the metallo-dependent hydrolases superfamily. Phosphotriesterase family.
Catalyzes the 2-thiolation of uridine at the wobble position (U34) of tRNA, leading to the formation of s(2)U34.
Homohexameric ring arranged as a trimer of dimers (Ref.3).
Phosphorolytic 3'-5' exoribonuclease that plays an important role in tRNA 3'-end maturation. Removes nucleotide residues following the 3'-CCA terminus of tRNAs; can also add nucleotides to the ends of RNA molecules by using nucleoside diphosphates as substrates, but this may not be physiologically important. Probably plays a role in initiation of 16S rRNA degradation (leading to ribosome degradation) during starvation.
Belongs to the radical SAM superfamily. MftC family.
Binds 3 [4Fe-4S] clusters. One cluster is coordinated with 3 cysteines and an exchangeable S-adenosyl-L-methionine. All three [Fe-S] clusters are required for MftC modification of MftA.
Radical S-adenosylmethionine (SAM) enzyme responsible for the first step of the biosynthesis of the enzyme cofactor mycofactocin (MFT). Catalyzes two reactions at the C-terminus of the mycofactocin precursor (the MftA peptide). The first one is the oxidative decarboxylation of the C-terminal L-tyrosine of MftA, forming an unsaturated tyramine moiety. The second reaction is the cross-linking of the tyramine with the penultimate L-valine residue, forming a five-membered lactam ring. Its activity requires the presence of the MftB chaperone.
Belongs to the helicase family. DinG subfamily.
Probable helicase involved in DNA repair and perhaps also replication.
Involved in DNA repair and RecF pathway recombination.
Cells lacking this gene show an expression level of icl higher than wild-type during incubation with glucose while remaining approximately at the same level than wild-type during incubation with acetate. ramB expression levels are found to be higher in the deletion mutant than in the wild-type during incubation with acetate or glucose.
Involved in the control of the glyoxylate cycle. RamB negatively controls the expression of icl expression during growth on acetate as the sole carbon source. Does not regulate the expression of other genes involved in acetate metabolism.
RamB represses its own expression (independently of the available carbon source) and is negatively regulated by PrpR.
To Synechocystis PCC 6803 sll0335 and to M.tuberculosis Rv2567.
Belongs to the carbon-nitrogen hydrolase superfamily. NIT1/NIT2 family.
Homodimer which binds Holliday junction (HJ) DNA. The HJ becomes 2-fold symmetrical on binding to RuvC with unstacked arms; it has a different conformation from HJ DNA in complex with RuvA. In the full resolvosome a probable DNA-RuvA(4)-RuvB(12)-RuvC(2) complex forms which resolves the HJ.
The RuvA-RuvB-RuvC complex processes Holliday junction (HJ) DNA during genetic recombination and DNA repair. Endonuclease that resolves HJ intermediates. Cleaves cruciform DNA by making single-stranded nicks across the HJ at symmetrical positions within the homologous arms, yielding a 5'-phosphate and a 3'-hydroxyl group; requires a central core of homology in the junction. The consensus cleavage sequence is 5'-(A/T)TT(C/G)-3'. Cleavage occurs on the 3'-side of the TT dinucleotide at the point of strand exchange. HJ branch migration catalyzed by RuvA-RuvB allows RuvC to scan DNA until it finds its consensus sequence, where it cleaves and resolves the cruciform DNA.
Catalyzes the conversion of the sulfur carrier protein CysO to CysO-thiocarboxylate. The reaction is thought to proceed in two steps: first, ATP-dependent activation of CysO as acyl-adenylate (CysO-COOAMP), followed by sulfur transfer to give CysO-thiocarboxylate (CysO-COSH) (Probable). The sulfur source is unknown.
In the N-terminal section; belongs to the HesA/MoeB/ThiF family.
May be involved in recombinational repair of damaged DNA.
Belongs to the CRISPR-associated Csm2 family.
This subunit may be involved in monitoring complementarity of crRNA and target RNA.
Belongs to the MurCDEF family. MurE subfamily.
Carboxylation is probably crucial for Mg(2+) binding and, consequently, for the gamma-phosphate positioning of ATP.
Catalyzes the addition of meso-diaminopimelic acid to the nucleotide precursor UDP-N-acetylmuramoyl-L-alanyl-D-glutamate (UMAG) in the biosynthesis of bacterial cell-wall peptidoglycan.
Belongs to the FKBP-type PPIase family. Tig subfamily.
Consists of 3 domains; the N-terminus binds the ribosome, the middle domain has PPIase activity, while the C-terminus has intrinsic chaperone activity on its own.
Expression in M.smegmatis enhances its survival within macrophages, adaptation to oxidative stress and biofilm formation.
Involved in protein export. Acts as a chaperone by maintaining the newly synthesized protein in an open conformation. Functions as a peptidyl-prolyl cis-trans isomerase (By similarity). Protects the cells against high-temperatures and aids in the restoration of enzyme activity of thermally denaturated proteins (PubMed:36671761). Contributes to tolerance and adaptation to host-generated stresses (PubMed:36671761). Has strong immunomodulatory potential and modifies the cytokine profile of the host towards the proinflammatory axis (PubMed:36671761).
Possibly the antitoxin component of a type II toxin-antitoxin (TA) system. Its cognate toxin is VapC49 (Potential).
Digests 23S rRNA in the absence of Mg(2+), increasing Mg(2+) concentrations decrease its efficiency.
Forms a complex with cognate antitoxin MazE3, possibly with 1:1 stoichiometry.
Mildly induced (5 to 9-fold) by starvation, when grown in a non-replicating state, in the presence of isoniazid, gentamycin or rifampicin.
Toxic component of a type II toxin-antitoxin (TA) system. Acts as an mRNA and 23S rRNA interferase, cleaving predominantly after the first 2 Us in the sequence 5'-UUCCU-3'; in 23S rRNA only cleaves once in the ribosomal A site in dissociated but not intact ribosomes. Cleavage of 23S rRNA inhibits protein translation; the 23S rRNA region cleaved is involved in tRNA-binding in the A site, 30S and 50S subunit interaction and ribosome recycling factor association (PubMed:23650345). Upon expression in E.coli and M.smegmatis inhibits cell growth and colony formation. It dramatically increases persister cell formation in M.smegmatis upon challenge with gentamicin or kanamycin. Overexpression leads to bacteriostasis rather than bacteriocide. Its toxic effect is neutralized by coexpression with cognate antitoxin MazE3.
Primarily hydroxylates the omega-carbon of a number of methyl-branched lipids, including (2E,6E)-farnesol, phytanate, geranylgeraniol, 15-methylpalmitate and (2E,6E)-farnesyl diphosphate (PubMed:19933331). Also catalyzes the sequential oxidation of the terminal methyl of cholest-4-en-3-one into (25R)-26-hydroxycholest-4-en-3-one (alcohol), (25R)-26-oxocholest-4-en-3-one (aldehyde), to finally yield the carboxylic acid (25R)-3-oxocholest-4-en-26-oate (PubMed:20843794). Cyp124 catalyzes preferentially the oxidation of (25R)-26-hydroxycholest-4-en-3-one diastereomer (PubMed:20843794). Also able to sequentially oxidize cholesterol itself, not only cholest-4-en-3-one (PubMed:20843794).
Belongs to the glycosyltransferase 28 family. MurG subfamily.
Cell wall formation. Catalyzes the transfer of a GlcNAc subunit on undecaprenyl-pyrophosphoryl-MurNAc-pentapeptide (lipid intermediate I) to form undecaprenyl-pyrophosphoryl-MurNAc-(pentapeptide)GlcNAc (lipid intermediate II).
Associates with the 50S ribosomal subunit.
Belongs to the TRAFAC class TrmE-Era-EngA-EngB-Septin-like GTPase superfamily. EngA (Der) GTPase family.
GTPase that plays an essential role in the late steps of ribosome biogenesis.
Belongs to the 'phage' integrase family. XerD subfamily.
Forms a cyclic heterotetrameric complex composed of two molecules of XerC and two molecules of XerD (By similarity). Co-immunoprecipitates with DarG in the presence and absence of darT (PubMed:32634279).
Site-specific tyrosine recombinase, which acts by catalyzing the cutting and rejoining of the recombining DNA molecules. The XerC-XerD complex is essential to convert dimers of the bacterial chromosome into monomers to permit their segregation at cell division. It also contributes to the segregational stability of plasmids.
A single deletion is slightly more sensitive to oxidative stress (cumene hydroperoxide and plumbagin). A double bfrA-bfrB mutant grows 40% less well in the presence of an iron chelator, is more sensitive to oxidative stress, has significantly reduced pathological effects in guinea pigs and a marked reduction in its survival in human macrophages.
Belongs to the ferritin-like superfamily. Bacterioferritin family.
Binds 1 heme b (iron(II)-protoporphyrin IX) group per dimer.
Binds 2 iron ions per subunit. The catalytic dinuclear iron-binding site within each subunit is known as the ferroxidase center.
Homooligomer of 24 subunits, arranged as 12 dimers, that are packed together to form an approximately spherical molecule with a central cavity, in which large amounts of iron can be deposited.
Iron-storage protein, whose ferroxidase center binds Fe(2+) ions, oxidizes them by dioxygen to Fe(3+), and participates in the subsequent Fe(3+) oxide mineral core formation within the central cavity of the protein complex.
Constitutively expressed at a low level under all conditions tested. Transcribed under control of SigJ.
Interacts transiently with the RNA polymerase catalytic core formed by RpoA, RpoB, RpoC and RpoZ (2 alpha, 1 beta, 1 beta' and 1 omega subunit) to form the RNA polymerase holoenzyme that can initiate transcription.
Sigma factors are initiation factors that promote the attachment of RNA polymerase to specific initiation sites and are then released. Extracytoplasmic function (ECF) sigma factors are held in an inactive form by a cognate anti-sigma factor until released, although no anti-sigma factor is known for this protein (By similarity).
The sigma-70 factor domain-4 contains a helix-turn-helix (H-T-H) motif that mediates interaction with the -35 element in promoter DNA. The domain also mediates interaction with the RNA polymerase subunit RpoA (By similarity).
Monomer and homodimer. Part of the essential Sec protein translocation apparatus which comprises SecA, SecYEG and auxiliary proteins SecDF. Other proteins may also be involved.
Belongs to the Mg-chelatase subunits D/I family. ComM subfamily.
Deletion of the gene does not affect the synthesis of the major virulence factor ESAT-6, but greatly reduces its secretion. In infected macrophages, Rv1057 deletion significantly reduces the secretion levels of cytokines IL-1 beta, IL-10, TNF-alpha, and INF-gamma, but does not affect IL-4 and IL-8 levels. Deletion of Rv1057 greatly impairs the ability of M.tuberculosis to replicate in macrophages.
Expression increases during early growth in macrophages (PubMed:16352831). Expression is directly regulated by both the MprAB and TrcRS two-component systems (PubMed:16352831, PubMed:22099420). Negatively regulated by TrcS/TrcR (PubMed:16352831). Activated by MprA/MprB under envelope stress (PubMed:22099420). Expression may also be regulated by sigma E (PubMed:16352831).
May play an important role in host-pathogen interactions and in ESAT-6 secretion.
Belongs to the GHMP kinase family. GalK subfamily.
Catalyzes the transfer of the gamma-phosphate of ATP to D-galactose to form alpha-D-galactose-1-phosphate (Gal-1-P).
Belongs to the class II fructose-bisphosphate aldolase family.
Binds 2 Zn(2+) ions per subunit. One is catalytic and the other provides a structural contribution.
Catalyzes the aldol condensation of dihydroxyacetone phosphate (DHAP or glycerone-phosphate) with glyceraldehyde 3-phosphate (G3P) to form fructose 1,6-bisphosphate (FBP) in gluconeogenesis and the reverse reaction in glycolysis.
EsxG, in complex with EsxH, disrupts ESCRT function and impairs host phagosome maturation, thereby promoting intracellular bacterial growth. The complex acts by interacting, via EsxH, with the host hepatocyte growth factor-regulated tyrosine kinase substrate (HGS/HRS), a component of the ESCRT machinery. EsxG stabilizes EsxH in the host cytosol.
Could be required for host endothelial-cell invasion and/or intracellular survival.
Invasion of the infant human brain microvascular endothelial-cell monolayer is significantly decreased in transposon mutant.
Belongs to the sterol desaturase family.
Involved in a F420-dependent anti-oxidant mechanism that protects M.tuberculosis against oxidative stress and bactericidal agents. Catalyzes the F420H(2)-dependent two-electron reduction of quinones to dihydroquinones, thereby preventing the formation of cytotoxic semiquinones obtained by the one-electron reduction pathway (PubMed:23240649). In vitro, catalyzes the reduction of both benzoquinone and naphthoquinone analogs; since menaquinone is the sole quinone electron carrier in the respiratory chain in M.tuberculosis, the physiological electron acceptor for Fqr-mediated F420H(2) oxidation is therefore likely to be the endogenous menaquinone found in the membrane fraction of M.tuberculosis (PubMed:23240649). Is able to use F420 species with two and five glutamate residues in its polyglutamate tail (PubMed:22023140). Cannot use NADH or NADPH instead of F420H(2) as the electron donor (PubMed:23240649).
Is involved in the bioreductive activation of bicyclic 4-nitroimidazole prodrugs such as PA-824 and delamanid developed for anti-tuberculosis therapy against both replicating and persistent bacteria. It converts PA-824 into three primary metabolites resulting from reduction of the imidazole ring at C-3; the major one is the corresponding des-nitroimidazole that generates lethal reactive nitrogen species, including nitric oxide (NO), which appears to be responsible for the anaerobic killing activity. Ddn uses the reduced F420 produced by FGD1 to activate PA-824. Delamanid (OPC-67683) is also reduced by Ddn to its des-nitro form.
Belongs to the NAD(P)-dependent epimerase/dehydratase family. GDP-mannose 4,6-dehydratase subfamily.
Catalyzes the conversion of GDP-D-mannose to GDP-4-dehydro-6-deoxy-D-mannose.
DNA repair enzyme that has both DNA N-glycosylase activity and AP-lyase activity. The DNA N-glycosylase activity releases various damaged pyrimidines from DNA by cleaving the N-glycosidic bond, leaving an AP (apurinic/apyrimidinic) site. The AP-lyase activity cleaves the phosphodiester bond 3' to the AP site by a beta-elimination, leaving a 3'-terminal unsaturated sugar and a product with a terminal 5'-phosphate. Has a preference for oxidized pyrimidines, such as thymine glycol (prefers 5S isomers) 5,6-dihydrouracil:G, 5-hydroxyuracil:G, 5-hydroxycytosine:G and urea:A. Cleaves ssDNA containing an AP site.
Belongs to the glycosyl hydrolase 15 family.
Catalyzes the hydrolysis of alpha,alpha-trehalose into two molecules of D-glucose.
Shows an absolute requirement for inorganic phosphate for activity. The function of the phosphate may involve stabilizing the protein conformation and/or initiating protein aggregation. Unlike the threhalase ortholog in M.smegmatis, does not require Mg(2+) for activity.
Probably plays a role in host phagosome maturation arrest (PubMed:20844580).
Disruption results in a growth defect in macrophage and mouse infections.
Function is positively regulated by phosphorylation.
Homodimer (Probable). Interacts with PknF.
In Rv1747 the ATP-binding domain (NBD) and the transmembrane domain (TMD) are fused. The two FHA domains are required for phosphorylation by PknF.
In the C-terminal section; belongs to the ABC-2 integral membrane protein family.
In the central section; belongs to the ABC transporter superfamily.
Involved in the translocation of an unknown substrate across the membrane. Transmembrane domains (TMD) form a pore in the membrane and the ATP-binding domain (NBD) is responsible for energy generation. Required for virulence.
Phosphorylated by PknF. Can probably be phosphorylated in vivo by other kinases when PknF is missing.
Belongs to the ATPase alpha/beta chains family.
F-type ATPases have 2 components, CF(1) - the catalytic core - and CF(0) - the membrane proton channel. CF(1) has five subunits: alpha(3), beta(3), gamma(1), delta(1), epsilon(1). CF(0) has three main subunits: a(1), b(2) and c(9-12). The alpha and beta chains form an alternating ring which encloses part of the gamma chain. CF(1) is attached to CF(0) by a central stalk formed by the gamma and epsilon chains, while a peripheral stalk is formed by the delta and b chains.
Produces ATP from ADP in the presence of a proton gradient across the membrane. The alpha chain is a regulatory subunit.
Part of a heme-iron acquisition system. Acts by binding heme and delivering it to the membrane proteins MmpL3 and MmpL11. Can use free heme or heme from host hemoglobin.
Cells lacking the core proteasome prcBA subunits exhibit reduced growth and persistence in mice. They are also attenuated in interferon-gamma-deficient mice. They also display increased sensitivity to reactive nitrogen intermediates (RNI) and increased resistance to oxidative stress.
Component of the proteasome core, a large protease complex with broad specificity involved in protein degradation. The M.tuberculosis proteasome is able to cleave oligopeptides not only after hydrophobic but also after basic, acidic and small neutral residues (PubMed:16468985). In complex with the ATPase Mpa, degrades protein targets conjugated to a prokaryotic ubiquitin-like protein (Pup). Among the identified substrates of the M.tuberculosis proteasome are the pupylated FabD, PanB and Mpa proteins (PubMed:17082771). One function of the proteasome is to contribute to M.tuberculosis ability to resist killing by host macrophages, since the core proteasome is essential for persistence of the pathogen during the chronic phase of infection in mice (PubMed:18059281). Likely functions to recycle amino acids under nutrient starvation, thereby enabling the cell to maintain basal metabolic activities (PubMed:20711362) (By similarity). The mechanism of protection against bactericidal chemistries of the host's immune response probably involves the degradation of proteins that are irreversibly oxidized, nitrated, or nitrosated. A proteolysis-independent activity of the proteasome core is required for optimal growth of M.tuberculosis in mouse lungs and for RNI resistance; in contrast, long-term survival of M.tuberculosis in stationary phase and during starvation in vitro and in the chronic phase of mouse infection required a proteolytically active proteasome (PubMed:20711362).
In contrast to Rhodococus, the M.tuberculosis proteasome does not require the propeptide of PrcB for correct folding and assembly.
In the course of search for new antibiotics, a class of oxathiazol-2-one compounds has been identified that selectively inhibits the M.tuberculosis proteasome over the human proteasome and that kills non-replicating M.tuberculosis.
The 20S proteasome core is composed of 14 alpha and 14 beta subunits that assemble into four stacked heptameric rings, resulting in a barrel-shaped structure. The two inner rings, each composed of seven catalytic beta subunits, are sandwiched by two outer rings, each composed of seven alpha subunits. The catalytic chamber with the active sites is on the inside of the barrel. Has a gated structure, the ends of the cylinder being occluded by the N-termini of the alpha-subunits. Is capped by the proteasome-associated ATPase, ARC (Mpa).
The formation of the proteasomal ATPase ARC-20S proteasome complex, likely via the docking of the C-termini of ARC into the intersubunit pockets in the alpha-rings, may trigger opening of the gate for substrate entry. Interconversion between the open-gate and close-gate conformations leads to a dynamic regulation of the 20S proteasome proteolysis activity. In vitro, chymotryptic and tryptic activities of the proteasome are both completely inhibited by epoxomicin and by the peptidyl boronate inhibitor MLN-273. Also inhibited by Mg(2+), Ca(2+) and SDS. It was also shown that certain oxathiazol-2-one compounds can act as selective suicide-substrate inhibitors of the M.tuberculosis proteasome by irreversibly cyclocarbonylating its active site threonine. Proteasome activity is potently inhibited by fellutamide B (Ki=6.8 nM), a lipopeptide aldehyde that forms a reversible bond with the beta-OH of the active site threonine (PubMed:20558127).
The unprocessed form of PrcB is phosphorylated by PknA. Processing of PrcB is greatly retarded in the presence of H(2)O(2).
Disulfide oxidoreductase that catalyzes the oxidation of reduced, unfolded secreted proteins to form disulfide bonds. Despite a weak homology to thioredoxin this cannot serve as a substrate for thioredoxin reductase.
A promising vaccine candidate, an rpfB-encoding DNA vaccine induces elevated cellular immune responses, confers modest but significant protection against intra-tracheal tuberculosis challenge in female C57BL/6 and BALB/c mice.
Activity on the artificial substrate MUF tri-NAG is inhibited by 2-nitrophenylthiocyanates (NPT) compounds. The synergistic effects on peptidoglycan degradation of RipA plus RpfB are inhibited by addition of PBP1A (ponA1).
An expressed fragment (residues 194-362) hydrolyzes an artificial lysozyme substrate 4-methylumbelliferyl-beta-D-N,N',N''-triacetylchitotrioside (MUF tri-NAG).
Monomer (Probable). Interacts with RipA.
Not essential, disruption of rpfB alone has no effect on growth or survival in liquid culture, nor in mouse infection models, colonies plated over a 52-week culture period are visibly drier and more friable. Alterations in gene expression are seen. All 5 genes in this family can be deleted without affecting growth in culture, however triple deletion mutants (rpfA-rpfC-rpfB or rpfA-rpfC-rpfD) are not able to resuscitate spontaneously in the presence or absence of O(2), and are attenuated in a mouse infection model.
Reduces lag phase and enhances the growth of quiescent (1 month-old culture) M.tuberculosis; works best between 8 and 128 pM. Increases the number of bacteria that can be recovered from a 3 month-old culture. Stimulates growth of stationary phase M.bovis (a slowly-growing Mycobacterium) as well as M.smegmatis cells (a fast grower). Binds N,N',N''-triacetylchitotriose (tri-NAG). A fragment (residues 194-362) hydrolyzes an artificial lysozyme substrate 4-methylumbelliferyl-beta-D-N,N',N''-triacetylchitotrioside (MUF tri-NAG). By itself has little activity on cell wall, in combination with RipA is active against cell wall extracts from a number of Actinobacteria; this activity is inhibited by PBP1A (ponA1). Sequential gene disruption indicates RpfB and RpfE are higher than RpfD and RpfC in functional hierarchy.
Belongs to the diaminopimelate epimerase family.
Catalyzes the stereoinversion of LL-2,6-diaminoheptanedioate (L,L-DAP) to meso-diaminoheptanedioate (meso-DAP), a precursor of L-lysine and an essential component of the bacterial peptidoglycan.
Inhibited by sulphydryl alkylating agents, 2-nitro-5-thiocyanatobenzoate (NTCB), 5,50-dithiobis(2-nitrobenzoic acid) (DTNB) and 1,2-benzisothiazolidine 3-one (BIT) at nanomolar concentrations.
Belongs to the carotenoid oxygenase family.
Catalyzes the oxidative cleavage of several carotenoids and apocarotenoids in vitro. In contrast to other carotenoid oxygenases, cleaves substrates at two different sites, namely the central C15-C15' and an excentric double bond at the C13-C14 position, leading to retinal (C20), beta-apo-14'-carotenal (C22) and beta-apo-13-carotenone (C18) from beta-carotene (C40), as well as the corresponding hydroxylated products from zeaxanthin and lutein. Converts beta-apo-10'-carotenal (C27) into beta-apo-13-carotenone (C18) and to minor amounts of beta-apo-15-carotenal (retinal; C20) from the cleavage at the C13-C14 and the C15-C15' double bonds, respectively. Can also cleave beta-apo-8'-carotenal, 3-OH-beta-apo-8'-carotenal and 3-OH-beta-apo-10'-carotenal. Does not use as substrates beta-apocarotenoids that have a chain length shorter than C25. Also cleaves lycopene into apo-13-lycopenone (C18) and apo-15'-lycopenal (acycloretinal, C20). Moreover, is able to cleave 3,3'-dihydroxy-isorenieratene representing aromatic carotenoids synthesized by other mycobacteria. Might be involved in the utilization of carotenoids from host cells to produce compounds required for normal growth.
M.tuberculosis is assumed to be unable to synthesize conventional colored carotenoids, but the data obtained in PubMed:20929460 reveal that M.tuberculosis may utilize carotenoids from host cells and interfere with their retinoid metabolism. The occurrence of suitable carotenoid-substrates (i.e. beta-carotene, lutein, zeaxanthin and lycopene) have been shown in human plasma and tissues, and the apocarotenoid substrate beta-apo-10'-carotenal may also be present in lungs.
Esterase activity is significantly inhibited by the serine modifier phenylmethylsulfonyl fluoride (PMSF).
Esterase that hydrolyzes short to medium chain fatty acid esters with the highest specific activity for p-nitrophenyl caproate (pNPC6). Has lower activity with p-nitrophenyl caprylate (pNPC8) and p-nitrophenyl butyrate (pNPC4). Has weak activity with p-nitrophenyl caprate (pNPC10) and p-nitrophenyl laurate (pNPC12). Does not possess lipolytic activity and cutinase activity.
Has no inosine-5'-monophosphate dehydrogenase activity.
Probably part of an ABC transporter complex. Probably responsible for energy coupling to the transport system (By similarity).
The complex is composed of two ATP-binding proteins (Rv0073), two transmembrane proteins (Rv0072) and a solute-binding protein.
Belongs to the ammonia transporter channel (TC 1.A.11.2) family.
Involved in the uptake of ammonium/ammonia (NH(4)(+)/NH(3)).
Binding to DNA is inhibited by nickel and, to some extent, cobalt ions.
Represses transcription of ctpJ/nmtA, by binding to its promoter region.
Binds 2 divalent metal cations per subunit. Magnesium or manganese.
Catalyzes the conversion of D-ribulose 5-phosphate to formate and 3,4-dihydroxy-2-butanone 4-phosphate.
Catalyzes the conversion of GTP to 2,5-diamino-6-ribosylamino-4(3H)-pyrimidinone 5'-phosphate (DARP), formate and pyrophosphate.
In the C-terminal section; belongs to the GTP cyclohydrolase II family.
In the N-terminal section; belongs to the DHBP synthase family.
Induced when cells are grown in human macrophages (THP-1 macrophage cell line) (PubMed:22375954).
May help load RecA onto ssDNA (By similarity).
Catalyzes the formation of a covalent CysO-cysteine adduct via a sulfur transfer, using the thiocarboxylated sulfur carrier protein CysO-COSH as sulfur donor and O-phospho-L-serine (OPS) as sulfur acceptor. Can also use sodium sulfide as sulfur donor in vitro, albeit with less efficiency, but not thiosulfate or thio-nitro-benzoate. O-acetylserine (OAS) is a very poor substrate in comparison with OPS. May be of particular importance for cysteine biosynthesis in the persistent phase of M.tuberculosis.
Strains lacking this gene are shown to be attenuated in macrophages.
The five C-terminal amino acid residues are inserted into the active site cleft in the closed conformation, protect the aminoacrylate intermediate and are involved in sulfur donor selectivity.
Belongs to the AB hydrolase superfamily.
Contains an N-terminal LytE region, which consists of three consecutive LysM domains, and a C-terminal esterase domain. LytM domains are essential for anchoring protein to the cell wall. The presence of LytM domains results in enhanced rate of protein aggregation at higher temperature.
Exhibits lipolytic activity with medium chain length esters as optimum substrates (PubMed:30560095). In vitro, pNP-caprylate (C8) is the optimum substrate followed by pNP-capricate (C10) (PubMed:30560095). May modulate the cell wall lipids to favor the survival of bacteria under stress conditions (PubMed:30560095).
Expression is up-regulated under nutrient depletion condition.
Overexpression in M.smegmatis leads to change in colony morphology, enhanced pellicle and aggregate formation, which may be linked with the changed lipid composition of the cell wall. Cell wall has higher amount of lipids, with a significant increase in trehalose dimycolate content. Overexpression also leads to increased drug resistance and enhanced intracellular survival inside the macrophage cell line.
Being a receptor for trehalose, which is essential for the survival and virulence of M.tuberculosis, this protein is a potential target for antitubercular drug design.
Belongs to the bacterial solute-binding protein 1 family.
Monomer (PubMed:35775983). The complex is composed of two ATP-binding proteins (SugC), two transmembrane proteins (SugA and SugB) and a solute-binding protein (LpqY) (PubMed:21118978).
Mutants show no growth on trehalose as the sole carbon and energy source, but grow normally on glucose. They secrete substantial amounts of trehalose during growth on glycerol.
Part of the ABC transporter complex LpqY-SugA-SugB-SugC, which is highly specific for uptake of trehalose. Involved in the recycling of extracellular trehalose released from trehalose-containing molecules synthesized by M.tuberculosis. Trehalose uptake is essential for virulence (PubMed:21118978). No binding affinity for maltose (PubMed:35775983).
The RCK N-terminal domain binds NAD and possibly other effectors. This is expected to cause a conformation change that regulates potassium transport (By similarity).
In the C-terminal section; belongs to the phosphoglycerate mutase family.
Induces maturation and activation of human dendritic cells (DCs), via TLR2-dependent activation of ERK1/2, p38 MAPK, and NF-kappa-B signaling pathways, and enhances the ability of DCs to stimulate CD4(+) T cells. By activating DCs, could potentially contribute to the initiation of innate immune responses during tuberculosis infection and hence regulate the clinical course of tuberculosis (PubMed:20176745). Involved in resistance to oxidative stress, via TLR2-dependent activation of the PI3K-ERK1/2-NF-kappa-B signaling pathway and expression of COX-2 and Bcl2. Also abolishes H(2)O(2)-triggered activation of p38 MAPK (PubMed:20558725).
Belongs to the haloalkane dehalogenase family. Type 2 subfamily.
Required for maintaining the appropriate mycolic acid composition and permeability of the envelope on its exposure to acidic pH (PubMed:15937179). Catalyzes the activation of long-chain fatty acids as acyl-coenzyme A (acyl-CoA), which are then transferred to the multifunctional polyketide synthase (PKS) type III for further chain extension (PubMed:19182784, PubMed:20027301, PubMed:22560731). It has preference for the fatty acid with long chain length in the following order: hexacosanoic acid (C26), tetracosanoic acid (C24) and palmitic acid (C16) (PubMed:20027301).
By salicylate. Part of the Rv0560c-Rv0559c operon. Operon induction is slow but is maintained for at least 2 weeks in aerobic culture in the presence of salicylate.
Toxic component of a type II toxin-antitoxin (TA) system. An RNase. Its cognate antitoxin is VapB24 (By similarity).
Belongs to the aspartate/glutamate racemases family.
Provides the (R)-glutamate required for cell wall biosynthesis.
Antitoxin component of a type II toxin-antitoxin (TA) system. Upon expression in M.smegmatis neutralizes the effect of cognate toxin VapC33.
Constitutively expressed, increases in stationary phase (at protein level). mRNA levels rise nearly 50-fold during mouse macrophage infection. Part of the glbN-lprI operon.
Glycosylated; alpha-D-mannosidase treatment decreases its apparent molecular weight. Glycosylation probably helps target protein to the cell surface; mutation of predicted glycosylation sites (Thr-24, Thr-28 and/or Thr-117) makes protein partially inaccesible to externally added trypsin. May also be glycosylated on other residues. Glycosylation is probably not necessary for inhibition of lysozyme.
In the C-terminal section; belongs to the MliC family.
Probably essential, it cannot be deleted.
Strongly binds and inhibits lysozyme, may help bacteria survive in lysozyme-producing host cells. When overexpressed in M.tuberculosis or M.smegmatis increases resistance to hen egg white lysozyme. M.smegmatis overexpressing LprI survive better during intracellular infection of peritoneal and monocyte-derived macrophages, both of which produce lysozyme during infection; M.smegmatis does not encode this protein. Somewhat better survival is seen in human cell lines when M.smegmatis cells express both proteins from this operon, i.e. GlbN (HbN) and LprI.
Belongs to the TRAFAC class translation factor GTPase superfamily. Classic translation factor GTPase family. EF-G/EF-2 subfamily.
Catalyzes the GTP-dependent ribosomal translocation step during translation elongation. During this step, the ribosome changes from the pre-translocational (PRE) to the post-translocational (POST) state as the newly formed A-site-bound peptidyl-tRNA and P-site-bound deacylated tRNA move to the P and E sites, respectively. Catalyzes the coordinated movement of the two tRNA molecules, the mRNA and conformational changes in the ribosome (By similarity).
Belongs to the bacterial ribosomal protein bL31 family. Type A subfamily.
Expressed during growth in culture; expression increases from lag to exponential phase. Has a weak SigL-independent promoter, is also weakly autoregulated, no other sigma factor allows its transcription. Forms an operon with rslA.
Extracytoplasmic function (ECF) sigma factors are held in an inactive form by an anti-sigma factor until released by regulated intramembrane proteolysis (RIP). RIP occurs when an extracytoplasmic signal triggers a concerted proteolytic cascade to transmit information and elicit cellular responses. The membrane-spanning anti-sigma factor is first cut extracytoplasmically (site-1 protease, S1P), then within the membrane itself (site-2 protease, S2P, Rip1), while cytoplasmic proteases finish degrading the regulatory protein, liberating SigL (Probable).
In a single sigL (PubMed:16199577) or double sigL-rslA (PubMed:16552079) disruption mutant, no visible phenotype; not more susceptible than the parental strain to several oxidative and nitrosative stresses. Infected BALB/c or DBA/2 mice showed a significantly prolonged survival time relative to mice infected with wild-type bacteria, although bacteria proliferate normally.
Interacts transiently with the RNA polymerase catalytic core formed by RpoA, RpoB, RpoC and RpoZ (2 alpha, 1 beta, 1 beta' and 1 omega subunit) to form the RNA polymerase holoenzyme that can initiate transcription. Interacts (via sigma-70 factor domain-4) with anti-sigma-L factor RslA.
Sigma factors are initiation factors that promote the attachment of RNA polymerase to specific initiation sites and are then released. Extracytoplasmic function (ECF) sigma factors are held in an inactive form by an anti-sigma factor until released by regulated intramembrane proteolysis. Over-expression of SigL induces 19-28 genes including polyketide synthases, secreted and membrane proteins. Might play a minor role in regulating SigB.
The sigma-70 factor domain-4 contains a helix-turn-helix (H-T-H) motif that mediates interaction with the -35 element in promoter DNA. The domain also mediates interaction with the RNA polymerase subunit RpoA. Interactions between sigma-70 factor domain-4 and anti-sigma factors prevents interaction of sigma factors with the RNA polymerase catalytic core (Probable).
Although found extracellularly, no signal sequence is present. An alternative secretory pathway may be used.
Belongs to the iron/manganese superoxide dismutase family.
Destroys superoxide anion radicals which are normally produced within the cells and which are toxic to biological systems.
Belongs to the major facilitator superfamily. Sugar transporter (TC 2.A.1.1) family.
Belongs to the fatty acid desaturase type 2 family.
May be a desaturase involved in mycobacterial fatty acid biosynthesis.
Protein expressed in vitro is immunologically active and reacts with antibodies from tuberculosis patient sera. Could provide a specific complementary diagnostic test for the presence of and infection with M.tuberculosis.
Belongs to the 6-phosphogluconate dehydrogenase family.
Belongs to the aspartate/ornithine carbamoyltransferase superfamily. OTCase family.
Competitively inhibited by L-norvaline (NVA).
Reversibly catalyzes the transfer of the carbamoyl group from carbamoyl phosphate (CP) to the N(epsilon) atom of ornithine (ORN) to produce L-citrulline, which is a substrate for argininosuccinate synthetase, the enzyme involved in the final step in arginine biosynthesis.
Belongs to the class-III pyridoxal-phosphate-dependent aminotransferase family. HemL subfamily.
Belongs to the PAPS reductase family. CysH subfamily.
Catalyzes the formation of sulfite from adenosine 5'-phosphosulfate (APS) using thioredoxin as an electron donor.
Inhibited by adenosine 5'-diphosphate (ADP).
Was identified as a high-confidence drug target (PubMed:19099550, PubMed:19678707, PubMed:25710356). Inhibitors that target the Fe-S cluster have been developed and studied (PubMed:25710356).
An IS6110 insertion element has been found in strain LCDC-194, interrupting the plcA gene.
Constitutively expressed (PubMed:11050656). Expression is induced in vitro in the presence of phosphatidylcholine. Also induced upon infection of THP-1 macrophages (PubMed:12100560).
Polymorphism was discovered in the phospholipase plcA/B/C region. Some strains seem to lack both plcA and plcB genes, while others lack only plcB.
Bifunctional enzyme that catalyzes both the deamination of dCTP to dUTP and the hydrolysis of dUTP to dUMP without releasing the toxic dUTP intermediate. It also acts as a dUTP diphosphatase. Affinity for dCTP and dUTP are very similar.
dTTP inhibits both the combined reaction and the dUTPase reaction.
Binds and transfers iron-sulfur (Fe-S) clusters to target apoproteins. Can hydrolyze ATP.
In the C-terminal section; belongs to the Mrp/NBP35 ATP-binding proteins family.
In the N-terminal section; belongs to the MIP18 family.
Belongs to the thymidylate synthase ThyX family.
Binds 4 FAD per tetramer. Each FAD binding site is formed by three monomers.
Catalyzes the reductive methylation of 2'-deoxyuridine-5'-monophosphate (dUMP) to 2'-deoxythymidine-5'-monophosphate (dTMP) while utilizing 5,10-methylenetetrahydrofolate (mTHF) as the methyl donor, and NADPH and FADH(2) as the reductant (PubMed:18493582). Is essential for growth of the pathogen on solid media in vitro; the essential function is something other than dTMP synthase (PubMed:12657046) (PubMed:22034487).
Cells lacking this gene display impaired growth (PubMed:12657046). Strains with a thyX deletion could not be obtained (PubMed:22034487).
Crystallographic studies have shown that NADPH/NADP(+) binding expels both FAD and dUMP from the active site, by competing for the binding site (PubMed:16730023). However, the location of NADPH binding might not be biologically relevant (PubMed:18192395).
Is expressed under the exponential phase of growth, and down-regulated upon starvation. Expression of thyX is significantly increased within murine macrophages or under acid stress. Is expressed at a lower level than thyA under all of the in vitro and in vivo growth conditions tested.
Is potently inhibited by 5-fluoro-2'-deoxyuridine 5'-monophosphate (FdUMP), but in contrast to ThyA, is not inhibited by the folate-based 1843U89 (PubMed:18493582). A 5-alkynyl dUMP analog has been shown to highly inhibit ThyX (IC(50) value of 0.91 uM), while lacking activity against the classical mycobacterial thymidylate synthase ThyA, and therefore is a selective mycobacterial FDTS inhibitor (PubMed:21657202).
Homodimer in active state (PubMed:17942407). In solution, exists as both a monomer and a dimer in a concentration-dependent equilibrium (PubMed:17942407).
Member of the two-component regulatory system SenX3/RegX3 involved in stress response (PubMed:12777483, PubMed:21698211, PubMed:35980355). The system is involved in phosphate starvation response (PubMed:28698272). Plays a role in modulating expression of aerobic response and in the regulation of response to hypoxia (PubMed:21698211, PubMed:35980355). Involved in virulence (PubMed:12777483). Regulates dozens of genes, directly or indirectly (PubMed:12777483, PubMed:35980355). Is directly involved in the regulation of the expression of gltA, cydAB and ald (PubMed:21698211). Binds to the upstream regions of the hypoxia-associated genes Rv3334, whiB7, Rv0195, Rv0196 and Rv1960c (PubMed:35980355).
Part of the senX3-regX3 operon (PubMed:9426136). The two genes are separated by a rather long intercistronic region composed of a class of duplicated sequences named mycobacterial interspersed repetitive units (MIRUs) (PubMed:9426136). Significantly up-regulated after 28 days of hypoxia (PubMed:35980355).
Phosphorylated by SenX3 (By similarity). Phosphorylated and inhibited by PknB (PubMed:31160336).
Phosphorylation by SenX3 stimulates binding to the target promoters (PubMed:21698211). Activation of the SenX3-RegX3 two-component system is inhibited by PhoY1 and PhoY2 when phosphate is readily available (PubMed:28698272). Overexpression of the kinase domain of PknB (PknB-KDMtb) inhibits the transcriptional activity of RegX3 by phosphorylating Thr-100, Thr-191 and Thr-217 (PubMed:31160336). Phosphorylation at Thr-191 and Thr-217 abolishes the DNA-binding ability of RegX3 and phosphorylation at Thr-100 likely prevents RegX3 from being activated through conformational changes induced by SenX3-mediated phosphorylation (PubMed:31160336).
The senX3-regX3 deletion mutant shows a growth defect after infection of macrophages and is attenuated in both immunodeficient and immunocompetent mice (PubMed:12777483). Deletion of the gene leads to differential regulation of a set of genes involved in, among others, cell wall and cell processes, intermediary metabolism, respiration, virulence and transcriptional regulation (PubMed:35980355). Deletion mutant is attenuated in terms of its ability to withstand hypoxia (PubMed:35980355).
Involved in the biosynthesis of the enzyme cofactor mycofactocin (MFT). Acts as a glycosyltransferase that catalyzes the oligoglycosylation of pre-mycofactocin (PMFT), adding up to nine beta-1,4-linked glucose residues.
Interacts with (phosphorylated) PknB via the FHA domain. Interacts with PapA5 via a phosphoindependent interaction involving N-terminal residues preceding the FHA domain.
Phosphorylated by PknB (PubMed:19826007). Dephosphorylated by PstP (PubMed:19826007).
Fragments of the mature protein (residues 61-80, 101-120 and 121-140) prevent uptake of M.tuberculosis by a human macrophage-like cell line (PubMed:25041568).
Probably involved in bacterial recognition and uptake by its host (human) (PubMed:25041568).
Participates in various redox reactions through the reversible oxidation of its active center dithiol to a disulfide and catalyzes dithiol-disulfide exchange reactions.
Belongs to the OctT acyltransferase family.
Sugar octanoyltransferase likely involved in the biosynthesis of mycobacterial methylglucose lipopolysaccharide (MGLP). Catalyzes the transfer of an octanoyl group from octanoyl-CoA to the C6 OH of the second glucose in diglucosylglycerate (DGG). DGG is the preferred acceptor, but to a lesser extent, GG (glucosylglycerate) can also be used as substrate. DGG and GG are the two earliest intermediates in MGLP biosynthesis.
Belongs to the DNA polymerase type-A family.
In addition to polymerase activity, this DNA polymerase exhibits 3'-5' and 5'-3' exonuclease activity.
Single-chain monomer with multiple functions. Co-immunoprecipitates with DarG in the presence and absence of darT (PubMed:32634279).
Belongs to the ATP-dependent AMP-binding enzyme family. MenE subfamily.
Converts 2-succinylbenzoate (OSB) to 2-succinylbenzoyl-CoA (OSB-CoA). May be involved in the biosynthesis of menaquinone (By similarity).
Bifunctional enzyme that catalyzes two enzymatic reactions in biochemically unrelated pathways: acts as an aminodeoxychorismate (ADC) lyase (ADCL) in folate biosynthesis, converting 4-amino-4-deoxychorismate (ADC) to 4-aminobenzoate (PABA), and as a D-amino acid transaminase (DAAT) in peptidoglycan (PG) biosynthesis (PubMed:33950161). DAAT activity is strictly restricted to D-alanine and D-glutamate (PubMed:33950161). May function as a metabolic toggle that alternates between ADCL and DAAT activity, prioritizing the former over the latter in response to substrate accumulation (PubMed:33950161). Bifunctionality of this enzyme provides a failsafe mechanism for a metabolic coupling between nucleic acid and cell wall biosynthesis that appears to ensure prioritization of PABA production over D-alanine/D-glutamate biosynthesis (PubMed:33950161).
Deletion mutant exhibits a growth defect in liquid culture (PubMed:33950161). Mutant is significantly impaired for folate biosynthesis and exhibits minor defects in D-amino acid metabolism (PubMed:33950161). It shows a marked and selective accumulation of ADC, while the levels of PABA and downstream intermediates of folate biosynthesis are markedly depleted (PubMed:33950161). It also exhibits a selective and genetically complementable defect in D-glutamate pools, but not D-alanine pools (PubMed:33950161).
Belongs to the GTP-binding SRP family. FtsY subfamily.
Depletion of ffh (SRP) and ftsY results in differential expression of 14 proteins.
Involved in targeting and insertion of nascent membrane proteins into the cytoplasmic membrane. Acts as a receptor for the complex formed by the signal recognition particle (SRP) and the ribosome-nascent chain (RNC) (By similarity). Most of the substrate proteins are involved in stress regulation, lipid metabolism, intermediary metabolism, and cell wall processes (PubMed:29361248). Shows GTPase activity (PubMed:29361248, PubMed:33412199). Can also hydrolyze ATP, UTP and CTP (PubMed:33412199).
Part of the signal recognition particle protein translocation system, which is composed of SRP and FtsY.
The SRP-FtsY complex formation results in mutual stimulation of their GTP hydrolysis activity (PubMed:29361248). GTPase activity is stimulated by Mg(2+) or a high concentration of Mn(2+). Increasing Mg(2+) decreases the activity (PubMed:33412199). GDP acts as an inhibitor (PubMed:33412199).
Putative antitoxin component of a possible type II toxin-antitoxin (TA) system. The cognate toxin is VapC18.
Catalyzes the first step in hexosamine metabolism, converting fructose-6P into glucosamine-6P using glutamine as a nitrogen source.
Five Rv2301 high activity binding peptides (HABPs) could be included as components of an antituberculosis vaccine.
Induces interferon-gamma (IFN-gamma) release in animal models and in human TB patients (PubMed:9673225, PubMed:10076913). Also induces a strong delayed-type hypersensitivity (DTH) response in animal models (PubMed:9673225).
Belongs to the thymidylate synthase family. Bacterial-type ThyA subfamily.
Catalyzes the reductive methylation of 2'-deoxyuridine-5'-monophosphate (dUMP) to 2'-deoxythymidine-5'-monophosphate (dTMP) while utilizing 5,10-methylenetetrahydrofolate (mTHF) as the methyl donor and reductant in the reaction, yielding dihydrofolate (DHF) as a by-product. This enzymatic reaction provides an intracellular de novo source of dTMP, an essential precursor for DNA biosynthesis.
Cells lacking this gene display an in vitro growth defect, but deletion of thyA does not affect M.tuberculosis in vivo growth. Moreover, thyA deletion confers PAS resistance.
Is expressed under the exponential phase of growth, and down-regulated upon reaching the stationary phase or under both oxidative and nitrosative stress. Expression of thyA is significantly increased within murine macrophages or under acid stress. Is expressed at a higher level than thyX under all of the in vitro and in vivo growth conditions tested.
Is potently inhibited by 5-fluoro-2'-deoxyuridine 5'-monophosphate (FdUMP), and by the folate-based 1843U89.
Mutations within this gene have been associated with resistance to p-aminosalicylic acid (PAS) in some PAS-resistant M.tuberculosis clinical isolates and spontaneous mutants (PubMed:19237648) (PubMed:15225321). It seems that functional ThyA is required for M.tuberculosis to be sensitive to PAS (PubMed:22034487).
Fumarate dehydrogenase forms part of an enzyme complex containing four subunits: a flavoprotein, an iron-sulfur, and two hydrophobic anchor proteins.
Catalyzes the transfer of a palmitoyl moiety from palmitoyl-CoA to the 6-position of the mannose ring linked to the 2-position of myo-inositol in phosphatidyl-myo-inositol monomannoside (PIM1) or dimannoside (PIM2) (PubMed:12851411). Essential for growth and survival in axenic cultures and during macrophage infection and in a mouse model of infection (PubMed:33468587).
Essential, gene silencing is bactericidal (PubMed:33468587). Depletion of PatA causes a block in the biosynthesis of PIMs, resulting in severe changes in the composition of the mycobacterial cell wall membrane, which correlates with the loss of viability (PubMed:33468587).
Belongs to the TRAFAC class translation factor GTPase superfamily. Classic translation factor GTPase family. LepA subfamily.
Required for accurate and efficient protein synthesis under certain stress conditions. May act as a fidelity factor of the translation reaction, by catalyzing a one-codon backward translocation of tRNAs on improperly translocated ribosomes. Back-translocation proceeds from a post-translocation (POST) complex to a pre-translocation (PRE) complex, thus giving elongation factor G a second chance to translocate the tRNAs correctly. Binds to ribosomes in a GTP-dependent manner.
Involved in virulence (PubMed:20736081). Induces cytotoxic effects on mouse macrophage cell lines, via direct or indirect enzymatic hydrolysis of cell membrane phospholipids (PubMed:20736081). Hydrolyzes phosphatidylcholine (PubMed:20736081). Does not have hemolytic activity (PubMed:20736081).
Catalyzes the conversion of 4-hydroxy-tetrahydrodipicolinate (HTPA) to tetrahydrodipicolinate (Probable). Can use both NADH and NADPH as a reductant, with NADH being 6-fold as effective as NADPH.
Was originally thought to be a dihydrodipicolinate reductase (DHDPR), catalyzing the conversion of dihydrodipicolinate to tetrahydrodipicolinate. However, it was shown in E.coli that the substrate of the enzymatic reaction is not dihydrodipicolinate (DHDP) but in fact (2S,4S)-4-hydroxy-2,3,4,5-tetrahydrodipicolinic acid (HTPA), the product released by the DapA-catalyzed reaction.
Interacts with DesA3 to form a functional acyl-CoA desaturase complex.
Is likely involved in the aerobic desaturation system responsible for the synthesis of oleic acid from stearoyl-CoA; oleic acid is a precursor of mycobacterial membrane phospholipids and triglycerides. Is the electron transfer partner for the stearoyl-CoA 9-desaturase DesA3. Catalyzes electron transfer reaction between NADPH and the diiron center of DesA3. Cannot use NADH.
Belongs to the methyltransferase superfamily. RNA methyltransferase RsmG family.
Confers low-level streptomycin resistance. Seems to be an important cause of resistance in resistant M.tuberculosis isolates.
Specifically methylates the N7 position of guanine in position 518 of 16S rRNA.
Arabinosyl transferase responsible for the polymerization of arabinose into the arabinan of arabinogalactan.
Positively regulated by the transcriptional regulatory protein EmbR.
This is one of the target of the anti-tuberculosis drug ethambutol [(S,S')-2,2'-(ethylenediimino)di-1-butanol; EMB]. EMB is a first-line drug used to treat tuberculosis. EMB inhibits the transfer of arabinogalactan into the cell wall.
May regulate a gene cluster involved in mycofactocin expression. Mycofactocin is a conserved polypeptide that might serve as an electron carrier.
Part of an export system, which is required for biosynthesis and secretion of siderophores (PubMed:23431276). Essential for normal replication during the active-growth phase of the murine tuberculosis model (PubMed:15908378).
Belongs to the dethiobiotin synthetase family.
Catalyzes a mechanistically unusual reaction, the ATP-dependent insertion of CO2 between the N7 and N8 nitrogen atoms of 7,8-diaminopelargonic acid (DAPA, also called 7,8-diammoniononanoate) to form a ureido ring (PubMed:20565114). Can use a range of NTPs; has highest affinity for CTP (KD is measured as 17.2 uM or 0.160 uM in 2 different papers) while KD for ATP is 331 uM or 75 uM in the same papers. Gly-169 plays a role in NTP discrimination (PubMed:25801336, Ref.5).
While ADP, ATP, ITP, TTP and UTP can be crystallized in the enzyme in approximately the same place as CTP, it is their phosphate tails that anchor them to the enzyme, their nucleoside moieties do not bind in the same way CTP does.
Deletion experiments show that amino acids 95-133 are required for activation of MprA.
Induced by MprA. Differentially up-regulated under different stress conditions, such as low concentrations of detergents and alkaline pH. Induced by low concentrations of sodium dodecyl sulfate (SDS) in a SigE-dependent manner. In strain ATCC 25618 / H37Rv, repressed during growth in macrophages. Highly up-regulated during the early stages of invasion of the human blood-brain barrier.
Member of the two-component regulatory system MprB/MprA which contributes to maintaining a balance among several systems involved in stress resistance and is required for establishment and maintenance of persistent infection in the host. In response to environmental signals MprB acts as both a membrane-associated protein kinase that undergoes autophosphorylation and subsequently transfers the phosphate to MprA, and a protein phosphatase that dephosphorylates phospho-MprA. MprB/MprA is involved in regulation of numerous stress-responsive genes, including up-regulation of two sigma factors, sigE and sigB as well as pepD and mprA, and repression of multiple genes from regulons associated with hypoxia, starvation and iron metabolism. The majority of genes regulated by MprB/MprA under a particular stress condition are different from those induced during normal growth, but several genes are commonly regulated under more than one condition.
Catalyzes the conversion of (8S)-3',8-cyclo-7,8-dihydroguanosine 5'-triphosphate to cyclic pyranopterin monophosphate (cPMP).
Interacts with human TLR2 (PubMed:23819907). Monomer in solution (PubMed:22719925). In vitro, binds to E.coli ribosomes (PubMed:22719925).
Involved in translation regulation (PubMed:19795912, PubMed:22719925). Inhibits protein synthesis and decreases bacterial growth when expressed in E.coli (PubMed:22719925). Can also stimulate macrophages and peripheral blood mononuclear cells (PBMC) to secrete important cytokines that may be significant in granuloma formation and its maintenance. Increases secretion of IFN-gamma, TNF-alpha, IL-1 beta and IL-8 through human Toll-like receptor 2 (TLR2) signaling pathway (PubMed:23819907).
Belongs to the N-acetylmuramoyl-L-alanine amidase 3 family.
Cell-wall hydrolase that hydrolyzes the amide bond between N-acetylmuramic acid and L-alanine in cell-wall glycopeptides. Is able to lyse whole mycobacteria, release peptidoglycan from the cell wall of M.luteus and M.smegmatis, and cleave N-acetylmuramoyl-L-alanyl-D-isoglutamine, releasing free N-acetylmuramic acid and dipeptide.
A member of the dormancy regulon. Induced in response to reduced oxygen tension (hypoxia), low levels of nitric oxide (NO) and carbon monoxide (CO). It is hoped that this regulon will give insight into the latent, or dormant phase of infection. Also induced when grown at pH 5.0 for 3 weeks.
Catalyzes the terminal and only committed step in triacylglycerol synthesis by using diacylglycerol and fatty acyl CoA as substrates. Required for storage lipid synthesis (Probable).
No detectable TG under hypoxic growth conditions, or when grown at pH 5.0. However, about 30% of normal levels of TG accumulated when grown in the presence of NO but there was virtually no C(26:0) TG produced.
Upon expression in E.coli functions as a triacylglycerol synthase, making triacylglycerol (TG) from diolein and long-chain fatty acyl-CoA. Prefers C(26:0)-CoA over C(18:1)-CoA. TG synthesis activity increases in M.tuberculosis upon oxygen depletion and NO treatment, with concomitant accumulation of TG in inclusion bodies. As disruption of the gene encoding this protein obviates TG synthesis this seems to be the major enzyme involved in production of TG. Has no wax synthase activity to produce wax esters.
Belongs to the class-III pyridoxal-phosphate-dependent aminotransferase family. ArgD subfamily.
May also have succinyldiaminopimelate aminotransferase activity, thus carrying out the corresponding step in lysine biosynthesis.
Converts 2,5-diamino-6-(ribosylamino)-4(3h)-pyrimidinone 5'-phosphate into 5-amino-6-(ribosylamino)-2,4(1h,3h)-pyrimidinedione 5'-phosphate.
In the C-terminal section; belongs to the HTP reductase family.
In the N-terminal section; belongs to the cytidine and deoxycytidylate deaminase family.
An redox-regulated anti-sigma factor for extracytoplasmic function (ECF) sigma factor SigH. ECF sigma factors are held in an inactive form by a cognate anti-sigma factor. RshA and some peptides derived from it inhibit the sigma factor activity of SigH. Probably releases SigH during oxidative stress.
Binds 1 iron-sulfur cluster per subunit. As the iron-sulfur cluster is unstable, it is not clear from the contradictory experimental evidence whether it is 2Fe-2S, 4Fe-4S or something intermediate. Nor is it clear which other residues besides Cys-53 and Cys-56 are involved in metal binding (PubMed:22937074).
Interacts (affinity=15 nM) 1:1 with cognate sigma factor SigH under reducing conditions; the complex is disrupted under oxiding conditions or as temperatures rise. Binding inhibits the interaction of SigH with the RNA polymerase catalytic core.
Phosphorylated, probably by PknB. Phosphorylation decreases interaction with SigH, leading to increased SigH-mediated transcription.
Belongs to the cysteine dioxygenase family.
A cysteine desulfhydrase that generates hydrogen sulfide, H(2)S. The H(2)S produced by this enzyme stimulates respiration in M.tuberculosis, mediated primarily via cytochrome bd with a lesser contribution from cytochrome bc1/aa3. H(2)S modulates the balance between respiration and glycolysis, and also contributes to redox homeostasis. Probably eliminates toxic levels of Cys (which can induce oxidative stress).
Belongs to the cysteine synthase/cystathionine beta-synthase family. Cds1 subfamily.
Probably inhibited by aminooxyacetic acid (AOAA) but not by DL-propargylglycine (PAG); the former inhibits pyridoxal 5'-phosphate-dependent enzymes, the latter only inhibits cystathionine gamma-lyase.
Probably part of the Rv3682-Rv3683-cds1 operon.
Significantly reduced production of H(2)S in all media tested, cells grow significantly less well in the presence of 4 mM cysteine, no change in survival in mouse macrophages. 40% reduction in basal oxygen consumption (respiration rate), increased levels of amino acids, glycolytic and TCA cycle metabolites, decreased levels of the redox couple ergothioneine and mycothiol. Increased ATP levels in the presence of 100 uM exogenous Cys. Increased cell survival after clofazimine or rifampicin treatment.
There is a large variation in the ability of different strains to produce H(2)S; H37Rv, CDC 1551 and 2 clinical strains were the highest producers of H(2)S.
Catalyzes the sequential condensations of isopentenyl pyrophosphate (IPP) with dimethylallyl diphosphate (DMAPP) to yield geranyl diphosphate (GPP) and with GPP to yield (2E,6E)-farnesyl diphosphate (E,E-FPP).
Belongs to the CorA metal ion transporter (MIT) (TC 1.A.35) family.
Allosterically regulated by all of the three aromatic amino acids (phenylalanine, tyrosine and tryptophan). Inhibited by low concentrations of aromatic amino acids and highly activated at higher concentrations. Ionic interactions are required for optimal activity.
Both domains are absolutely required for activity. In the absence of the ACT domain, the enzyme not only loses its regulatory activity, but also its catalytic activity.
Belongs to the prokaryotic pantothenate kinase family.
Is irreversibly inactivated by the beta-lactams carbapenems via the formation of a covalent adduct resulting from enzyme acylation; imipenem is the most efficient drug for in vitro LdtMt3 inactivation.
Probable L,D-transpeptidase that may perform as-yet-unknown cross-linking reactions in M.tuberculosis. Is not able to generate 3->3 cross-links in peptidoglycan, using tetrapeptide stems as acyl donor substrates. May function in the anchoring of proteins to peptidoglycan.
Belongs to the acetyltransferase Eis family.
Can also acetylate multiple amine groups of many aminoglycoside (AG) antibiotics, leading to their inactivation, and thus contributes to drug resistance (PubMed:19906990, PubMed:21628583, PubMed:24106131). Is also able to acetylate and deactivate the cyclic peptide antibiotic capreomycin, but not the other anti-tuberculous drugs isoniazid and pyrazinamide (PubMed:23233486). Acetylates kanamycin (KAN) more efficiently than amikacin (AMK), even though Eis seems to bind AMK with higher affinity (PubMed:19906990). Does not acetylate and inactivate streptomycin, apramycin and spectinomycin (PubMed:19906990, PubMed:21628583).
Effector that is released into the host cell and affects host immune responses; it negatively modulates inflammation, macrophage autophagy, and cell death through redox-dependent signaling (PubMed:17259625, PubMed:21187903). Acts as an acetyltransferase. Acetylates 'Lys-55' of dual-specificity protein phosphatase 16 (DUSP16)/mitogen-activated protein kinase phosphatase-7 (MKP-7), a JNK-specific phosphatase; this leads to the inhibition of JNK-dependent autophagy, phagosome maturation, and ROS (reactive oxygen species) generation for enhanced intracellular survival of M.tuberculosis (PubMed:22547814). Inhibits Con A-mediated T-cell proliferation in vitro (PubMed:17449476). Treatment of T-cells with Eis inhibits ERK1/2, JAK pathway, and subsequent production of tumor necrosis factor-alpha (TNF-alpha) and interleukin-4 (IL-4); on the contrary, there is increased production of interferon-gamma (IFN-gamma) and interleukin-10 (IL-10), which indicates that immunity in response to Eis treatment is skewed away from a protective T(H)1 response and Eis disturbs the cross regulation of T-cells (PubMed:17449476). When expressed in M.smegmatis, enhances intracellular survival of the bacteria in host macrophages during infection (PubMed:10629183).
Increased expression of eis due to point mutations in the promoter region of eis is responsible for resistance to the second-line injectable drug kanamycin in a number of M.tuberculosis clinical isolates, through acetylation of its amino groups, which leads to inactivation of the drug.
Is potently inhibited by several small-molecules that share an isothiazole S,S-dioxide heterocyclic core. Some of these inhibitors, when used in combination with KAN against resistant M.tuberculosis, efficiently overcome Eis-mediated KAN resistance by restoring the antibacterial activity of KAN (PubMed:27010218). Some of these compounds also inhibit in vitro acetylation of DNA-binding protein HupB (PubMed:29345920).
No significant difference in terms of intracellular survival in U-397 macrophages and in an in vivo mouse aerosol model of infection (PubMed:17259625). A strain lacking this gene induces more TNF-alpha but less IL-10 production in primary human monocytes than wild-type (PubMed:17259625). Macrophages infected with a M.tuberculosis eis-deletion mutant display markedly increased accumulation of massive autophagic vacuoles and formation of autophagosomes in vitro and in vivo (PubMed:21187903). Infection of macrophages with this mutant increases the production of tumor necrosis factor-alpha and interleukin-6 over the levels produced by infection with wild-type or complemented strains (PubMed:21187903). Elevated ROS generation in macrophages infected with this mutant (for which NADPH oxidase and mitochondria are largely responsible) render the cells highly sensitive to autophagy activation and cytokine production; despite considerable activation of autophagy and pro-inflammatory responses, these infected macrophages undergo caspase-independent cell death (PubMed:21187903).
The Eis monomer consists of three regions that are assembled into a heart-shaped molecule (PubMed:21628583). This shape is formed by an unusual fusion of two general control non-derepressible 5 (GCN5)-related N-acetyltransferase (GNAT) regions and a C-terminal region (PubMed:21628583). The N-acetyltransferase domain of Eis is responsible for its modulation of ROS generation and pro-inflammatory responses in macrophages (PubMed:21187903).
Catalyzes the adenylation of p-hydroxybenzoic acid (pHBA) to form p-hydroxybenzoic acid-AMP (pHBA-AMP), which is converted directly to p-hydroxybenzoyl-S-FadD22 (pHBA-S-FAdD22) thioester intermediate in a CoA-independent manner by attack of the phosphopantetheine thiol of FadD22. Usually, this intermediate primes the biosynthesis of the phenolphthiocerol (PPOL) by presenting the pHBA starter unit for elongation by Pks15/1, but M.tuberculosis lacks Pks15/1 due to a natural frameshift and thus is unable to produce PPOL.
Disruption of fadD22 abolishes the production of PPOL.
Bioinformatics programs predicts this could have a signal sequence.
Physically interacts with non-cognate antitoxin VapB27 and cognate antitoxin VapB40.
Toxic component of a type II toxin-antitoxin (TA) system. An RNase (By similarity). Its cognate antitoxin is VapB40.
May play only a redundant role in maintaining cell wall viability and bacterial virulence.
Was originally thought (PubMed:14960574) to be a mannosyltransferase involved in the biosynthesis of phosphatidylinositol mannosides (PIMs), but further in vivo and in vitro characterizations (PubMed:18585090) clearly show that inactivation of Rv1500 does not affect the expression pattern of PIMs.
Involved in protein export. Participates in an early event of protein translocation (By similarity).
In BALB/c mice, immunization with EsxL-FIA induces a pro-inflammatory response with elevated levels of TNF and IL-6, along with low induction of IFN-gamma, IL-2 and IL-10, but no induction of IL-4.
Induces apoptosis of host cells (PubMed:25242740). Is immunogenic with highly specific seroreactivity towards TB patients' serum (PubMed:27751956).
Strongly interacts with EsxK to form a heterodimeric complex under reducing conditions. The complex is regulated by the redox state of EsxL.
Involved in sulfur transfer in the conversion of molybdopterin precursor Z to molybdopterin (By similarity). Probably plays a role in host phagosome maturation arrest (PubMed:20844580).
Disruption of fadD28 abolishes the production of phthiocerol dimycocerosate (DIM) on the cell envelope (PubMed:10573420, PubMed:11279114). Grows normally in liquid culture, traffics into host (human and mouse) acidified compartments early after phagocytosis, suggesting it no longer arrests phagosome maturation as well as wild-type, impaired growth in mouse macrophages (PubMed:20844580).
Inhibited by acylsulfamoyl (acyl-AMS) analogs.
Involved in the biosynthesis of phthiocerol dimycocerosate (PDIM), a cell wall-associated lipid found only in pathogenic mycobacteria (PubMed:10573420, PubMed:11279114). Catalyzes the activation of long-chain fatty acids as acyl-adenylates (acyl-AMP), which are then transferred to the multifunctional polyketide synthase Mas for further chain extension (PubMed:24831705). Probably plays a role in host phagosome maturation arrest (Probable).
Belongs to the precorrin-6x reductase family.
Catalyzes the reduction of the macrocycle of precorrin-6X into precorrin-6Y.
Cell envelope-associated glycolipid phthiocerol dimycocerosate (PDIM)-positive mutants with simultaneous deletion of PPE31/PPE32/PPE33 genes have a growth defect in Mg(2+) restricted media, particularly at mildly acidic pH, but the PDIM-negative mutants grow normally.
Deletion of this gene results in phthiocerol dimycocerosates (DIM) deficiency and decreases the ability of the bacteria to infect macrophages.
The C-terminal region interacts with TesA (PubMed:15668773). Interacts with MmpL7 (PubMed:16201014).
Key component of the proton channel; it plays a direct role in the translocation of protons across the membrane.
Belongs to the peroxiredoxin family. AhpE subfamily.
Homodimer (PubMed:19737009, PubMed:27417938). Forms both dimers and octamers; a tightly-associated dimer and a ring-like octamer (PubMed:15701515).
The active site is a conserved redox-active cysteine residue, the peroxidatic cysteine (C(P)), which makes the nucleophilic attack on the peroxide substrate. The peroxide oxidizes the C(P)-SH to cysteine sulfenic acid (C(P)-SOH), which then reacts with another cysteine residue, the resolving cysteine (C(R)), to form a disulfide bridge. The disulfide is subsequently reduced by an appropriate electron donor to complete the catalytic cycle. In this 1-Cys peroxiredoxin, no C(R) is present and C(P) instead forms a disulfide with a cysteine from another protein or with a small thiol molecule. C(P) can be reduced through a mixed disulfide with the N-terminal cysteine of mycoredoxin-1 (Mrx1), resolved by its C-terminal cysteine, or by a mixed disulfide with mycothiol, resolved by a second molecule of mycothiol or by mycoredoxin-1.
Thiol-specific peroxidase that catalyzes the reduction of hydrogen peroxide and organic hydroperoxides to water and alcohols, respectively. Plays a role in cell protection against oxidative stress by detoxifying peroxides. May represent an important antioxidant defense against cytotoxic peroxides, especially peroxynitrite, which can be formed by activated macrophages during infection.
Belongs to the transglycosylase MltG family.
Functions as a peptidoglycan terminase that cleaves nascent peptidoglycan strands endolytically to terminate their elongation.
Belongs to the HpcH/HpaI aldolase family. Citrate lyase beta subunit-like subfamily.
May play a role in fatty acid biosynthesis.
This organism lacks the other subunits that are necessary for ATP-independent citrate lyase activity. Even though this protein has clear similarity to citrate lyase beta subunit, it is expected to have a somewhat different enzyme activity.
Acetylated on Lys-617 by Pat in the presence of acetyl-CoA as an acetyl donor and ATP. Acetylation results in the inactivation of the enzyme. Deacetylation by the SIR2-homolog deacetylase CobB is required to activate the enzyme.
Catalyzes the conversion of acetate into acetyl-CoA (AcCoA), an essential intermediate at the junction of anabolic and catabolic pathways. AcsA undergoes a two-step reaction. In the first half reaction, AcsA combines acetate with ATP to form acetyl-adenylate (AcAMP) intermediate. In the second half reaction, it can then transfer the acetyl group from AcAMP to the sulfhydryl group of CoA, forming the product AcCoA. M.tuberculosis may use AcsA for both acetate and propionate assimilation.
Could be also autoacetylated on Lys-617 in the presence of acetate as an acetyl donor and ATP. Autoacetylation is effectively inhibited by CoA. If CoA is not available or the concentration of CoA is low in vivo, the enzyme can transfer acetyl group from AcAMP to itself, resulting in autoacetylation and inactivation. When CoA is available, the acetyl group is donated to CoA forming AcCoA (PubMed:21896569).
Magnesium, but can also use calcium, manganese, nickel or zinc ions.
Belongs to the class-II aminoacyl-tRNA synthetase family. Phe-tRNA synthetase alpha subunit type 1 subfamily.
Increased susceptibility to oxidative stress (H(2)O(2), cumene hydroperoxide and diamide, PubMed:12123450) and heat shock (45 and 52 degrees Celsius). Loss of stress-induced expression of a number of genes including clpB, dnaK, sigE and trxB (PubMed:11567012), sigB and itself (PubMed:12123450). No effect on infection of human derived macrophages, and murine J774.1 activated and unactivated macrophages (PubMed:12123450).
Interacts transiently with the RNA polymerase catalytic core formed by RpoA, RpoB, RpoC and RpoZ (2 alpha, 1 beta, 1 beta' and 1 omega subunit) to form the RNA polymerase holoenzyme that can initiate transcription. Interacts (affinity=15 nM) 1:1 (via sigma-70 factor domain-4) with RshA under reducing conditions; the complex is disrupted as temperatures rise. Phosphorylation of RshA decreases its interaction with SigH, leading to increased SigH-mediated transcription.
Phosphorylated, possibly on 2 residues, probably by PknB. Phosphorylation of SigH has no effect on interaction with RshA.
Poorly expressed in exponential phase; induced by heat shock (20-fold, 45 degrees Celsius). Induced 10-fold by the thiol-oxidative agent diamide within 30 minutes of exposure, by 2 hours expression is again normal. Autoregulates its own expression, part of the sigH-rshA operon.
Sigma factors are initiation factors that promote the attachment of RNA polymerase to specific initiation sites and are then released. Extracytoplasmic function (ECF) sigma factors are held in an inactive form by a cognate anti-sigma factor (RshA) until released. This sigma factor is involved in heat shock and oxidative stress responses; it positively regulates the expression of itself, sigE, sigB and a number of transcriptional regulators as well as other effectors of heat and oxidative stress, leading to direct and indirect control of up to 25% of the bacterial genome. Modulates expression of host genes for intercrine beta (chemokine CC) and apoptosis, altering the host immune response.
The sigma-70 factor domain-4 contains a helix-turn-helix (H-T-H) motif that mediates interaction with the -35 element in promoter DNA. The domain also mediates interaction with the RNA polymerase subunit RpoA. Interactions between sigma-70 factor domain-4 and anti-sigma factors prevents interaction of sigma factors with the RNA polymerase catalytic core.
Part of the twin-arginine translocation (Tat) system that transports large folded proteins containing a characteristic twin-arginine motif in their signal peptide across membranes. Together with TatB, TatC is part of a receptor directly interacting with Tat signal peptides.
Autoregulated. Up-regulated by amoxicillin.
Belongs to the BlaI transcriptional regulatory family.
Transcription regulator that binds to an inverted DNA repeat with the consensus sequence 5'-TAC[GT]AC-NNNNN-GT[AC]GTA-3' and regulates genes involved in antibiotic transport, detoxification and cell wall function. Also regulates its own transcription. Binds DNA as a dimer.
Upon exposure to beta-lactams, proteolytic cleavage at a single site may impair dimerization and abolish repressor activity.
The central subunit of the protein translocation channel SecYEG. Consists of two halves formed by TMs 1-5 and 6-10. These two domains form a lateral gate at the front which open onto the bilayer between TMs 2 and 7, and are clamped together by SecE at the back. The channel is closed by both a pore ring composed of hydrophobic SecY resides and a short helix (helix 2A) on the extracellular side of the membrane which forms a plug. The plug probably moves laterally to allow the channel to open. The ring and the pore may move independently.
Belongs to the PNP/MTAP phosphorylase family. MTAP subfamily.
Catalyzes the reversible phosphorylation of S-methyl-5'-thioadenosine (MTA) to adenine and 5-methylthioribose-1-phosphate. Involved in the breakdown of MTA, a major by-product of polyamine biosynthesis. Responsible for the first step in the methionine salvage pathway after MTA has been generated from S-adenosylmethionine. Prefers MTA, with 2% activity on adenosine, 0.8% activity on S-adenosyl-L-homocysteine and no activity on other tested nucleosides.
Not inhibited by adenosine, potently inhibited by MT-DADMe-immucillin A.
Belongs to the SIMIBI class G3E GTPase family. ArgK/MeaB subfamily.
Probable GTPase. May also bind and hydrolyze ATP. May function as chaperone (Probable).
An ATPase (By similarity). Part of the ESX-3 specialized secretion system, which is important for iron and zinc uptake or homeostasis.
A reversible dehydrogenase involved in cholesterol side-chain degradation. Catalyzes the oxidation of hydroxyl-cholesterol-CoA ester metabolic intermediate (22S)-HOCO-CoA (3-oxo-chol-4-ene-(22S)-hydroxy-24-oyl-CoA), the product of ChsH3, has no activity on (22R)-HOCO-CoA (the product of EchA19). Also acts on (3R)-hydroxyoctanoyl-CoA and 17-beta-hydroxyandrost-4-en-3-one, but not on 7-alpha-hydroxyandrost-4-en-3-one, uses NAD(+) but not NADP(+).
Cells lacking this gene are shown to be highly attenuated in a mouse tuberculosis model (PubMed:14569030). Required for growth on cholesterol (PubMed:21980284).
Homodimer, with 1 active site on each face.
The protein surface forms a large groove around the active sites which is larger than homologs, probably to accommodate bulky sterol substrates.
Belongs to the urease gamma subunit family.
Protease that hydrolyzes the covalent CysO-cysteine adduct synthesized by CysM to release L-cysteine and regenerate CysO.
Belongs to the 3-oxoacid CoA-transferase subunit B family.
Heterodimer of a subunit A and a subunit B.
Belongs to the ATPase gamma chain family.
Produces ATP from ADP in the presence of a proton gradient across the membrane. The gamma chain is believed to be important in regulating ATPase activity and the flow of protons through the CF(0) complex.
Activity is abolished by EDTA. Inhibited by Ro 48-8071, which is non-competitive with regard to DHNA and competitive with regard to the isoprenyldiphosphate substrate.
Belongs to the MenA family. Type 1 subfamily.
Can also use Fe(2+) or Zn(2+), with lower efficiency.
Conversion of 1,4-dihydroxy-2-naphthoate (DHNA) to demethylmenaquinone (DMK). Can use a variety of allylic isoprenyl diphosphates as substrates but has a requirement for at least three isoprene units.
Constitutively expressed during exponential phase, normoxic and hypoxic stationary phase.
No visible phenotype under normal or hypoxic and normoxic stationary phase growth.
BTP15, an inhibitor of ESX-1 secretion, decreases secretion of this protein without being bacteriocidal. BTP15 inhibits autophosphorylation of MprB with subsequent up-regulation of espA and decreased secretion of EspB and EsxA (PubMed:25299337).
Cleaved in the C-terminal region by MycP1 (PubMed:17676952, PubMed:20227664, PubMed:23620593, PubMed:24113528). The exact location of the cleavage sites has been the subject of conflicting reports (PubMed:20227664, PubMed:23620593). Further in vitro studies confirmed that Ala-358 is the primary cleavage site and Ala-386 is a secondary cleavage site (PubMed:24113528). Likely translocated as a full-length protein into the periplasm, where it is proteolyzed by MycP1 (PubMed:17676952, PubMed:20227664). Proteolysis may serve to limit the secretion of other ESX-1 substrates (PubMed:20227664).
Mature EspB oligomerizes and forms donut-shaped rings. In contrast, the full-length protein does not oligomerize (PubMed:26051906). Interacts with the C-terminal region of EspK (PubMed:17676952).
Required for host-cell death and may support an EsxA-independent virulence function (PubMed:23869560). Secreted processed form of EspB binds to phosphatidic acid and phosphatidylserine (PubMed:23869560). Inhibits IFN-gamma-induced autophagy in murine macrophages (PubMed:25641595).
The N-terminal region contains a fused PE/PPE homology domain. The C-terminal region is disordered.
Disruption of this gene attenuates M.tuberculosis growth and survival in untreated mice.
Involved in the biosynthesis of a unique class of isonitrile lipopeptides (INLPs) that seem to function as virulence factors in M.tuberculosis and to play a role in metal acquisition (PubMed:28634299). Catalyzes the conversion of (3R)-3-[(carboxymethyl)amino]fatty acids to (3R)-3-isocyanyl-fatty acids through an oxidative decarboxylation mechanism, thereby generating the isonitrile group of INLPs (By similarity).
Isonitrile formation goes through two consecutive, but distinctive, 2-oxoglutarate-dpendent reactions catalyzed by this enzyme. In the first reaction, an Fe(IV)-oxo species is utilized to generate a (3R)-3-{[carboxy(hydroxy)methyl]amino}fatty acid. Then, its conversion into a (3R)-3-isocyanyl-fatty acid likely proceeds by decarboxylation-assisted desaturation.
Belongs to the short-chain dehydrogenases/reductases (SDR) family. FabI subfamily.
Enoyl-ACP reductase of the type II fatty acid syntase (FAS-II) system, which is involved in the biosynthesis of mycolic acids, a major component of mycobacterial cell walls (PubMed:25227413). Catalyzes the NADH-dependent reduction of the double bond of 2-trans-enoyl-[acyl-carrier protein], an essential step in the fatty acid elongation cycle of the FAS-II pathway (PubMed:7599116). Shows preference for long-chain fatty acyl thioester substrates (>C16), and can also use 2-trans-enoyl-CoAs as alternative substrates (PubMed:7599116). The mycobacterial FAS-II system utilizes the products of the FAS-I system as primers to extend fatty acyl chain lengths up to C56, forming the meromycolate chain that serves as the precursor for final mycolic acids (PubMed:25227413).
Homodimer (PubMed:7599116). Homotetramer (PubMed:10336454, PubMed:16647717).
InhA activity is controlled via phosphorylation: phosphorylation on Thr-266 decreases InhA activity (5-fold reduction) and likely negatively regulates biosynthesis of mycolic acids and growth of the bacterium (PubMed:20864541, PubMed:21143326). The antitubercular pro-drug isoniazid (INH) is oxidatively activated by the catalase-peroxidase KatG and then covalently binds NAD to form an adduct that inhibits the activity of InhA (Ref.5, PubMed:14623976, PubMed:9417034). The inhibitory adduct is the isonicotinic-acyl-NADH where the isonicotinic-acyl group replaces the 4S (and not the 4R) hydrogen of NADH (PubMed:9417034). Similarly, the antitubercular pro-drugs ethionamide (ETH) and prothionamide (PTH) are activated by the flavoprotein monooxygenase EthA, and forms an adduct with NAD (ETH-NAD and PTH-NAD, respectively) that is a tight-binding inhibitor of InhA (PubMed:17227913). Is inhibited by triclosan and derivatives, pyrazole derivative Genz-8575, indole-5-amide Genz-10850, alkyl diphenyl ethers, pyrrolidine carboxamides, arylamides, pyridomycin, methyl-thiazoles, 4-hydroxy-2-pyridones, and N-benzyl-4-((heteroaryl)methyl)benzamides (PubMed:12606558, PubMed:17163639, PubMed:17034137, PubMed:17723305, PubMed:19130456, PubMed:20200152, PubMed:22987724, PubMed:24107081, PubMed:24616444, PubMed:25568071). Pyridomycin shows a unique mode of InhA inhibition by simultaneously blocking parts of the NADH and the lipid substrate-binding pocket of InhA (PubMed:24292073). Is also inhibited by thiadiazole compounds, that have very attractive antitubercular properties (PubMed:27428438).
Is phosphorylated on Thr-266 in vivo. In vitro, can be phosphorylated by multiple Ser/Thr protein kinases (STPK) such as PknA, PknB, PknE, PknH and PknL. Phosphorylation decreases enzymatic activity.
Is the primary target of the first-line antitubercular drug isoniazid (INH) and of the second-line drug ethionamide (ETH) (PubMed:8284673, PubMed:12406221, PubMed:16906155, PubMed:17227913). Overexpressed inhA confers INH and ETH resistance to M.tuberculosis (PubMed:12406221). The mechanism of isoniazid action against InhA is covalent attachment of the activated form of the drug to the nicotinamide ring of NAD and binding of the INH-NAD adduct to the active site of InhA (PubMed:9417034, PubMed:16906155). Similarly, the ETH-NAD adduct binds InhA (PubMed:17227913).
Many isoniazid- and ethionamide-resistant clinical isolates contain mutations within the inhA locus. Resistance to isoniazid and ethionamide can be conferred by the single substitution of alanine for serine 94; this drug resistance seems to be directly related to a perturbation in the hydrogen-bonding network that decreases the binding of NADH and the INH-NAD adduct.
Putative toxic component of a type II toxin-antitoxin (TA) system. Its cognate antitoxin would be HigA3. Not toxic upon expression in M.smegmatis.
Belongs to the helicase family. SKI2 subfamily.
Glycosylated. Glycosylation may protect the protein from proteolytic degradation and be important for hemagglutination. It suggests that the carbohydrate moiety may be located within the C-terminal domain of HbhA.
Heparin binding seems to require the C-terminal domain of HbhA. Progressive truncations from the C-terminal end diminish the affinity for heparin.
Required for extrapulmonary dissemination. Mediates adherence to epithelial cells by binding to sulfated glycoconjugates present at the surface of these cells; binds heparin, dextran sulfate, fucoidan and chondroitin sulfate. Promotes hemagglutination of erythrocytes of certain host species. Induces mycobacterial aggregation.
Serum from patients diagnosed with active tuberculosis that had not been vaccinated contains antibodies that recognize HbhA, whereas serum from healthy individuals does not contain any.
In the N-terminal section; belongs to the NADH:flavin oxidoreductase/NADH oxidase family.
Antitoxin component of a type II toxin-antitoxin (TA) system. Upon expression in E.coli and M.smegmatis neutralizes the effect of cognate toxin VapC11.
Induced during infection of mouse macrophages.
Apo-AcpS adopts different conformations depending upon the pH conditions of the crystallization solution.
Belongs to the P-Pant transferase superfamily. AcpS family.
Transfers the 4'-phosphopantetheine moiety from coenzyme A to a Ser of acyl-carrier-protein (PubMed:16709676, PubMed:21697604). Involved in the post-translational modification of Fas-I and the AcpM subunit of Fas-II (PubMed:21697604).
Divalent metal cations. Prefers magnesium or manganese.
Putative antitoxin component of a possible type II toxin-antitoxin (TA) system. The cognate toxin is VapC16.
Belongs to the 5-formyltetrahydrofolate cyclo-ligase family.
Belongs to the metallophosphoesterase superfamily.
Catalyzes the hydrolysis of the phosphopantetheine group from substrate holo-carrier proteins.
Deletion mutant is highly and selectively resistant to the amidino-urea compound 1-[(2,6-diethylphenyl)-3-N-ethylcarbamimodoyl]urea (compound 8918).
Catalyzes the NADP(+)-dependent oxidation of succinate semialdehyde to succinate. Although it has succinate semialdehyde dehydrogenase activity, is likely to act physiologically on a different aldehyde(s). NAD(+) can substitute for NADP(+), but enzymatic activity is three times reduced.
Involved in preservation of envelope integrity and tolerance to surface stress (PubMed:25899163). Reverses the inhibitory effect of PspA on ClgR activity (PubMed:25899163). Facilitates intracellular growth of M.tuberculosis (PubMed:25899163).
The Rv2743c-Rv2742c double mutation reduces intracellular ATP levels under surface-stress conditions to less than 60% of wild-type levels (PubMed:25899163). Inactivation of Rv2743c reduces mprA and sigB expression to 20% and 10% of wild-type levels, respectively, after treatment with SDS (PubMed:25899163). Inactivation increases M.tuberculosis susceptibility to the intramacrophage environment (PubMed:25899163).
Pyrophosphatase that catalyzes the hydrolysis of nucleoside triphosphates to their monophosphate derivatives, with a high preference for the non-canonical purine nucleotides XTP (xanthosine triphosphate), dITP (deoxyinosine triphosphate) and ITP. Seems to function as a house-cleaning enzyme that removes non-canonical purine nucleotides from the nucleotide pool, thus preventing their incorporation into DNA/RNA and avoiding chromosomal lesions.
Involved in the lysine biosynthetic pathways. It catalyzes the transfer of an amino group from L-glutamate to N-succinyl-2-l-amino-6-oxoheptanedioate (N-succinyl-2-l-amino-6-ketopimelate) in a PLP-dependent reaction, yielding as products N-succinyl-l-2,6-diaminoheptanedioate (N-succinyl-diaminopimelate) and 2-oxoglutarate (Probable).
Belongs to the saccharopine dehydrogenase family. Enoyl reductase subfamily.
Involved in the reduction of the double bond between C-4 and C-5 during phthiocerol dimycocerosates (DIM A) and glycosylated phenolphthiocerol dimycocerosates (PGL) biosynthesis.
Binds 1 Mg(2+) or Mn(2+) ion per subunit.
No change in H(2)S production, no change in basal oxygen consumption (respiration rate).
Expressed in mid-log phase cells and in gamma-interferon stimulated, mouse macrophage-like cell line J774.
Negatively regulates the expression of its operon as well as expression of end (endonuclease 4).
Part of an operon comprising at least mce2R and yrbE2A and probably extending to at least mce2A.
Belongs to the MurCDEF family. MurF subfamily.
Involved in cell wall formation. Catalyzes the final step in the synthesis of UDP-N-acetylmuramoyl-pentapeptide, the precursor of murein.
Belongs to the complex I 20 kDa subunit family.
Forms a heterodimer with PE25. The dimer forms a 1:1:1 heterotrimeric complex with EspG5. PPE41 interacts directly with EspG5.
The PE25/PPE41 dimer induces both a strong humoral and cellular immune response (PubMed:18974870). The dimer induces necrosis, but not apoptosis, in mouse macrophage cells (PubMed:25379378). It also induces activation and maturation of mouse dendritic cells and drives Th2-biased immune responses (PubMed:26318856).
Expressed in growing cells (at protein level). Transcription not induced under oxygen-limiting conditions.
Provides the precursors necessary for DNA synthesis. Catalyzes the biosynthesis of deoxyribonucleotides from the corresponding ribonucleotides (By similarity). Two genes for this protein are present in M.tuberculosis; this is thought to not be the active form. When coexpressed in E.coli with nrdE the 2 proteins do not complement a temperature-sensitive E.coli mutant, whereas the other gene (nrdF2) does complement.
Contains a large occluded hydrophilic cavity that spans the entire thickness of the membrane and extends into the intracellular part of the protein. It consists of two connected chambers. The larger chamber is located in the transmembrane domain, and the smaller chamber is formed by the part of the protein that connects the NBDs and transmembrane domains.
Disruption results in bleomycin resistance and alters the outcome of a chronic infection within the host, but does not alter sensitivity to other membrane-disrupting agents and resistance to clinically important antituberculosis drugs (PubMed:18996991). Deletion eliminates the ability of the bacterium to transport vitamin B12 and related corrinoids (PubMed:23407640).
Multi-solute ABC transporter that mediates uptake of unrelated hydrophilic compounds (PubMed:32296172). Can transport vitamin B12 and related corrinoids, and antimicrobial peptides such as bleomycin (PubMed:18996991, PubMed:32296172, PubMed:23407640). Transmembrane domains (TMD) form a pore in the membrane and the ATP-binding domain (NBD) is responsible for energy generation (PubMed:32296172). Contributes to maintenance of chronic infections (PubMed:18996991).
The presence of cobalamin does not affect the ATPase activity.
Autophosphorylated (PubMed:30642988, PubMed:19700407). Phosphorylated by PknD on multiple threonine and serine residues (PubMed:30642988). Phosphorylation is antagonized by the phosphatase activity (PubMed:19700407).
Binds 2 manganese or magnesium ions per subunit.
Exists in solution as both monomer and dimer (PubMed:21220116). Both the phosphorylated and unphosphorylated proteins form extended dimers (PubMed:19700407). Interacts with SigF (PubMed:30642988). Can efficiently bind to SigF independently of its autophosphorylation (PubMed:30642988). Interaction between SigF and Rv1364c is reduced significantly upon the phosphorylation of both proteins by PknD (PubMed:30642988).
Multidomain protein in which the components of the entire signal transduction cascade for SigF regulation appear to be encoded in a single polypeptide. Contains an N-terminal PAS sensor domain, followed by an adjacent PAC (PAS domain-associated C-terminus) region, a phosphatase domain, an anti-sigma factor kinase domain, and a C-terminal anti-anti-sigma factor domain (or substrate domain) (Probable). Phosphorylation at Ser-600 leads to a change in the overall shape of the dimer (PubMed:19700407).
Overexpression switch off espA induction under osmotic stress.
Primarily acts as an independent SigF regulator that is sensitive to the osmosensory signal, mediating the cross talk of PknD with the SigF regulon (PubMed:30642988). Possesses both phosphatase and kinase activities (PubMed:30642988, PubMed:19700407). The kinase domain functions as a classic anti-sigma factor-like kinase to phosphorylate the anti-anti-sigma factor domain at the canonical regulatory site, and the phosphatase domain antagonizes this activity (PubMed:19700407).
The phosphatase domain is activated by the anti-sigma factor kinase domain.
Catalyzes the reversible transfer of the terminal phosphate group between ATP and AMP. Plays an important role in cellular energy homeostasis and in adenine nucleotide metabolism. Has a broad specificity for nucleoside triphosphates, being highly active with ATP or dATP as phosphate donors, and less active with GTP or UTP.
Competitively inhibited by the bisubstrate analog Ap5A, by 7-deazaadenosine 5'-monophosphate (TuMP) and 8-bromo-AMP.
Consists of three domains, a large central CORE domain and two small peripheral domains, NMPbind and LID, which undergo movements during catalysis. The LID domain closes over the site of phosphoryl transfer upon ATP binding. Assembling and dissambling the active center during each catalytic cycle provides an effective means to prevent ATP hydrolysis. The LID domain is a solvent-exposed domain that is much shorter in Mycobacterium than in many other bacteria like E.coli.
Forms a tight complex with EsxR (PubMed:15336430). Exists in heterodimeric and heterotetrameric forms (PubMed:20629176).
In the heterotetrameric form, EsxS adopts a long helical conformation that pairs with a second EsxS monomer in an antiparallel manner that allows the N- and C-termini of two EsxS subunits to interact with an EsxR subunit at each end of the EsxS dimer thus creating a molecule with four-helix bundles at its extremities.
Expression is controlled by VirS. Induced at acidic pH and in macrophages. Induced by low levels of nitric oxide (NO), but not by hypoxia.
Required for maintaining the appropriate mycolic acid composition and permeability of the envelope on its exposure to acidic pH. Upon expression in E.coli functions as a triacylglycerol synthase, making triacylglycerol (TG) from diolein and long-chain fatty acyl-CoA. Has very weak wax synthase activity, incorporating palmityl alcohol into wax esters in the presence of palmitoyl-CoA.
Consists of two tandem immunoglobulin-like Big_5 domains in the N-terminal region (residues 56-145 and 150-250), followed by a L,D-transpeptidase catalytic domain (residues 251-378) and a C-terminal tail (residues 379-408).
Is irreversibly inactivated by the beta-lactams carbapenems via the formation of a covalent adduct resulting from acylation of the catalytic Cys; imipenem is the most efficient drug for in vitro LdtMt2 inactivation.
Belongs to the class I-like SAM-binding methyltransferase superfamily. RNA M5U methyltransferase family.
Can autophosphorylate the carboxyl terminal region in addition to Thr-179 and Thr-181.
Deletion affects cell size and cell wall composition, increases survival during persistent infection in mice, and increases resistance to acidic pH, hypoxia, oxidative and stationary-phase stresses in vitro.
Induced during early infection in human macrophages.
Key microbial factor involved in regulation of early and late events in tuberculosis infection, and in host-pathogen interactions. Modulates host immunity during early infection. Slows mycobacterial growth during chronic infection in host and during a variety of stress conditions in vitro. Regulates the expression of a large subset of tRNA genes as a means to facilitate adaptation to changing growth environments. In vitro, directs the inhibition of transcription and translation processes in a phosphorylation-dependent manner. Phosphorylates the transcriptional regulator VirS, thereby increasing the affinity of VirS for the mycobacterial monooxygenase (mymA) promoter. In vitro, can also phosphorylate the mycobacterial monooxygenase operon products Rv3083 (MymA), Rv3084 (LipR), Rv3085 and Rv3088.
The C-terminal region exerts intrasteric control that autoregulates kinase activity.
5'-deoxyadenosylcobalamine (coenzyme B12).
Belongs to the ribonucleoside diphosphate reductase class-2 family.
No visible phenotype, even under low-oxygen growth conditions, nor in aerosol-infected B6D2/F1 mice.
Provides the precursors necessary for DNA synthesis. Catalyzes the biosynthesis of deoxyribonucleotides from the corresponding ribonucleotides (By similarity).
In the C-terminal section; belongs to the flavoprotein pyridine nucleotide cytochrome reductase family.
Catalyzes the activation of long-chain fatty acids as acyl-coenzyme A (acyl-CoA), which are then transferred to the multifunctional polyketide synthase (PKS) type III for further chain extension.
Belongs to the dihydroorotate dehydrogenase family. Type 2 subfamily.
Catalyzes the conversion of dihydroorotate to orotate with quinone as electron acceptor.
Possibly the antitoxin component of a type II toxin-antitoxin (TA) system. Its cognate toxin is VapC50.
Belongs to the F420-dependent hydroxymycolic acid dehydrogenase family.
Catalyzes the coenzyme F420-dependent oxidation of hydroxymycolic acids (H-MAs) to ketomycolic acids (K-MAs), a lipid class making up the mycobacterial pseudo-outer membrane and over one-third of the dry weight of M.tuberculosis (PubMed:24349169). Does not exhibit F420-dependent glucose-6-phosphate dehydrogenase (FGD) activity (PubMed:23110042).
Is exported by the Tat system. The position of the signal peptide cleavage has not been experimentally proven.
Is inhibited by the anti-tuberculous drug PA-824, a bicyclic 4-nitroimidazole class compound (PubMed:24349169). Therefore, this is consistent with the finding that PA-824 inhibits the formation of K-MAs and causes an accumulation of hydroxymycolic acids (H-MAs) in M.tuberculosis (PubMed:10879539).
Belongs to the metallo-dependent hydrolases superfamily.
Belongs to the triosephosphate isomerase family.
Involved in the gluconeogenesis. Catalyzes stereospecifically the conversion of dihydroxyacetone phosphate (DHAP) to D-glyceraldehyde-3-phosphate (G3P).
Belongs to the prokaryotic sulfate-binding protein family.
Toxic component of a type II toxin-antitoxin (TA) system. An RNase (By similarity). Upon expression in M.smegmatis inhibits colony formation. Its toxic effect is neutralized by coexpression with cognate antitoxin VapB33.
Deletion of the gene results in reduced growth in acidic medium under low oxygen conditions. The mutant shows better intracellular growth and survival inside THP-1 cells compared to wild-type and complemented strains. The colony morphology and antibiotic sensitivity of mutant and wild-type strains are similar (PubMed:22138550). The double knockout mutant pknI/dacB2 shows smoother colony morphology on solid agar and exhibits defective biofilm and cord formation. Double mutant is hypersensitive to cell wall damaging agents such as lysozyme, malachite green, ethidium bromide and to isoniazid, a first line anti-TB drug (PubMed:25467937).
Inhibited by the beta-lactam antibiotic meropenem (PubMed:22906310). Inhibited by the non-specific inhibitor phenylmethylsulfonyl fluoride (PMSF) (Probable).
Overexpression in Mycobacterium smegmatis results in reduced growth, an altered colony morphology, and a defect in sliding motility and biofilm formation. Overexpression of the S69C mutant shows similar results, indicating that the effects produced are independent of protein's penicillin binding function.
Probably cleaves the terminal D-Ala-D-Ala dipeptide of the peptidoglycan stem peptide (Probable). Shows significant D,D-carboxypeptidase activity in vitro (PubMed:22906310). Acts on the synthetic penta-peptide substrate Penta-DAP (L-Ala-gamma-D-Gln-DAP-D-Ala-D-Ala). Shows also weak activity on Penta-Lys (L-Ala-gamma-Glu-L-Lys-D-Ala-D-Ala) (PubMed:22906310). The catalytic domain binds weakly to peptidoglycan in vitro (PubMed:25551456). Plays an important role in the maintenance of colony morphology and cell wall permeability and integrity (PubMed:25467937).
Belongs to the DNA polymerase type-C family. DnaE2 subfamily.
DNA polymerase involved in damage-induced mutagenesis and translesion synthesis (TLS). It is not the major replicative DNA polymerase. Does not appear to be essential for chromosomal replication. May be involved in generating antibiotic resistance.
Up-regulated in response to all forms of DNA damage. LexA-regulated.
ATP-dependent specificity component of the Clp protease. It directs the protease to specific substrates. Can perform chaperone functions in the absence of ClpP (By similarity). Degrades anti-sigma-E factor RseA in the presence of ClpP2.
Belongs to the ClpA/ClpB family. ClpC subfamily.
Depletion experiments (using anti-sense RNA) stops degradation of anti-sigma-E factor RseA.
Involved in base excision repair of DNA damaged by oxidation or by mutagenic agents. Acts as DNA glycosylase that recognizes and removes damaged bases. Has a preference for oxidized purines, such as 7,8-dihydro-8-oxoguanine (8-oxoG) when paired with C, G or T, as well as methyl-faPy (formanidopyrimidine residues) in poly(dG-dC) and spiroiminodihydantoin:C base pairs. Unlike its E.coli ortholog has no activity on 8-oxoG:A. Has AP (apurinic/apyrimidinic) lyase activity and introduces nicks in the DNA strand. Cleaves the DNA backbone by beta-delta elimination to generate a single-strand break at the site of the removed base with both 3'- and 5'-phosphates. Cleaves ssDNA containing an AP site. Complements the H(2)O(2) sensitivity of an M.smegmatis fpg disruption mutant; upon expression in M.smegmatis excises 8-oxoG from dsDNA.
Disruption of pks1 abolishes the production of phthiocerol dimycocerosate (DIM) on the cell envelope, but the production of mycocerosic acid is not deficient. The pks10 mutants show a major attenuation of virulence.
M.bovis (strains ATCC BAA-935 / AF2122/97 and BCG / Pasteur 1173P2) and M.marinum (strain ATCC BAA-535 / M) have a single fused pks15/1 ORF, but M.tuberculosis (strains ATCC 25618 / H37Rv and CDC 1551 / Oshkosh) have 2 separate ORFs. This is due to the natural deletion of a single base, a guanine, that causes a frameshift and thus the two ORFs, pks15 and pks1, instead of pks15/1. This frameshift led to the inactivation of Pks15/1, which in turn caused the inability of these strains to elongate the putative p-hydroxybenzoic acid precursor and thus to produce phenolphthiocerol derivatives.
May play a role in phthiocerol biosynthesis.
A transcription factor that is probably redox-responsive. Probably plays a role in immunomodulation and reactivation after chronic infection. Its induction results in transcription of a number of genes including sigM, and the genes for 2 type VII secretion systems ESX-2 and ESX-4. Seems to negatively regulate its own expression. The apo-form has been shown to act as a protein disulfide reductase. The apo- but not holo-form probably binds DNA.
Maximal expression during progressive infection is between 2-4 weeks, however low, stable expression during chronic infection.
Not essential in culture. Gives an attenuated infection during both progressive and chronic mouse infections. Mice infected with the disrupted strain induce a stronger host immune response than wild-type. Growth inhibited by S-nitrosoglutathione (GSNO), a source of glutathione and nitric oxide. Mutant cells are less metabolically active. When chronic infection was reactivated by corticosterone the mutant strain was not able to resume growth, suggesting that WhiB5 might be involved with bacillary proliferation during reactivation.
Belongs to the peroxiredoxin family. BCP/PrxQ subfamily.
The active site is a conserved redox-active cysteine residue, the peroxidatic cysteine (C(P)), which makes the nucleophilic attack on the peroxide substrate. The peroxide oxidizes the C(P)-SH to cysteine sulfenic acid (C(P)-SOH), which then reacts with another cysteine residue, the resolving cysteine (C(R)), to form a disulfide bridge. The disulfide is subsequently reduced by an appropriate electron donor to complete the catalytic cycle. In this atypical 2-Cys peroxiredoxin, C(R) is present in the same subunit to form an intramolecular disulfide. The disulfide is subsequently reduced by thioredoxin.
Thiol-specific peroxidase that catalyzes the reduction of hydrogen peroxide and organic hydroperoxides to water and alcohols, respectively. Plays a role in cell protection against oxidative stress by detoxifying peroxides and as sensor of hydrogen peroxide-mediated signaling events.
Belongs to the extradiol ring-cleavage dioxygenase family.
Part of the ABC transporter complex Rv2686c/Rv2687c/Rv2688c involved in fluoroquinolones export. Confers resistance to ciprofloxacin and, to a lesser extent, norfloxacin, moxifloxacin and sparfloxacin. Probably responsible for the translocation of the substrate across the membrane.
Belongs to the DAPG/phloretin hydrolase family.
Interacts with PafC; with which it probably forms a heterocomplex.
Part of the pafABC operon, however PafB does not seem to be involved in pupylation or substrate degradation. Appears to play at least a small role in resistance to reactive nitrogen intermediates (RNI) in vitro.
Catalyzes the hydrolytic removal of ribose 5'-monophosphate from nitrogen N6-modified adenosines, the final step of bioactive cytokinin synthesis. Is involved in the synthesis of isopentenyladenine (iP) and 2-methylthio-iP (2MeS-iP), the most abundant cytokinins detected in M.tuberculosis lysates and supernatants. Is also able to convert trans-zeatin-riboside monophosphate (tZRMP) to trans-zeatin (tZ) in vitro; however, it may not be involved in the biosynthesis of this minor cytokinin in vivo. Accumulation of Rv1205 sensitizes M.tuberculosis to nitric oxide since cytokinin breakdown products synergize with NO to kill M.tuberculosis. Shows a slow AMP hydrolase activity, but is not able to hydrolyze ATP. Displays no lysine decarboxylase (LDC) activity (L-lysine conversion to cadaverine).
Disruption of this gene suppresses the NO-sensitive phenotype of an mpa mutant, and therefore restores NO resistance to a proteasomal-degradation-deficient M.tuberculosis strain. In addition, the disruption mutation in Rv1205 partially rescues the defective growth of the mpa mutant in the lungs and spleens of mice. Strains lacking Rv1205 show a significant reduction in the amount of several cytokinins: iP levels are almost 30 times lower in mutant supernatants, along with a corresponding increase in the concentration of the cytokinin precursors, and the level of 2MeS-iP is reduced by almost two orders of magnitude in these strains.
Pupylated at Lys-74 by the prokaryotic ubiquitin-like protein Pup, which leads to its degradation by the proteasome. The proteasomal control of cytokinin synthesis is essential to protect M.tuberculosis against host-produced NO.
Member of the two-component regulatory system NarS/NarL that regulates genes involved in aerobic nitrate metabolism (PubMed:25659431). Upon phosphorylation by NarS, functions as a transcription regulator by direct binding to promoter regions of target genes together with DevR to regulate their expression during aerobic nitrate metabolism (PubMed:25659431).
Monomer in solution (PubMed:19052358). Interacts with DevR (PubMed:25659431).
Mutants show no change in virulence in mouse model of infection.
Antioxidant protein with alkyl hydroperoxidase activity. Required for the reduction of the AhpC active site cysteine residues and for the regeneration of the AhpC enzyme activity.
Homotrimer. Identified in a complex with AhpC, DlaT and Lpd.
Together with AhpC, DlaT and Lpd, constitutes an NADH-dependent peroxidase active against hydrogen and alkyl peroxides as well as serving as a peroxynitrite reductase, thus protecting the bacterium against reactive nitrogen intermediates and oxidative stress generated by the host immune system.
Belongs to the isocitrate and isopropylmalate dehydrogenases family.
Catalyzes the phosphorylation of D-glycero-alpha-D-manno-heptose 7-phosphate at the C-1 position to form D-glycero-alpha-D-manno-heptose 1,7-bisphosphate (By similarity). Exhibits ATPase activity in vitro (PubMed:33412198).
Involved in the latter stages of the biosynthesis of the alpha-(1->6) mannan core of lipomannan (LM). Catalyzes the addition of alpha-(1->6)-mannose residue.
Belongs to the asparagine synthetase family.
Member of the three-protein two-component system HK1/HK2/TcrA. Kinase that binds ATP and catalyzes the transfer of a phosphoryl group from ATP to HK2.
Identified as a drug target (PubMed:10747933, PubMed:12023885, PubMed:22076471, PubMed:27581223, PubMed:32196311, PubMed:32197094). Inhibited by isoniazid (INH), thiolactomycin (TLM) and related analogs (PubMed:10747933, PubMed:12464486, PubMed:19604480, PubMed:24108128). Highly sensitive to cerulenin (PubMed:12023885). Is the biological target of GSK3011724A, an indazole sulfonamide (PubMed:27581223). Inhibited by the indazole JSF-3285, which is a promising preclinical candidate for tuberculosis (PubMed:32197094).
Part of the mycobacterial fatty acid elongation system FAS-II, which is involved in mycolic acid biosynthesis. Catalyzes the elongation of long chain acyl-ACP substrates by the addition of two carbons from malonyl-ACP to an acyl acceptor (PubMed:11600501, PubMed:12023885, PubMed:12464486, PubMed:16873379, PubMed:22017312, PubMed:24108128). Involved in the initial extension of the mycolate chain and forms monounsaturated fatty acids that averaged 40 carbons in length (PubMed:12464486).
Phe-404 residue probably plays a key role in the activation of the enzyme at the beginning of the catalytic cycle. A conformational change of Phe-404, possibly triggered by the substrate, is central for the activation because it switches KasA to the sufficiently reactive zwitterionic state.
Phosphorylated in vitro by several Ser/Thr protein kinases (STPKs). Highly phosphorylated in vivo on threonines. Can be dephosphorylated by the Ser/Thr phosphatase PstP.
Phosphorylation decreases the condensation activity.
Activity is probably potentiated by the DAT/PAT transporter MmpL10. Inhibited by the lipase inhibitor tetrahydrolipstatin (THL).
Involved in the final steps of polyacyltrehalose (PAT) biosynthesis. Catalyzes the transfer of three mycolipenoyl groups onto diacyltrehalose (DAT) to form PAT.
Mutant accumulates DAT in the cytoplasm and at the cell surface. Does not produce PAT.
The topology of this protein is unsure. According to PubMed:25124040, the C-terminal catalytic site is on the periplasmic side of the inner membrane. However, PubMed:25331437 authors conclude that Chp2 has the opposite topology, and that the C-terminal catalytic site is on the cytoplasmic side of the membrane.
Catalyzes the dehydrogenation at the alpha-beta position of ACP-bound acyl chains. This results in the introduction of a double bond in the lipidic chain, which is further transferred to the epsilon-amino group of lysine residue in the mycobactin core by MbtK.
Required for maturation of urease via the functional incorporation of the urease nickel metallocenter.
UreD, UreF and UreG form a complex that acts as a GTP-hydrolysis-dependent molecular chaperone, activating the urease apoprotein by helping to assemble the nickel containing metallocenter of UreC. The UreE protein probably delivers the nickel.
Toxic component of a type II toxin-antitoxin (TA) system. Its cognate antitoxin is VapB29 (By similarity). Has ribonuclease activity.
Forms a heterotetramer with UvrA during the search for lesions. Interacts with UvrC in an incision complex.
The UvrABC repair system catalyzes the recognition and processing of DNA lesions. A damage recognition complex composed of 2 UvrA and 2 UvrB subunits scans DNA for abnormalities. Upon binding of the UvrA(2)B(2) complex to a putative damaged site, the DNA wraps around one UvrB monomer. DNA wrap is dependent on ATP binding by UvrB and probably causes local melting of the DNA helix, facilitating insertion of UvrB beta-hairpin between the DNA strands. Then UvrB probes one DNA strand for the presence of a lesion. If a lesion is found the UvrA subunits dissociate and the UvrB-DNA preincision complex is formed. This complex is subsequently bound by UvrC and the second UvrB is released. If no lesion is found, the DNA wraps around the other UvrB subunit that will check the other stand for damage.
The beta-hairpin motif is involved in DNA binding.
Exhibits vaccine potential (PubMed:18719176, PubMed:23788727). Immunogenicity is demonstrated in BALB/c mice (PubMed:18719176). Interaction with TLR2 induces activation of human dendritic cells (DCs) (PubMed:23788727). Immunization with this protein induces a significant number of CD8+ T cells and a strong Th1-type response, with high gamma interferon (IFN-gamma) and low interleukin-4 responses, and activation of the bactericidal activity of macrophages. Identified T-cell epitopes may contribute to immunity against tuberculosis if included in a vaccine (PubMed:18719176).
Expression in Mycobacterium smegmatis, a nonpathogenic species naturally deficient in PE_PGRS genes, results in enhanced resistance to various in vitro stresses (PubMed:30937925). It also leads to phagosome maturation arrest and increased survival in macrophages (PubMed:30937925, PubMed:23167250).
Interacts with host Toll-like receptor 2 (TLR2).
Supports mycobacterial virulence via inhibition of phagosome maturation and host inducible nitric oxide synthase (iNOS) expression (PubMed:23167250). May promote the survival within macrophages by disturbing the cytokines profiles and blocking the endoplasmic reticulum (ER) stress-mediated apoptosis (PubMed:30937925). May also affect bacterial cell wall composition (PubMed:23167250).
Exhibits vaccine potential. Immunogenicity is demonstrated in BALB/c mice. Immunization with this protein induces a significant number of CD8+ T cells and a strong Th1-type response, with high gamma interferon (IFN-gamma) and low interleukin-4 responses, and activation of the bactericidal activity of macrophages. Identified T-cell epitopes may contribute to immunity against tuberculosis if included in a vaccine.
Was originally thought to be a dihydrofolate reductase.
Catalyzes the transfer of the diacylglyceryl group from phosphatidylglycerol to the sulfhydryl group of the N-terminal cysteine of a prolipoprotein, the first step in the formation of mature lipoproteins.
Negatively regulates the expression of the efflux pump Rv0191 upon chloramphenicol exposure. Acts by binding to the Rv0191 promoter region.
May be a S-adenosylmethionine-dependent methyltransferase involved in fatty acid metabolism.
Binds 2 heme groups non-covalently per subunit.
Cytochrome b subunit of the cytochrome bc1 complex, an essential component of the respiratory electron transport chain required for ATP synthesis. The bc1 complex catalyzes the oxidation of ubiquinol and the reduction of cytochrome c in the respiratory chain. The bc1 complex operates through a Q-cycle mechanism that couples electron transfer to generation of the proton gradient that drives ATP synthesis. The cytochrome b subunit contains two ubiquinol reactive sites: the oxidation (QP) site and the reduction (QN) site.
Inhibited by the anti-tuberculous drug Q203, an optimized imidazopyridine amide (IPA) compound. Q203 triggers a rapid ATP depletion in M.tuberculosis grown under an aerobic or anaerobic atmosphere (PubMed:23913123). Also inhibited by LPZS (lansoprazole sulfide), a metabolite of LPZ (lansoprazole) generated by intracellular sulfoxide reduction into the host cytoplasm; LPZS is a potent anti-mycobacterial agent that inhibits growth of intracellular M.tuberculosis with good activity against drug-resistant isolates. The inhibition of QcrB by LPZS leads to disruption of the mycobacterial respiratory chain and massive and rapid ATP depletion (PubMed:26158909). Both compounds target the same active site in QcrB (the ubiquinol oxidation QP site), but they have distinct drug-binding mechanisms (PubMed:26158909).
A member of the dormancy regulon. Induced in response to reduced oxygen tension (hypoxia), low levels of nitric oxide (NO) and carbon monoxide (CO). It is hoped that this regulon will give insight into the latent, or dormant phase of infection. Induced in mouse lungs at the same time that adaptive host immunity induces bacterial growth arrest; induction is dependent on interferon gamma.
May play a role in the establishment of a persistent infection (latency) in the host, as strains without this gene are hypervirulent. Overexpression of the protein retards growth in culture; Glu-15 and Ala-117 mutant proteins which bind less ATP do not show this retardation, suggesting growth may be regulated through an ATP-dependent function.
The deletion strain is hypervirulent compared to the wild-type strain in infection studies with outbred Hartley guinea pigs and with C3H/HeJ mice but not with C57BL/6 mice. No phenotype when grown in culture upon disruption, probably due to functional redundancy among paralogs.
Belongs to the NAD-dependent DNA ligase family. LigA subfamily.
DNA ligase that catalyzes the formation of phosphodiester linkages between 5'-phosphoryl and 3'-hydroxyl groups in double-stranded DNA using NAD as a coenzyme and as the energy source for the reaction. It is essential for DNA replication and repair of damaged DNA.
Toxic component of a type II toxin-antitoxin (TA) system. An RNase (By similarity). Upon expression in M.smegmatis inhibits colony formation. Its toxic effect is neutralized by coexpression with cognate antitoxin VapB19.
Up-regulated 2.3-fold 7 days after infection of human macrophages.
Participates in transcription elongation, termination and antitermination.
ATPase activity is stimulated by Cu(+) ions.
Involved in copper export. Could be involved in the copper detoxification of mycobacterial cells.
Up-regulated in pulmonary and extrapulmonary TB patients.
Toxic component of a type II toxin-antitoxin (TA) system. Acts as an RNase. Upon expression in E.coli and M.smegmatis inhibits translation, cell growth and colony formation. Its toxic effects on cell growth and colony formation are neutralized by coexpression with cognate antitoxin VapB11; the effect on translation has not been tested but is probably also neutralized.
Antitoxin component of a hybrid type II/IV toxin-antitoxin (TA) system. De-ADP-ribosylates DNA (probably) modified on thymidine by its cognate toxin DarT, which neutralizes the activity of DarT (PubMed:27939941). Experiments in which DarG levels are depleted lead to cell death; expression of wild-type DarG protein from M.tuberculosis or T.aquaticus restores growth. Cells depleted of DarG are more sensitive to bedaquilline (targets respiration), DNA-damaging drugs (mitomycin C, netropsin) and transcription-targeted drugs (rifabutin and rifampicin). When depleted, a DNA-damage response is induced and mutability is increased (PubMed:32634279). In E.coli the macrodomain alone neutralizes DarT toxin from non-cognate T.aquaticus. The same domain de-ADP-ribosylates genomic DNA (PubMed:34408320).
As expression of DarT is bactericidal (rather than bacteriostatic as are most TA systems in this bacteria), inactivation of DarG may be an attractive drug target.
Belongs to the DarG ADP-ribosyl glycohydrolase family.
Cells lacking this gene display impaired growth (PubMed:12657046). A double darT-darG deletion shows no change in growth in culture, upon infection of mice, or upon exposure to a variety of stresses (PubMed:32634279). Another group finds the double knockout gives a competitive advantage over wild-type cells in liquid culture growth experiments. Knock-down of darG expression leads to increased RecA expression, ADP-ribosylation of OriC and growth arrest (PubMed:34408320).
Forms a complex with cognate toxin DarT; this complex neutralizes the toxic effect of DarT (PubMed:32634279). Co-immunoprecipitates with a number proteins known to be involved in DNA metabolism, in the presence and absence of darT; includes alkA, dnaB, dnaE1, dnaG, dus, embR, mtrA, nrdE, nrdR, polA, recA, recB, recF, xerD, Rv2258c (PubMed:32634279).
The macro domain alone is sufficient to neutralize DarT from non-cognate T.aquaticus in E.coli, DarT in M.bovis, and to de-ADP-ribosylate DNA in vitro.
Could be involved in regulation of growth and intracellular survival.
Elicits a prominent immune response in human tuberculosis patients. Contains several epitopes, particularly in the C-terminal region.
Inactivation does not abolish EsxA (ESAT-6) secretion, EsxA-specific immunogenicity and enhanced virulence (PubMed:16368961). Deletion mutants multiply more efficiently compared to wild-type strains (PubMed:26228622).
Residues 76-280 interact with EsxB and an artificial EsxB-EsxA heterodimer (PubMed:19854905).
Toxic component of a type II toxin-antitoxin (TA) system. An RNase (By similarity). Upon expression in M.smegmatis inhibits colony formation. Its toxic effect is neutralized by coexpression with cognate antitoxin VapB30.
An anti-sigma factor for extracytoplasmic function (ECF) sigma factor SigM. ECF sigma factors are held in an inactive form by an anti-sigma factor until released by regulated intramembrane proteolysis (RIP). RIP occurs when an extracytoplasmic signal triggers a concerted proteolytic cascade to transmit information and elicit cellular responses. The membrane-spanning regulatory substrate protein is first cut extracytoplasmically (site-1 protease, S1P), then within the membrane itself (site-2 protease, S2P, Rip1), while cytoplasmic proteases finish degrading the regulatory protein, liberating the sigma factor (By similarity).
Interacts with ECF RNA polymerase sigma factor SigM; this should inhibit the interaction of SigM with the RNA polymerase catalytic core.
The cytosolic domain interacts with sigma factor SigM.
Catalyzes the transfer of a formyl group from 10-formyltetrahydrofolate to 5-phospho-ribosyl-glycinamide (GAR), producing 5-phospho-ribosyl-N-formylglycinamide (FGAR) and tetrahydrofolate.
Belongs to the class I-like SAM-binding methyltransferase superfamily. Cation-dependent O-methyltransferase family.
Catechol O-methyltransferase that can use various catechol-like compounds such as gallic acid (GA), 3,4-dihydroxy-5-methoxy-benzoic acid (5OMeBA), protocatechuic acid (PCA), 3,4-dihydroxy-benzaldehyde (DHA), dopamine, caffeic acid (CA), luteolin, quercetin, and 5-hydroxyuridine.
Belongs to the DeoC/FbaB aldolase family. DeoC type 1 subfamily.
Catalyzes a reversible aldol reaction between acetaldehyde and D-glyceraldehyde 3-phosphate to generate 2-deoxy-D-ribose 5-phosphate.
Ferredoxin that is the redox partner of cytochrome CYP143, a cytochrome P450 encoded by an adjacent gene.
Interacts with the cytochrome P450 143 with high affinity (Kd=84 nM).
Belongs to the universal ribosomal protein uL11 family.
Forms part of the ribosomal stalk which helps the ribosome interact with GTP-bound translation factors.
One or more lysine residues are methylated.
Part of the ribosomal stalk of the 50S ribosomal subunit. Interacts with L10 and the large rRNA to form the base of the stalk. L10 forms an elongated spine to which L12 dimers bind in a sequential fashion forming a multimeric L10(L12)X complex.
Expression in M.smegmatis enhances the ability to resist in vitro stress and early survival in macrophages. Macrophages infected with recombinant M.smegmatis produce significantly greater amounts of interleukin (IL)-1beta, IL-6, tumor necrosis factor (TNF)-alpha and an early decrease in IL-10 along with higher levels of host cell death.
May play an important role in the persistence of mycobacteria in host cells. May regulate the innate immune response of macrophages by promoting the production of pro-inflammatory cytokines and inhibiting the production of anti-inflammatory cytokines. Promotes the death of macrophages during infection.
Involved in the first cycle of side chain dehydrogenation in the beta-oxidation of cholesterol catabolism (PubMed:26161441). It contributes partly to the virulence by increasing the efficiency of beta-oxidation. Catalyzes the dehydrogenation of acyl-CoA ester side chains of (25S)-3-oxo-cholest-4-en-26-oyl-CoA (3-OCS-CoA) to yield (24E)-3-oxo-cholest-4,24-dien-26-oyl-CoA (PubMed:26348625, PubMed:26161441). Also able to dehydrogenate steroyl-CoA such as 3-oxo-chol-4-en-24-oyl-CoA (3-OCO-CoA) as well as 3-oxo-4-pregnene-20-carboxyl-CoA (3-OPC-CoA) (PubMed:26161441). It dehydrogenates only (25S)-OCS-CoA diastereomer (Probable).
Expressed in broth-grown cultures and after 18 hours of M.tuberculosis growth in cultured human primary macrophages, but not after longer periods of macrophage infection (PubMed:11914351). Positively autoregulated (PubMed:11914351).
Member of the two-component regulatory system TrcS/TrcR (PubMed:10089160, PubMed:11914351). Activates its own expression by binding specifically to the AT-rich sequence of the trcR promoter region (PubMed:11914351). Also negatively regulates the expression of Rv1057 by binding to an AT-rich sequences within the Rv1057 upstream sequence (PubMed:16352831, PubMed:22099420). The TrcR-TrcS regulatory system may act as a transition regulatory system involved in adapting to an intracellular environment and transitioning from latency to reactivation (PubMed:11914351).
Belongs to the Orn/Lys/Arg decarboxylase class-II family. LysA subfamily.
Homodimer; disulfide-linked. Can also form homotetramer at higher protein concentrations.
Specifically catalyzes the decarboxylation of meso-diaminopimelate (meso-DAP) to L-lysine (Probable). Is essential for the viability of M.tuberculosis in the host (PubMed:12637582).
Strains lacking this gene are lysine auxotrophs. They cannot survive in immunocompromised mice.
A type II topoisomerase that negatively supercoils closed circular double-stranded (ds) DNA in an ATP-dependent manner to maintain chromosomes in an underwound state, while in the absence of ATP it relaxes supercoiled dsDNA (PubMed:15047530, PubMed:16876125, PubMed:19060136, PubMed:16377674, PubMed:18426901, PubMed:22844097, PubMed:19596812, PubMed:20805881). Also catalyzes the interconversion of other topological isomers of dsDNA rings, including catenanes (PubMed:16876125, PubMed:19060136, PubMed:22457352). Gyrase from M.tuberculosis has higher decatenation than supercoiling activity compared to E.coli; as M.tuberculosis only has 1 type II topoisomerase, gyrase has to fulfill the decatenation function of topoisomerase IV as well (PubMed:16876125, PubMed:22457352, PubMed:23869946). At comparable concentrations M.tuberculosis gyrase cannot introduce as many negative supercoils into DNA as the E.coli enzyme, and its ATPase activity is lower, perhaps because it does not couple DNA wrapping and ATP binding as well as E.coli (PubMed:22457352, PubMed:24015710).
Belongs to the type II topoisomerase GyrB family.
DNA supercoiling inhibited by (fluoro)quinoline antibiotics such as sparfloxacin and levofloxacin, which usually act on GyrA subunit (PubMed:15047530). DNA supercoiling inhibited by the coumarin antibiotic novobiocin which acts on GyrB (PubMed:16876125). Quinolones lead to gyrase-mediated dsDNA cleavage while preventing reclosure (PubMed:15047530, PubMed:16876125, PubMed:23869946). DNA supercoiling activity inhibited by aminopyrazinamide and pyrrolamide derivatives, probably via effects on the GyrB subunit (PubMed:23268609, PubMed:24126580). DNA relaxation inhibited by ATP and its analogs (PubMed:16876125). DNA supercoiling, relaxation, decatenation and quinolone-promoted DNA cleavage are inhibited by MfpA (50% inhibition occurs at 2 uM), inhibition of gyrase activities is enhanced in a concentration-dependent manner by MfpA (PubMed:19060136).
Few gyrases are as efficient as E.coli at forming negative supercoils. Not all organisms have 2 type II topoisomerases; in organisms with a single type II topoisomerase this enzyme also has to decatenate newly replicated chromosomes.
Heterotetramer, composed of two GyrA and two GyrB chains (PubMed:15047530). In the heterotetramer, GyrA contains the active site tyrosine that forms a transient covalent intermediate with DNA, while GyrB binds cofactors and catalyzes ATP hydrolysis.
Mg(2+) required for DNA supercoiling, DNA relaxation, DNA cleavage and DNA decatenation, Mn(2+) substitutes for relaxation but not supercoiling or cleavage activity (PubMed:16876125). Ca(2+) does not substitute for supercoiling activity (PubMed:22844097).
The B' domain (residues 448-675, Toprim plus a tail domain) forms a dimer; when reconstituted with intact GyrA the complex has ATP-independent DNA relaxation activity (PubMed:19596812). The same fragment (also called TopBK) when reconstituted with intact GyrA or the N-terminus of GyrA (residues 1-502) can catalyze quinolone-mediated DNA breaks (PubMed:20805881).
When the enzyme transiently cleaves DNA a phosphotyrosine bond is formed between GyrA and DNA (PubMed:15047530). In the presence of quinolones this intermediate can be trapped and is used as an indicator of drug toxicity (PubMed:16377674, PubMed:16876125, PubMed:23869946). DNA gyrase is intrinsically more resistant to fluoroquinolone drugs than in E.coli, mutating it to resemble E.coli increases its susceptibility to fluoroquinolones (most quinolone-resistant mutations are in the GyrA subunit) (PubMed:18426901).
Belongs to the chaperonin (HSP60) family.
Each subunit is composed of an apical domain, an intermediate domain and an equatorial domain (PubMed:32808291). The apical domain is sufficient for substrate recognition (PubMed:21094166). Contains a characteristic histidine-rich C terminus which is essential for copper binding (PubMed:32808291). Copper binding causes conformational rearrangement (PubMed:32808291).
Forms a cylinder of 14 subunits composed of two heptameric rings stacked back-to-back (Probable). Also exists as lower oligomers, including monomeric, dimeric and heptameric forms (PubMed:15327959, PubMed:19717599, PubMed:32808291, PubMed:32812602). The switch between the single-ring (heptameric) and double-ring (tetradecameric) forms is mediated by phosphorylation on Ser-393 (PubMed:19717599). Interacts with the co-chaperonin GroES (By similarity).
In response to heat shock (45 degrees Celsius) and hyperosmolarity.
Involved in copper homeostasis (PubMed:32808291, PubMed:32812602). Binds copper and may help maintaining copper homeostasis when copper is present in excess, notably in the macrophage phagosome, by acting as a metal storage protein (PubMed:32808291, PubMed:32812602). Could be involved in copper resistance during mycobacterial biofilm formation (PubMed:32812602). Protects from copper stress in vitro (PubMed:32808291). Can also bind other metals, but binds copper with relatively higher affinity compared to nickel and cobalt (PubMed:32808291). May play an important role in survival under low aeration by affecting the expression of genes known for hypoxia response (PubMed:26822628).
M.tuberculosis contains two copies of the groEL gene, groEL1 and groEL2. GroEL2 is probably the housekeeping chaperonin, with the GroEL1 proteins having evolved, following an ancestral gene duplication event, to take on a more specialized role or roles.
Not essential (PubMed:18227175, PubMed:26822628). Increased heat sensitivity (at 55 degrees Celsius) (PubMed:18227175). Inactivation of the gene does not affect cell wall lipids, or growth and survival in macrophages, but mutant shows slower growth in the mouse lung and spleen in early infection and fails to produce granulomatous inflammation in either mice or guinea pigs (PubMed:18227175). This is associated with reduced cytokine expression in infected animals and macrophages (PubMed:18227175). Knockout of the gene leads to differential gene expression under low aeration stress, including down regulation of genes in copper response and genes encoding members of folate synthesis super pathway (PubMed:26822628). Survival under low aeration is significantly compromised in this knockout mutant (PubMed:26822628). Knockout mutant shows increased sensitivity to Cu(2+) (PubMed:32808291).
Oligomerization, which is mediated by phosphorylation, is required for chaperone activity. Lower oligomeric GroELs possess substrate binding activity but are inefficient in promoting refolding (PubMed:19717599). The binding of copper protects GroEL1 from destabilization and increases its ATPase activity (PubMed:32812602).
Phosphorylated on Thr-25 and Thr-54 by PknF (PubMed:19201798). Phosphorylated on Ser-393 by an unknown kinase (PubMed:19717599).
Prevents aggregation of substrate proteins and promotes their refolding (PubMed:15327959, PubMed:19717599, PubMed:21094166). In vitro, activity may be independent of the presence or absence of the GroES co-chaperonin or ATP (PubMed:15327959). Shows weak ATPase activity (PubMed:15327959, PubMed:32812602).
Recombinant GroEL of M.tuberculosis is unable to act as effective molecular chaperone when expressed in Escherichia coli (PubMed:18227175, PubMed:19717599, PubMed:22834700). Although M.tuberculosis GroEL1 is capable of oligomerization in its native environment, it cannot do the same in E.coli, which probably explains its lack of chaperone activity in E.coli (PubMed:19717599). Can complement M.smegmatis mutants (PubMed:22834700).
Belongs to the F420H(2)-dependent biliverdin reductase family.
F420H(2)-dependent reductase able to catalyze the reduction of biliverdin-IXalpha to bilirubin-IXalpha in vitro. However, kinetic parameters show that it is less efficient than the biliverdin reductase Rv2074 and suggest biliverdin-IXalpha is unlikely to be the native substrate of Rv1155, which probably catalyzes the reduction of an alternative molecule in vivo (PubMed:27364382). Binds coenzyme F420, but does not bind FMN or other flavins (PubMed:25644473). Cannot use pyridoxine 5'-phosphate, pyridoxamine 5'-phosphate, pyridoxal 5'-phosphate (PLP), the anti-tuberculosis drug PA-824 or aflatoxin analogs as substrates (PubMed:25644473).
FMN and PLP are seen in the crystal structures published in PubMed:16239726, however, the enzyme does not bind these compounds in vitro, and the complexes obtained in the crystal structures may be the result of weak FMN/PLP binding that is stabilized by the crystal lattice.
Was originally thought to be an FMN-dependent pyridoxine 5'-phosphate oxidase.
Important for the siderophore-mediated iron-acquisition function of ESX-3 (PubMed:26729876). May play a pivotal role in the evasion of host immune response by M.tuberculosis. Mediates production of IL-10 via activation of the p38 and ERK1/2 mitogen-activated protein kinase (MAPK) signaling pathways (PubMed:23284742).
Belongs to the LDH/MDH superfamily. MDH type 2 family.
Catalyzes the reversible oxidation of malate to oxaloacetate.
Belongs to the helicase family. DnaB subfamily.
Participates in initiation and elongation during chromosome replication; it exhibits DNA-dependent ATPase activity.
An ammonia tunnel 40 Angstroms long allows transfer of ammonia from the glutaminase active site, where it is produced, to the synthetase active site, where it is used for the ATP-dependent formation of NAD(+).
Catalyzes the ATP-dependent amidation of deamido-NAD to form NAD. Uses L-glutamine as a nitrogen source. In vitro, can also use ammonia with comparable specific activity.
Homooctamer; composed of two stacked homotetramers that form a ring-like structure.
In the C-terminal section; belongs to the NAD synthetase family.
The formation of the intermediates complex at the synthetase domain stimulates the glutaminase activity.
Belongs to the class I-like SAM-binding methyltransferase superfamily. RsmB/NOP family.
Can use Ca(2+), Mn(2+), and, to a lesser extent, Mg(2+).
Cells lacking this gene show an increase in virulence in mouse model of infection, with significantly shorter survival times (PubMed:12595424). In strain Mt103, disruption of the gene does not affect the intracellular multiplication capacity of the mutants in mouse bone marrow-derived macrophages (PubMed:11953357).
Expressed in broth-grown cultures and after 18 hours of M.tuberculosis growth in cultured human primary macrophages, but not after longer periods of macrophage infection.
Member of the two-component regulatory system TrcS/TrcR (PubMed:10089160, PubMed:11914351). Phosphorylates TrcR (PubMed:10089160). The TrcR-TrcS regulatory system may act as a transition regulatory system involved in adapting to an intracellular environment and transitioning from latency to reactivation (PubMed:11914351).
Overexpression in M.smegmatis mtrB background reverses the mtrB mutant phenotype including the expression of the MtrA-regulon. TrcS interacts with MtrA and is capable of phosphorylating MtrA in vitro. These results suggest that under certain specific conditions in vivo, TrcS could phosphorylate MtrA, independent of MtrB.
Likely catalyzes the dephosphorylation of O-phospho-L-serine into L-serine.
Contains two distinct structural domains: an almost globular alpha/beta fold domain and an inserted cap domain which interacts with the alpha/beta fold domain (PubMed:21637775). A flexible loop plays a functional role in the metal-dependent allosteric regulation of the enzyme (PubMed:33914998).
Esterase likely involved in ester/lipid metabolism. Shows strong substrate selectivity toward short, straight chain alkyl esters with the highest activity toward four atom chains. The physiological substrate is unknown (PubMed:25354081). Is able to hydrolyze ester bonds within a wide range of p-nitrophenyl derivatives (C2-C14) in vitro (PubMed:20957207).
Hydrolysis of a fluorogenic ester substrate (MOAME) is allosterically inhibited by divalent transition metal cations (Cu(2+), Zn(2+), Ni(2+) and Co(2+)) (PubMed:33914998). Inhibition is largely due to a two order of magnitude drop in kcat, with relatively little change in KM (PubMed:33914998). The thermal stability decreases with increasing concentrations of Ni(2+) (PubMed:33914998).
Toxic component of a type II toxin-antitoxin (TA) system. Upon expression in E.coli inhibits cell growth and colony formation. Its toxic effect is neutralized by coexpression with cognate antitoxin ParD2.
Deletion of the gene does not impact in vitro growth, but it leads to aberrations in the cell length. Deletion enhances sensitivity to nisin and vancomycin. Also exhibits hypersensitivity to moenomycin. Mutant shows compromised bacterial virulence in the host.
Phosphorylated on Thr-463, probably by PknB and PknH.
Phosphorylation at Thr-463 may be important for modulating interactions with other cell division proteins, thus regulating the cell division process.
Transglycosylase involved in peptidoglycan cell wall formation (PubMed:29530985). Required for the regulation of cell length. Plays critical roles for the survival of the pathogen inside the host. Required for both bacterial survival and formation of granuloma structures in a guinea pig infection model (PubMed:29530985).
Functions in inorganic phosphate uptake, although probably not the main uptake protein under phosphate starvation (PubMed:15731097, PubMed:20933472). Part of the ABC transporter complex PstSACB involved in phosphate import (Probable).
No growth phenotype in phosphate-rich medium (3.6 mM Pi) (PubMed:15731097). In restricted medium (Sauton) grows better than wild-type even after nutrient starvation (PubMed:20933472). Decreased phosphate uptake in phosphate-depleted medium (PubMed:15731097). Decreased growth in infected BALB/c and C57BL/6 mice for up to 5 months after infection (PubMed:15731097).
Transcription not induced by phosphate starvation, protein levels do not increase either (at protein level). Part of the pstS2-pknD operon.
Belongs to the monomeric-type IDH family.
Involved in the biosynthesis of mycocyclosin. It uses activated amino acids in the form of aminoacyl-tRNAs (aa-tRNAs) as substrates to catalyze the ATP-independent formation of cyclodipeptides which are intermediates in diketopiperazine (DKP) biosynthetic pathways. Catalyzes the formation of cyclo(L-Tyr-L-Tyr) (cYY) from L-tyrosyl-tRNA(Tyr). Can incorporate various nonpolar residues, such as L-phenylalanine, L-leucine, L-tyrosine and L-methionine, and to a much lesser extent L-alanine, into cyclodipeptides. Cyclodipeptides synthesized by Rv2275 always contain L-tyrosine.
The reaction proceeds following a ping-pong mechanism forming a covalent intermediate between an active site Ser-88 and the L-phenylalanine residue.
Homodimer (Probable). Interacts with LigD in the absence of DSBs, and with the isolated Pol domain of LigD in the presence of DNA. Interacts with Sir2, possibly in a trimeric complex with LigD.
With LigD forms a non-homologous end joining (NHEJ) repair enzyme. Binds linear dsDNA with 5'- and 3'-overhangs but not closed circular dsDNA nor ssDNA. One dimer binds for every 30 bp. Recruits and stimulates the ligase activity of LigD but not of T4 ligase or a human ligase complex (LIG4/XRCC4). Attenuates the 3'- to 5'-exonuclease activity of LigD. Stimulates the template-directed addition of dNTPs by LigD on 5'-overhangs and nuclease activity on 3'-overhangs.
Disruption of the gene enhances resistance to osmotic stress, increases resistance to several peptidoglycan biosynthesis inhibitors, decreases peptidoglycan thickness, enhances antibiotic resistance and activates genes in the SigF regulon.
Highly up-regulated by osmotic stress (PubMed:24309377, PubMed:17485404). Also induced during oxidative and starvation stresses (PubMed:17485404).
Interacts with Rv2638. Phosphorylation abolishes binding to Rv2638.
Part of a signaling pathway that enables adaptation to osmotic stress through cell wall remodeling and virulence factor production (PubMed:24309377). Unphosphorylated OprA forms a complex with the anti-anti-sigma-factor paralog Rv2638 that dissociates on OprA phosphorylation by PknD (PubMed:17411339). Phosphorylation of OprA may stimulate the release of SigF from an inhibitory complex and enable the transcription of osmotically regulated genes, such as oprA and the ESX-1-associated virulence factor espA (PubMed:24309377).
Phosphorylated on Thr-2 by the serine/threonine-protein kinase PknD (PubMed:17411339, PubMed:24309377). Also phosphorylated to a lesser extent by PknB and PknE (PubMed:17411339). Dephosphorylated by PstP (PubMed:17411339).
Belongs to the universal ribosomal protein uS15 family.
Forms an intersubunit bridge (bridge B4) with the 23S rRNA of the 50S subunit in the ribosome.
One of the primary rRNA binding proteins, it binds directly to 16S rRNA where it helps nucleate assembly of the platform of the 30S subunit by binding and bridging several RNA helices of the 16S rRNA.
Part of the 30S ribosomal subunit. Forms a bridge to the 50S subunit in the 70S ribosome, contacting the 23S rRNA.
Monomer (PubMed:11073936). SapM interacts with host RAB7 via its C-terminus (PubMed:25896765).
Phosphatase activity is inhibited in vitro by low concentrations of several heavy metals (zinc chloride, sodium molybdate, magnesium chloride, and copper sulfate) and moderately high concentrations (>8 mM) of EDTA.
Strain lacking this gene is defective in the arrest of phagosomal maturation as well as for growth in human THP-1 macrophages. The mutant strain is severely attenuated for growth in the lungs and spleen of guinea pigs and has a significantly reduced ability to cause pathological damage in the host when compared with the parental strain. Also, the guinea pigs infected with the mutant strain exhibit a significantly enhanced survival when compared with M.tuberculosis infected animals.
The C-terminus of SapM is required for interaction with RAB7 and SapM-mediated autophagy block.
Virulence factor that plays an important role in blocking phagosome-lysosome fusion and thus participates in the intracellular survival of the pathogen (PubMed:15753315, PubMed:23923000). Acts as a phosphatase that dephosphorylates phosphatidylinositol 3-phosphate (PI3P), a membrane trafficking regulatory lipid essential for phagosomal acquisition of lysosomal constituents (PubMed:15753315). Therefore, SapM eliminates PI3P from the phagosomal membrane by catalyzing its hydrolysis, and thus contributes to inhibition of phagosome maturation (PubMed:15753315). Also interferes with autophagy: SapM blocks autophagosome-lysosome fusion in macrophages by binding to the small GTPase RAB7, which prevents RAB7 from being involved in this process and thus negatively regulates autophagy flux (PubMed:25896765). In vitro, displays phosphatase activity with broad specificity; can dephosphorylate a variety of phosphoester substrates, with the highest activity against phosphoenolpyruvate, glycerophosphate, GTP, NADPH, phosphotyrosine and trehalose-6-phosphate (PubMed:11073936). In contrast, the enzyme exhibits poor activity against glucose-6-phosphate, phosphothreonine, and a number of nucleotides (NADP, ATP, AMP, and GMP) (PubMed:11073936).
Esterase and beta-lactamase activities are inhibited by the active site residue modifiers phenylmethanesulfonylflouride (PMSF) and diethylpyrocarbonate (DEPC).
Shows both esterase and beta-lactamase activities, with a much higher activity against phenyl esters than against beta-lactams (PubMed:26398213, PubMed:26672466). Shows esterase activity against both long-chain and short-chain p-nitrophenol (pNP) esters, with a preference for shorter chain esters (PubMed:26398213, PubMed:26672466). Hydrolyzes substrates containing beta-lactam ring such as nitrocefin and ampicillin (PubMed:26672466). Functions as an immunogen that activates both humoral and cell-mediated responses (PubMed:26398213).
Up-regulated in acidic and oxidative stress conditions.
Pupylated at Lys-173 by the prokaryotic ubiquitin-like protein Pup, which leads to its degradation by the proteasome.
Monomer. Interacts with anti-sigma-F factor RsbW (UsfX) under reducing conditions, with a possible 2:1 RbsW:RsfA stoichiometry.
Positive, redox-sensitive regulator of sigma-F (SigF) activity. When reduced binds to anti-sigma-F factor RsbW (UsfX) preventing its binding to SigF, thus activating transcription.
Activity is modulated by the formation of a disulfide bound within the N-terminal Cys-X-X-X-Cys (CXXXC) motif (PubMed:34018220). This intramolecular disulfide bond is formed in response to oxidative stress, and results in oxidative stress-dependent interaction with the sigma factor SigH (PubMed:34018220).
Deletion mutant shows no growth difference in vitro in nutrient rich or limiting media, but its survival is compromised within peritoneal macrophages at day 4 post-infection (PubMed:34018220). Mutant shows a marginal decrease in the survival upon exposure to nitrosative stress and markedly compromised survival upon exposure to peroxide radicals (PubMed:34018220). Failure of the mutant to upregulate cysteine biosynthesis during oxidative stress generates a domino effect, causing differential expression of 6% of M.tuberculosis genes, resulting in attenuated survival (PubMed:34018220).
Homodimer (PubMed:34018220). Under oxidative stress, interacts with the extracytoplasmic-function (ECF) RNA polymerase sigma factor SigH (PubMed:34018220).
Transcription factor crucial for intra-mycobacterial redox homeostasis and protection against host-derived oxidative and nitrosative radicals (PubMed:34018220). In response to oxidative stress, interacts with the ECF sigma factor SigH and, in conjunction with SigH, binds to an auxiliary promoter upstream of mec-cysO-cysM, leading to the transcriptional activation of these genes encoding a non-canonical actinomycete-specific cysteine biosynthesis pathway (PubMed:34018220). Increased transcription of mec-cysO-cysM results in enhanced production of L-cysteine and cysteine-derived antioxidant molecules (PubMed:34018220). Increased production of cysteine protects mycobacteria cells from host phagocyte-derived oxidative and nitrosative stress, thus facilitating the mycobacterial growth in the host (PubMed:34018220).
Belongs to the trans-sulfuration enzymes family. MetZ subfamily.
Catalyzes the formation of L-homocysteine from O-succinyl-L-homoserine (OSHS) and hydrogen sulfide.
Methyltransferase that modifies short-chain fatty acids. In vitro, catalyzes the transfer of the methyl group from S-adenosyl-L-methionine (SAM) to the double bond of phospholipid-linked oleic acid to produce tuberculostearic acid (10-methylstearic-acid or TSA).
Because the enzyme that would modify Asp-89 to 3-methylthioaspartic acid has not been found in the proteome of this organism, that modification is not predicted.
Belongs to the universal ribosomal protein uS12 family.
Interacts with and stabilizes bases of the 16S rRNA that are involved in tRNA selection in the A site and with the mRNA backbone. Located at the interface of the 30S and 50S subunits, it traverses the body of the 30S subunit contacting proteins on the other side and probably holding the rRNA structure together. The combined cluster of proteins S8, S12 and S17 appears to hold together the shoulder and platform of the 30S subunit (By similarity).
Part of the 30S ribosomal subunit. Contacts proteins S8 and S17. May interact with IF1 in the 30S initiation complex (By similarity).
With S4 and S5 plays an important role in translational accuracy.
Putative antitoxin component of a type II toxin-antitoxin (TA) system. Its cognate toxin would be HigB3.
Catalyzes the methylation of methanethiol (MeSH) to yield dimethylsulphide (DMS).
Belongs to the cytidylate kinase family. Type 1 subfamily.
Cell-wall hydrolase that hydrolyzes the amide bond between N-acetylmuramic acid and L-alanine in cell-wall glycopeptides (PubMed:24311595, PubMed:24019530). Is able to hydrolyze the cell walls of several bacterial species (i.e. Paenibacillus sp., B.avium, E.coli DH5alpha, E.aerogenes, L.acidophilus, B.thuringiensis, B.pumilus, B.subtilis and E.coli W3110), thereby showing that it is a cell-wall hydrolase with broad-spectrum activity (PubMed:24311595). May have a role in peptidoglycan fragment recycling (PubMed:24019530).
Disulfide oxidation is not required for folding of the enzyme core or in vitro muramyl dipeptide hydrolysis.
The structure reveals a short flexible hairpin turn that partially occludes the active site and may be involved in autoregulation.
Catalyzes the attachment of tryptophan to tRNA(Trp).
Belongs to the universal ribosomal protein uL4 family.
Forms part of the polypeptide exit tunnel.
One of the primary rRNA binding proteins, this protein initially binds near the 5'-end of the 23S rRNA. It is important during the early stages of 50S assembly. It makes multiple contacts with different domains of the 23S rRNA in the assembled 50S subunit and ribosome.
The IMP cyclohydrolase activity resides in the N-terminal region.
May be involved in the GO system responsible for removing an oxidatively damaged form of guanine (7,8-dihydro-8-oxoguanine, 8-oxo-dGTP) from DNA and the nucleotide pool. 8-oxo-dGTP is inserted opposite dA and dC residues of template DNA with almost equal efficiency thus leading to A.T to G.C transversions. MutT specifically degrades 8-oxo-dGTP to the monophosphate (By similarity). In vitro has 8-oxo-dGTPase activity.
Belongs to the acetyltransferase family. RimI subfamily.
Monomer (PubMed:27353550). Interacts with TsaD (PubMed:27353550). Interacts with GroS/GroES (PubMed:27353550).
N-alpha-acetyltransferase that specifically mediates the acetylation of N-terminal residues. Able to mediate acetylation of a wide variety of N-terminal residues, with preference for hydrophobic N-termini. Acetylates GroS/GroES and GroEL1. Able to acetylate the ribosomal protein S18, but it is unclear whether it acetylates its N-terminal alanine residue.
Belongs to the PAPS reductase family. CysD subfamily.
With CysN forms the ATP sulfurylase (ATPS) that catalyzes the adenylation of sulfate producing adenosine 5'-phosphosulfate (APS) and diphosphate, the first enzymatic step in sulfur assimilation pathway. APS synthesis involves the formation of a high-energy phosphoric-sulfuric acid anhydride bond driven by GTP hydrolysis by CysN coupled to ATP hydrolysis by CysD.
Antitoxin component of a type II toxin-antitoxin (TA) system. In M.smegmatis neutralizes the toxic effect of mRNA interferase MazF4, its cognate toxin, on growth.
Forms a complex with cognate toxin MazF4.
Belongs to the GMC oxidoreductase family. Highly divergent.
Cells lacking this gene show attenuated pathogenicity in peritoneal macrophages.
Likely catalyzes the oxidation and isomerization of cholesterol to cholestenone (4-cholesten-3-one), which is an initial step in the cholesterol degradation process. Required for virulence.
Esterase that shows preference for short chain fatty acids (PubMed:26398213, PubMed:28164792, PubMed:28327423). Contributes to the growth of M.tuberculosis during the nutritive stress (PubMed:28164792). Elicits strong humoral response in both extrapulmonary and relapsed cases of tuberculosis patients (PubMed:28327423).
Inhibited by the ionic detergent SDS and by the serine protease inhibitor PMSF (PubMed:28164792). Inhibited by the FDA approved drugs Diosmin, Acarbose and Ouabain. These drugs remain bound in the active site pocket and could be probable drug candidates to combat TB disease (PubMed:29557724).
Up-regulated in nutritive stress but not in acidic and oxidative stress.
Degradation of the cholesterol side chain involves 3 multistep beta-oxidation cycles, this is involved in the second cycle. Hydrates bulky steroid enoyl-CoA esters, has highest activity with 3-OCDO-CoA (3-oxochol-4,22-dien-24-oyl-CoA) making (22S)-HOCO-CoA, followed by octenoyl-CoA, with weaker activity on 3-OCDS-CoA (3-oxocholest-4,24-dien-26-oyl-CoA) and none on 3-OPDC-CoA (3-oxo-pregna-4,17-diene-20- carboxyl-CoA). Hydrates the same substrate as EchA19, but the 2 enzymes make different stereoisomers of the product.
Not required for growth in a mouse tuberculosis model (PubMed:14569030). Required for growth on cholesterol (PubMed:21980284).
Catalyzes the epimerization of (2R)- and (2S)-methylacyl-coenzyme A (CoA) thioesters (PubMed:15632186, PubMed:19854148, PubMed:26348625). Accepts as substrates a wide range of alpha-methylacyl-CoAs, including (2R)-2-methylmyristoyl-CoA and (2S)-2-methylmyristoyl-CoA, (2R)-pristanoyl-CoA and (2S)-pristanoyl-CoA, and the cholesterol esters (25R)-3-oxo-cholest-4-en-26-oyl-CoA and (25S)-3-oxo-cholest-4-en-26-oyl-CoA (PubMed:15632186, PubMed:26348625). Can also catalyze the interconversion of the non-physiologic substrates (2R)-ibuprofenoyl-CoA and (2S)-ibuprofenoyl-CoA, which are potential competitive inhibitors of the enzyme (PubMed:19854148).
Development of gem-disubstituted substrate-product analogs as inhibitors of racemases and epimerases is elaborated using alpha-methylacyl-CoA racemase from Mycobacterium tuberculosis as a model enzyme. These non-physiologic substrates could be used as a therapeutic agent to inhibit human AMACR, which is overexpressed in prostate cancer.
Inactivated by N,N-dialkylcarbamoyl-CoA substrate-product analogs.
Interconversion is achieved via a planar enolate intermediate.
Component of the 30S ribosomal translation pre-initiation complex which assembles on the 30S ribosome in the order IF-2 and IF-3, IF-1 and N-formylmethionyl-tRNA(fMet); mRNA recruitment can occur at any time during PIC assembly.
One of the essential components for the initiation of protein synthesis. Stabilizes the binding of IF-2 and IF-3 on the 30S subunit to which N-formylmethionyl-tRNA(fMet) subsequently binds. Helps modulate mRNA selection, yielding the 30S pre-initiation complex (PIC). Upon addition of the 50S ribosomal subunit IF-1, IF-2 and IF-3 are released leaving the mature 70S translation initiation complex.
Belongs to the sulfotransferase 1 family.
Involved in the synthesis of cell wall sulfolipids with activity towards mycobacterial trehalose glycolipids and eukaryotic glycolipids such as glucosylceramide and galactosylceramide (type I and II) but not towards eukaryotic 3'-sulfate galactosylceramide.
Binds 1 [4Fe-4S] cluster per subunit. The cluster responds to both O(2) and NO. Following nitrosylation of the [4Fe-4S] cluster binds 1 [4Fe-8(NO)] cluster per subunit.
Can be nitrosylated by NO, leading to the formation of a tetrakis-cysteinyl [Fe4-(NO)8] complex.
During aerobic growth in culture grows more slowly over the whole life cycle, a 2X reduced ratio of NAD(+)/NADH (reflects redox metabolism) and a 1.5X reduction in membrane potential. Has increased resistance to oxidative stress. Enhanced growth in uninduced and activated macrophages, as well as enhanced growth at reduced O(2) tension. However reduced survival in guinea pig spleen but not lungs following aerosol infection. A number of genes are induced, including whiB4, whiB6, genes involved in antioxidant systems, redox factor PQQ and several members of the PE-PPE family.
Homodimer in the presence of reducing agents (PubMed:17302817); the oxidized apo-form makes dimers and trimers while the redeced apo-form does not (PubMed:22780904). Upon over expression in aerobically grown M.smegmatis, apo-WhiB4 forms trimers held together by disulfide bonds.
Redox-responsive transcriptional regulator that regulates a set of genes involved in protection against environmental stresses encountered during infection. The loss of the O(2) and NO-responsive 4Fe-4S cluster and subsequent redox modifications of Cys residue thiols (possibly by disulfide bond formation) may activate its role in gene regulation. The thiol-oxidized apo-form binds in a sequence non-specific manner to GC-rich DNA, probably in the minor groove. Represses transcription of a number of genes including itself. The reduced apo-form and holo-form do not bind DNA. The apo-form can act as protein disulfide reductase.
The 4Fe-4S cluster is very sensitive to air, degrading from 4Fe-4S via 3Fe-3S to 2Fe-2S then cluster loss. Upon cluster removal intramolecular disulfide bonds are formed.
Involved in the catabolism of short chain fatty acids (SCFA) via the tricarboxylic acid (TCA)(acetyl degradation route) and via the 2-methylcitrate cycle I (propionate degradation route). Catalyzes the dehydration of 2-methylcitrate (2-MC) to yield the cis isomer of 2-methyl-aconitate (PubMed:18375549, PubMed:22365605). Could also catalyze the dehydration of citrate and the hydration of cis-aconitate (By similarity).
The vitamin B12 restores growth of the prpDC mutant on propionate as the sole carbon source. It suggests the capacity of the MCM-dependent methylmalonyl pathway to support the metabolism of propionate independently of the methylcitrate cycle.
Contains an N-terminal region that probably interacts with RNA polymerase and a C-terminal region composed of 3 RNA binding domains, S1, KH 1 and KH 2.
Monomer. Binds directly to the core enzyme of the DNA-dependent RNA polymerase and to nascent RNA.
Participates in both transcription termination and antitermination.
Bifunctional enzyme that catalyzes the epimerization of the S- and R-forms of NAD(P)HX and the dehydration of the S-form of NAD(P)HX at the expense of ADP, which is converted to AMP. This allows the repair of both epimers of NAD(P)HX, a damaged form of NAD(P)H that is a result of enzymatic or heat-dependent hydration (By similarity).
In the C-terminal section; belongs to the NnrD/CARKD family.
In the N-terminal section; belongs to the NnrE/AIBP family.
Belongs to the aspartate/ornithine carbamoyltransferase superfamily. ATCase family.
Cells lacking the sdh2 operon (sdhCDAB) display a stationary phase exit defect after 60 days in culture. They show only slight difference in intracellular succinate and malate concentrations during aerobic growth or hypoxia when compared to wild-type. The mutant strain is more susceptible to proton motive force (PMF) inhibition than the parental strain, and it was impossible to recover colonies from mutant cultures after 21 days. Cells harboring a deletion of sdh2 consume oxygen at a reduced rate and are able to modulate respiration as dissolved oxygen (DO) is depleted to about 6%.
Membrane-anchoring subunit of succinate dehydrogenase 2 (Sdh2). Sdh2 may catalyze the two-electron oxidation of succinate to fumarate with a corresponding reduction of quinone to quinol under low oxygen conditions, when the primary aerobic succinate dehydrogenase (Sdh1) is inhibited. Sdh2 seems to be the generator of the proton motive force (PMF) under hypoxia.
Part of an enzyme complex containing four subunits: a flavoprotein (SdhA), an iron-sulfur protein (SdhB), plus two membrane-anchoring proteins (SdhC and SdhD).
The heme is bound between the two transmembrane subunits.
Contributes to evasion of both innate and adaptive immunity. Inhibits autophagy in infected host phagocytes and inhibits major histocompatibility complex (MHC) class II antigen presentation by mycobacteria-infected dendritic cells. Has an important role in the growth and survival of M.tuberculosis, particularly during intracellular growth and in the later chronic phase of infection.
Deletion mutant is attenuated in vitro and in vivo, and shows enhanced MHC class II-restricted antigen presentation during in vivo infection of mice. Also shows a reduced capability to inhibit autophagy and an increased acidification and lysosomal fusion of phagosomes during infection of phagocytic cells.
Binds 1 Mg(2+) ion per subunit. Can also utilize other divalent metal cations, such as Ca(2+), Mn(2+) and Co(2+).
Catalyzes the reversible transfer of a two-carbon ketol group from sedoheptulose-7-phosphate to glyceraldehyde-3-phosphate, producing xylulose-5-phosphate and ribose-5-phosphate. Catalyzes the transfer of a two-carbon ketol group from a ketose donor to an aldose acceptor, via a covalent intermediate with the cofactor thiamine pyrophosphate.
Binding to DNA is abolished in the presence of high concentration of iron. Specifically binds to tetracycline, which leads to a conformational change in the structure of the protein and inhibits the DNA binding activity.
Its association with indispensable iron homeostasis makes Rv1474c an attractive target for designing novel anti-mycobacterials.
Represses the expression of the aconitase gene acn and its own expression, in an iron-responsive manner. Binds to the inverted repeat element present in the upstream region of acn (Rv1475c)-Rv1474c operon. Preferentially binds to major groove of the DNA.
Disruption of this gene suppresses trans cyclopropanated mycolate without accumulation of trans-unsaturated oxygenated mycolates and shows an increased ability to form cords, thus establishing MmaA1 as a negative regulator of cording in M.tuberculosis.
Involved in the conversion of a cis-olefin into a trans-olefin with concomitant introduction of an allylic methyl branch at the proximal position of the precursor to both the methoxy and ketomycolic acids. It directly affects the cis- to trans ratio and indirectly affects the keto to methoxy ratio.
Cells lacking this gene display an increase in susceptibility to some beta-lactam antibiotics and, despite slower growth in vitro, enhanced virulence in both cellular and murine models of tuberculosis. No detectable difference in the lipid profiles.
May function as a peptidoglycan hydrolase with glycosidase activity (PubMed:25260828). In vitro, displays esterase activity toward p-nitrophenyl esters of various acyl chain length (C4 to C16), with a preference for p-nitrophenyl butyrate (C4) (PubMed:25869294).
Upon exposure to antituberculous drugs such as isoniazid, ethionamide or PA-824, Rv2525c expression is significantly up-regulated together with those of other genes involved in cell wall processes.
Double mutants lacking both pncB1 and pncB2 show an absence of incorporation of nicotinamide.
Involved in the Preiss-Handler pathway, which is a recycling route that permits the salvage of free nicotinamide (NM) and nicotinic acid (Na) involved in the NAD biosynthesis. Catalyzes the synthesis of beta-nicotinate D-ribonucleotide from nicotinate and 5-phospho-D-ribose 1-phosphate at the expense of ATP. It is not able to use nicotinamide. PncB2 appears to be responsible for the increased salvage synthesis of NAD during infection of host tissues.
Belongs to the RNA polymerase beta' chain family.
Belongs to the universal ribosomal protein uL13 family.
This protein is one of the early assembly proteins of the 50S ribosomal subunit, although it is not seen to bind rRNA by itself. It is important during the early stages of 50S assembly.
Belongs to the group II decarboxylase family.
Part of the binding-protein-dependent transport system ModABCD for molybdenum; probably responsible for the translocation of the substrate across the membrane.
Upon expression in E.coli functions weakly as a triacylglycerol synthase, making triacylglycerol (TG) from diolein and long-chain fatty acyl-CoA. Has very weak wax synthase activity, incorporating palmityl alcohol into wax esters in the presence of palmitoyl-CoA.
Hydrolyzes various short-chain esters, such as triacylglycerols and vinyl esters. Has no activity against emulsified substrates.
Strongly inhibited by diethyl paranitrophenyl phosphate, which is a specific inhibitor of serine hydrolases.
Necessary for efficient RNA polymerase transcription elongation past template-encoded arresting sites. The arresting sites in DNA have the property of trapping a certain fraction of elongating RNA polymerases that pass through, resulting in locked ternary complexes. Cleavage of the nascent transcript by cleavage factors such as GreA or GreB allows the resumption of elongation from the new 3'terminus. GreA releases sequences of 2 to 3 nucleotides.
This is one of the targets of the anti-tuberculosis drug ethambutol [(S,S')-2,2'-(ethylenediimino)di-1-butanol; EMB]. EMB is a first-line drug used to treat tuberculosis. EMB inhibits the transfer of arabinogalactan into the cell wall.
Might catalyze the phosphorylation of aminoglycosides and confer aminoglycoside antibiotics resistance.
Belongs to the universal ribosomal protein uS10 family.
Involved in the binding of tRNA to the ribosomes.
Toxic component of a possible type II toxin-antitoxin (TA) system. A putative RNase. Its cognate antitoxin is VapB34 (By similarity).
Belongs to the AP endonuclease 2 family.
Endonuclease IV plays a role in DNA repair. It cleaves phosphodiester bonds at apurinic or apyrimidinic (AP) sites, generating a 3'-hydroxyl group and a 5'-terminal sugar phosphate.
Repressed by transcription regulator Mce2R.
Forms a complex with cognate antitoxin MazE9.
Mildy induced (5 to 9-fold) by oxidative and nitrosative stress, starvation, growth in the presence of isoniazid or gentamycin, strongly induced (24-fold) when grown in a non-replicating state.
Toxic component of a type II toxin-antitoxin (TA) system. Upon expression in E.coli and M.smegmatis inhibits cell growth and colony formation. Its toxic effect is neutralized by coexpression with cognate antitoxin MazE9. Acts as an mRNA interferase, specifically cleaving between U and C in UAC sequences. May cleave its cognate antitoxin's gene (PubMed:25608501). In E.coli expression with non-cognate antitoxins VapB27 and VapB40 partially neutralizes the toxin.
ATP is required for the transferase activity but it does not seem to be hydrolyzed during the reaction.
Belongs to the phytoene/squalene synthase family.
Involved in the biosynthesis of carotenoids. Catalyzes the condensation of two molecules of geranylgeranyl diphosphate (GGPP) to give prephytoene diphosphate (PPPP) and the subsequent rearrangement of the cyclopropylcarbinyl intermediate to yield phytoene (By similarity).
An anti-sigma factor for extracytoplasmic function (ECF) sigma factor SigE. ECF sigma factors are held in an inactive form by an anti-sigma factor.
Degraded following vancomycin treatment (surface stress) by a ClpC1-ClpP2 complex.
Interacts with cognate ECF RNA polymerase sigma factor SigE under reducing conditions; this inhibits the interaction of SigE with the RNA polymerase catalytic core.
Phosphorylated by PknB on Thr-39; can be dephosphorylated (at least in vitro) by PstP. Phosphorylation is the signal for subsequent degradation by the ClpC1-ClpP2 complex.
Belongs to the phosphoglycerate kinase family.
Attempts to disrupt both the Rv3032 gene and glgA in order to create a mutant simultaneously deficient in both alpha-1,4-glucosyltransferases turned out to be unsuccessful. Thus, M.tuberculosis H37Rv requires a functional copy of at least one of these two genes for growth. Moreover, it is not possible to inactivate Rv3032 in a mutant lacking treS, suggesting the joint essentiality of the different alpha-(1->4)-glucans biosynthesis pathways involving these two genes.
Belongs to the glycosyltransferase group 1 family.
Glucosyltransferase that uses UDP-glucose as the sugar donor to elongate alpha-(1->4)-glucans. Is involved in the biosynthesis of both 6-O-methylglucosyl lipopolysaccharides (MGLP) and glycogen. May also use ADP-glucose as substrate.
Inactivation of Rv3032 affects the production of both glycogen (two-fold reduction) and 6-O-methylglucosyl lipopolysaccharides (MGLP), but not that of capsular alpha-D-glucan. Cells lacking this gene are not affected in their multiplication or persistence in the BALB/c mouse infection model. They also show a slightly slower growth than that of wild-type at 37 degrees Celsius and a completely abolished growth at 39 degrees Celsius. Moreover, in contrast to wild-type, they are exceptionally sensitive to the TreS inhibitor validamycin A; the sensitivity is abolished by overexpression of TreS.
Toxic component of a type II toxin-antitoxin (TA) system. Upon expression in M.smegmatis inhibits colony formation. Its toxic effect is neutralized by coexpression with cognate antitoxin Rv0909. Does not exert its toxic effect via translation.
Belongs to the tRNA pseudouridine synthase TruA family.
Formation of pseudouridine at positions 38, 39 and 40 in the anticodon stem and loop of transfer RNAs.
Belongs to the DEAD box helicase family.
Catalyzes the specific phosphorylation of the 3-hydroxyl group of shikimic acid using ATP as a cosubstrate.
Consists of three domains: the CORE domain which forms the binding site for nucleotides, the LID domain which closes over the active site upon ATP or shikimate binding, and the substrate-binding domain which functions to recognize and bind shikimate.
The phosphoryl transfer proceeds by an in-line associative mechanism. The random sequential binding of shikimate and nucleotide is associated with domain movements that suggest a synergic mechanism by which binding of the first substrate may enhance the affinity for the second substrate.
Contains an N-terminal DNA-binding domain and a C-terminal ligand-binding domain, which can accommodate a variety of structurally unrelated antimicrobial agents. The C-terminal domain is also involved in dimerization.
Homodimer (PubMed:24424575, PubMed:25012658). Interacts with long chain acyl-CoA derivatives (PubMed:25012658). Interacts with several drugs such rhodamine 6G, ethidium and safranin O (PubMed:24424575).
Interaction with long chain acyl-CoA derivatives (oleoyl-CoA and, to lesser extent, stearoyl-CoA) prevents binding to DNA, leading to the expression of the target genes. Long chain acyl-CoA derivatives may serve as biological indicators of the bacterial metabolic state.
Knockout mutant is impaired in long-term survival at stationary phase and does not persist during macrophage infection.
Regulates the expression of the Rv1217c-Rv1218c multidrug efflux system and its own expression. Acts by binding to promoter regions of Rv1219c and upstream of the Rv1218c gene (PubMed:24424575). Important for survival in prolonged stationary phase and during macrophage infection (PubMed:24590482). May be used to eliminate non-growing mycobacteria (PubMed:25012658).
The start codon for this sequence is CTG, which is very rare.
Methylated by PrmC. Methylation increases the termination efficiency of RF1 (By similarity).
Peptide chain release factor 1 directs the termination of translation in response to the peptide chain termination codons UAG and UAA.
Belongs to the complex I 24 kDa subunit family.
Up-regulated 17-fold 7 days after infection of human macrophages.
A single enc deletion survives less well after 3 days in 2.5 mM H2O2, pH 4.5 (mimics growth in the phagolysosome). A double dyp-enc deletion mutant cannot produce encapsulin nanocompartments, cells are highly sensitive to H2O2 at pH 4.5, mutants exhibit significant dysregulation of redox homeostasis, survive less well in C57BL/6 mouse-derived bone marrow cells and are more sensitive to pyrazinamide treatment in infected BALB/C mice.
Belongs to the encapsulin family. Family 1 subfamily.
Multimeric (PubMed:9596740). The encapsulin nanocompartment is formed by 60 subunits (Probable). Monomers form pentamers which assemble to form shells. There are 12 pores where the pentamers meet as well as 3-fold axis channels and dimer channels; none are larger than 3-4 Angstroms in diameter. The N-terminus of the protein is inside the shell, the C-terminus is outside (Probable).
Shell component of a type 1 encapsulin nanocompartment in situ; its cargo protects against oxidative stress at low pH. In situ and in E.coli assembles into proteinaceous shells about 22 nm in diameter with 2.5 nm thick walls (PubMed:34751132, PubMed:24855650). Cargo proteins are targeted to the interior via their C-terminal extensions; empty intact shells can be isolated in E.coli in the absence of cargo protein. There are at least 4 possible cargo proteins, DyP (encoded in the same locus), FolB, BfrB and Rv1762c; DyP and Rv1762c have been identified in vivo (PubMed:24855650). Probably involved in protection against oxidative damage from the host immune response (Probable) (PubMed:34751132). A T-cell antigen found in bacterial culture cell filtrates, stimulates mouse immune response. Does not have detectable bacteriocin activity (PubMed:9596740).
Stimulates a strong IFN-gamma response in memory immune C57BL/6J mouse spleen T cells, recognized by monoclonal antibody HYB 71-2.
The initiator methionine is partially removed. When isolated from culture filtrate isoelectric focusing gives 3 bands, none of which are glycosylated.
ABC transporter involved in fatty acid import (PubMed:29360453). Transmembrane domains (TMD) form a pore in the membrane and the ATP-binding domain (NBD) is responsible for energy generation (Probable).
Belongs to the ABC transporter superfamily. Lipid exporter (TC 3.A.1.106) family.
The ATP-binding domain (NBD) and the transmembrane domain (TMD) are fused.
Belongs to the tRNA(Ile)-lysidine synthase family.
Ligates lysine onto the cytidine present at position 34 of the AUA codon-specific tRNA(Ile) that contains the anticodon CAU, in an ATP-dependent manner. Cytidine is converted to lysidine, thus changing the amino acid specificity of the tRNA from methionine to isoleucine.
The N-terminal region contains the highly conserved SGGXDS motif, predicted to be a P-loop motif involved in ATP binding.
Repressed by MmpR5 (PubMed:24737322). Repressed by iron (PubMed:12065475). Regulation is IdeR-independent (PubMed:12065475).
Belongs to the CitM (TC 2.A.11) transporter family.
In the C-terminal section; belongs to the FAH family.
Completely inhibited by tetrahydrolipstatin (THL), RHC-80267 and N-bromosuccinimide.
Expressed in macrophages after 6 hours of infection. In vitro, expressed only in acidic stress conditions.
Non specific carboxylic ester hydrolase. Hydrolyzes various pNP-esters, with a preference for short carbon chain substrates. Can also hydrolyze tributyrin to di- and monobutyrin and 4-hydroxyphenylacetate to hydroquinone.
Catalyzes the formation of the second messenger cAMP.
Consists of 3 structural domains. The pH-responsive N-terminus inhibits the adenylyl cyclase (AC) activity of the C-terminal catalytic domain. The length of the linker segment (aa 192-206) is decisive for regulation.
No visible phenotype following infection of SPF C57BL/6 mice.
The isolated catalytic domain prefers Mn(2+) over Mg(2+) as a cofactor.
Part of the ABC transporter complex LpqY-SugA-SugB-SugC, which is highly specific for uptake of trehalose. Involved in the recycling of extracellular trehalose released from trehalose-containing molecules synthesized by M.tuberculosis. Trehalose uptake is essential for virulence. Probably responsible for the translocation of the substrate across the membrane.
The complex is composed of two ATP-binding proteins (SugC), two transmembrane proteins (Suga and SugB) and a solute-binding protein (LpqY).
Belongs to the truncated hemoglobin family. Group I subfamily.
Binds oxygen cooperatively with very high affinity (P(50) = 0.013 mmHg at 20 degrees Celsius) because of a fast combination (25 microM(-1).sec(-1)) and a slow dissociation (0.2 sec(-1)) rate.
Catalyzes the condensation of para-aminobenzoate (pABA) with 6-hydroxymethyl-7,8-dihydropterin diphosphate (DHPt-PP) to form 7,8-dihydropteroate (H2Pte), the immediate precursor of folate derivatives.
Is involved in the bioactivation of the antituberculous drug para-aminosalicylic acid (PAS). PAS is a close structural analog of pABA and acts as an alternative substrate for DHPS, leading to hydroxy-dihydropteroate (H2PtePAS). Metabolomic studies show that PAS, despite its in vitro activity as a competitive inhibitor of DHPS, does not inhibit growth of M.tuberculosis by inhibiting DHPS. PAS exerts its antimycobacterial activity through its effects on M.tuberculosis folate metabolism downstream of DHPS. PAS poisons folate-dependent pathways not only by serving as a replacement substrate for DHPS but also by the products of that reaction serving as replacement substrates and/or inhibitors of subsequent enzymes.
Is potently inhibited by the sulfone dapsone and the two sulfonamides sulfamethoxazole and sulfamethoxypyridazine, with Kis in the range of 12 to 32 nM. Is only poorly inhibited by p-aminosalicylate (PAS) (PubMed:10542185). The inhibition of DHPS by sulfathiazole antagonizes PAS-mediated growth inhibition and therefore confers resistance to PAS (PubMed:23779105).
Magnesium is required for activity, even if it seems to interact primarily with the substrate.
Involved in base excision repair of DNA damaged by oxidation or by mutagenic agents. DNA glycosylase that recognizes and removes damaged pyrimidines. Excises Tg:A (thymine glycol, prefers 5R isomers), Tg:G, 5,6-dihydrouracil:G base pairs and urea:A, also excises oxidized purine derivatives guanidinohydantoin:C and spiroiminodihydantoin:C. Poorly cleaves dsDNA with uracil substitutions, thus also acting as a weak uracil-DNA glycosylase. Acts on DNA bubble and 3'-fork structures, suggesting a role in replication-associated DNA repair. Activity on 7,8-dihydro-8-oxoguanine (8-oxoG) is debated; a report shows weak activity (PubMed:18457574), whereas another shows none (PubMed:20031487). Has AP (apurinic/apyrimidinic) activity and introduces nicks in dsDNA strand, inefficiently cleaves ssDNA with AP sites and uracil. Probably cleaves the DNA backbone by beta-delta elimination to generate a single-strand break at the site of the removed base with both 3'- and 5'-phosphates. Cleaves ssDNA containing an AP site. Complements an E.coli fpg mutY but not nei nth double mutant (PubMed:18457574).
There are 2 paralogs in M.tuberculosis, in some references this gene is called nei2 (PubMed:18457574, PubMed:19496823).
Belongs to the universal ribosomal protein uS4 family.
One of the primary rRNA binding proteins, it binds directly to 16S rRNA where it nucleates assembly of the body of the 30S subunit.
Part of the 30S ribosomal subunit. Contacts protein S5. The interaction surface between S4 and S5 is involved in control of translational fidelity.
With S5 and S12 plays an important role in translational accuracy.
Belongs to the ThrE exporter (TC 2.A.79) family.
Catalyzes the export of L-threonine and L-serine from the cell to the extracellular environment (By similarity). Export is dependent on the proton motive force (By similarity). Required for in vitro growth and survival of bacteria inside macrophages (PubMed:35287590).
Deletion mutant exhibits decreased growth rate compared to wild-type strain in standard culture medium (PubMed:35287590). In addition, the mutant shows decreased survival rate in macrophages (PubMed:35287590). Infected macrophages produce a significantly higher level of TNF-alpha and IL-6 mRNA expression (PubMed:35287590).
Expression is significantly increased in clinical isolates (PubMed:35287590). Expression level is positively correlated with lung cavity number of TB patients (PubMed:35287590).
The glycine cleavage system catalyzes the degradation of glycine. The H protein shuttles the methylamine group of glycine from the P protein to the T protein.
Positively regulates the expression of at least groEL2. Cyclic AMP does not affect transcription in vitro.
Antitoxin component of a possible type II toxin-antitoxin (TA) system. The cognate toxin is VapC1.
Could be involved in mycobactin synthesis.
Belongs to the serine/threonine dehydratase family.
Catalyzes the anaerobic formation of alpha-ketobutyrate and ammonia from threonine in a two-step reaction. The first step involved a dehydration of threonine and a production of enamine intermediates (aminocrotonate), which tautomerizes to its imine form (iminobutyrate). Both intermediates are unstable and short-lived. The second step is the nonenzymatic hydrolysis of the enamine/imine intermediates to form 2-ketobutyrate and free ammonia. In the low water environment of the cell, the second step is accelerated by RidA (By similarity).
Acts as a processive, ATP-dependent zinc metallopeptidase for both cytoplasmic and membrane proteins. Plays a role in the quality control of integral membrane proteins.
Complements an E.coli null mutation. Upon overexpression in E.coli has been shown to degrade endogenous sigma-32, SecY and phage lambda cII protein.
In the C-terminal section; belongs to the peptidase M41 family.
In the central section; belongs to the AAA ATPase family.
Catalyzes the phosphorylation of the 3'-hydroxyl group of dephosphocoenzyme A to form coenzyme A (PubMed:19876400, PubMed:21264299). Can also use dATP, with lower efficiency, but cannot use GTP, dGTP or CTP (PubMed:19876400).
Forms monomers and homotrimers. The monomer is the active form and the trimeric form is inactive. Shift from inactive homotrimer to active monomer is induced in the presence of dephosphocoenzyme A. A dynamic equilibrium between the trimeric and monomeric forms regulates the effective concentration of active enzyme.
In the C-terminal section; belongs to the UPF0157 (GrpB) family.
In the N-terminal section; belongs to the CoaE family.
Inhibited by CTP (PubMed:19876400, PubMed:21731728). CTP strongly binds the enzyme at a site overlapping that of the leading substrate, dephosphocoenzyme A. Binding of CTP probably prevents interaction with dephosphocoenzyme A and oligomeric transformation to the active form, which limits the catalytic efficiency of the enzyme (PubMed:21731728).
The C-terminal UPF0157 domain is involved in the proper folding of the full length enzyme.
An article reported the role of PknB in phosphorylation of PbpA, but this paper was later retracted as some figures were modified prior to publication.
Essential for growth, it cannot be disrupted (PubMed:16980473). PknB depletion in M.tuberculosis results in cell death and aberrant cell morphology, and leads to complete clearance of the pathogen from the host tissues using the murine infection model (PubMed:24706757).
Expressed predominantly in exponential phase (PubMed:15985609). PknB levels are regulated in response to hypoxia; its expression is down-regulated during hypoxia and recovers to aerated levels upon reaeration (at mRNA and protein level) (PubMed:24409094).
Homodimer. Interacts with the FHA domain of GarA, FhaB and FhaA.
Interaction of the PASTA domains with peptidoglycan leads to septal and polar localization of PknB, and dimerization of the intracellular kinase domain. Dimerization activates the kinase domain via an allosteric mechanism, triggering autophosphorylation and phosphorylation of target proteins. Inhibited by mitoxantrone. Inhibition prevents mycobacterial growth.
Protein kinase that regulates many aspects of mycobacterial physiology, and is critical for growth in vitro and survival of the pathogen in the host (PubMed:24706757). Is a key component of a signal transduction pathway that regulates cell growth, cell shape and cell division via phosphorylation of target proteins such as GarA, GlmU, PapA5, FhaB (Rv0019c), FhaA (Rv0020c), MviN, PstP, EmbR, Rv1422, Rv1747, RseA and RmlA (PubMed:15978616, PubMed:15985609, PubMed:15987910, PubMed:16817899, PubMed:16980473, PubMed:19121323, PubMed:19826007, PubMed:20025669, PubMed:21423706, PubMed:22275220, PubMed:33868202). Also catalyzes the phosphorylation of the core proteasome alpha-subunit (PrcA), and thereby regulates the proteolytic activity of the proteasome (PubMed:25224505). Is a major regulator of the oxygen-dependent replication switch since PknB activity is necessary for reactivation of cells from the hypoxic state (PubMed:24409094). Shows a strong preference for Thr versus Ser as the phosphoacceptor. Overexpression of PknB alters cell morphology and leads to cell death (PubMed:24706757) (PubMed:24409094).
The intracellular kinase domain and all four extracytoplasmic PASTA domains are essential for PknB function and cell survival (PubMed:24706757). The PASTA domains interact with peptidoglycans and are required for PknB localization (PubMed:21829358).
Catalyzes the transfer of a dimethylallyl group onto the adenine at position 37 in tRNAs that read codons beginning with uridine, leading to the formation of N6-(dimethylallyl)adenosine (i(6)A).
Each trimer binds three substrate molecules. The ligands are bound between subunits, and for each substrate molecule, residues from adjacent subunits contribute to the binding interactions.
This enzyme is involved in nucleotide metabolism: it produces dUMP, the immediate precursor of thymidine nucleotides and it decreases the intracellular concentration of dUTP so that uracil cannot be incorporated into DNA.
Forms a complex with PE10. The complex interacts with human TLR4.
Together with PE10, induces macrophage apoptosis through human Toll-like receptor 4 (TLR4) signaling pathway. Interaction with TLR4 leads to increased levels of phospho-IRF-3, increase in the transcript levels of IFN-beta and pro-apoptotic genes, up-regulation of IL-10, down-regulation of IL-1b and enhanced levels of macrophage apoptosis.
An anti-sigma factor for extracytoplasmic function (ECF) sigma factor SigD. ECF sigma factors are held in an inactive form by an anti-sigma factor until released by regulated intramembrane proteolysis (RIP). RIP occurs when an extracytoplasmic signal triggers a concerted proteolytic cascade to transmit information and elicit cellular responses. The membrane-spanning regulatory substrate protein is first cut extracytoplasmically (site-1 protease, S1P), then within the membrane itself (site-2 protease, S2P), while cytoplasmic proteases finish degrading the regulatory protein, liberating the sigma factor. Neither S1P nor S2P proteases have been so far identified for this anti-sigma factor.
Interacts with ECF RNA polymerase sigma factor SigD; this should inhibit the interaction of SigD with the RNA polymerase catalytic core.
Positively regulated by alternative sigma factor SigD.
The cytosolic domain interacts with ECF sigma factor SigD.
The cytosolic fragment (residues 1-94) in both free and SigD-associated form, is degraded by a ClpP1-ClpP2-ClpX complex, as would be expected after S1P and S2P intramembrane proteolysis. This releases SigD so that it may bind to the RNA polymerase catalytic core.
Probably part of an ABC transporter complex. Probably responsible for the translocation of the substrate across the membrane (By similarity).
Acyltransferase required for the direct transfer of medium- to long-chain fatty acyl moieties from a carrier protein (MbtL) on to the epsilon-amino group of lysine residue in the mycobactin core.
Belongs to the lysine N-acyltransferase MbtK family.
Belongs to the trans-sulfuration enzymes family.
Catalyzes the formation of L-cystathionine from O-succinyl-L-homoserine (OSHS) and L-cysteine, via a gamma-replacement reaction (By similarity). In the absence of thiol, catalyzes gamma-elimination to form 2-oxobutanoate, succinate and ammonia.
Belongs to the glycosyl hydrolase 3 family.
Plays a role in peptidoglycan recycling by cleaving the terminal beta-1,4-linked N-acetylglucosamine (GlcNAc) from peptidoglycan fragments. Acts as a regulator for GlcNAc-MurNAc levels by cleaving disaccharides and allowing the breakdown of MurNAc.
Interacts with MtrB, probably extracytoplasmically.
May modulate activity of the MtrAB system in controlling homeostasis of the cell wall and cell division (By similarity). Partially restores antibiotic resistance to M.smegmatis in which this gene has been disrupted.
Adopts a simplified PTP fold, which combines features of the conventional PTPs and dual-specificity phosphatases (PubMed:16271885). In the presence of OMTS inhibitor, the enzyme undergoes a large conformational change, allowing the inhibitor to bind deep in the active-site pocket (PubMed:17437721).
Belongs to the protein-tyrosine phosphatase family.
Binding to host ubiquitin is required to activate the phosphatidylinositol phosphate phosphatase activity (PubMed:36227980). Phosphatase activity is inhibited by sodium orthovanadate, a specific inhibitor of tyrosine phosphatases, but not by okadaic acid, an inhibitor of serine/threonine phosphatases (PubMed:10986245). Inhibition of the enzyme reduces mycobacterial survival in infected macrophages (PubMed:19240079, PubMed:20167798, PubMed:21116447, PubMed:30153005). Inhibitors also enhance killing efficacy by first-line antibiotics (PubMed:30153005).
Disruption of the gene impairs the ability of the mutant strain to survive in activated murine macrophages and in guinea pigs, but not in resting murine macrophages (PubMed:14617138, PubMed:16256440). Infection of guinea pigs with the mutant strain results in a 70-fold reduction in the bacillary load of spleens in infected animals (PubMed:14617138, PubMed:16256440). Disruption of the gene has no significant effect on the morphology and growth of the mutant in defined liquid culture medium (PubMed:14617138).
Essential virulence factor that promotes mycobacterial survival within host macrophages (PubMed:14617138, PubMed:16256440, PubMed:20167798, PubMed:29888212, PubMed:36227980). Acts as a phosphatase that possesses triple substrate specificity toward phosphotyrosine, phosphoserine/threonine and phosphoinositides (PubMed:10986245, PubMed:16271885, PubMed:17584180, PubMed:36227980). Supports mycobacteria survival during infection by modulating the normal host signaling pathways, attenuating the bactericidal immune responses and promoting the host cell survival (PubMed:20167798, PubMed:29888212). Inhibits host pyroptosis by disrupting the membrane localization of host gasdermin-D (GSDMD): acts by catalyzing dephosphorylation of phosphatidylinositol (4,5)-bisphosphate and phosphatidylinositol 4-phosphate, thereby inhibiting the membrane targeting of GSDMD and subsequent cytokine release and pyroptosis (PubMed:36227980). Inhibits host inflammatory responses and apoptosis through impeding the NF-kappa-B and MAPK signal pathways and TP53/p53 expression in the macrophage (PubMed:29888212). Blocks the IL6/IL-6 production by down-regulating ERK1/2, p38 and p65 activity (PubMed:20167798, PubMed:29888212). Prevents macrophage cell death by activating the Akt pathway and blocking caspase 3 activity (PubMed:20167798, PubMed:29888212). Reduces the expression of iNOS in activated macrophages and inhibits the generation of destroying reactive nitrogen intermediate NO (PubMed:29888212).
Interacts (via UIM-like region) with host ubiquitin; activating the phosphatidylinositol phosphate phosphatase activity.
The UIM-like region mediates binding to host ubiquitin.
The important role played by PtpB in virulence and the lack of PtpB human orthologs make it a highly promising target for the treatment of tuberculosis infections. Several classes of potent inhibitors have been developed and studied to date. Drug candidates include, among others, (oxalylamino-methylene)-thiophene sulfonamide (OMTS), isoxazole-based compounds, highly substituted indolo[2,3-a]quinolizidines, benzofuran salicylic acid derivatives, chalcone derivatives and several 2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide and piperazinyl-thiophenyl-ethyl-oxalamide derivatives.
Belongs to the D-alanine--D-alanine ligase family.
Catalyzes the ATP-driven ligation of two D-alanine molecules to form the D-alanyl-D-alanine dipeptide. This molecule is a key building block in peptidoglycan biosynthesis.
Follows an ordered ter-ter mechanism. ATP is the first substrate to bind and is necessary for subsequent binding of D-alanine or DCS. ADP is the final product to dissociate.
Is inhibited by the antituberculous drug D-cycloserine (DCS), which is a structural analog of D-alanine (PubMed:20956591, PubMed:23286234). Is activated by K(+) (PubMed:23286234).
Belongs to the adenosylhomocysteinase family.
May play a key role in the regulation of the intracellular concentration of adenosylhomocysteine.
3'-to-5' exoribonuclease specific for small oligoribonucleotides.
Belongs to the oligoribonuclease family.
Belongs to the class-II fumarase/aspartase family. Fumarase subfamily.
Competitively inhibited by N-(5-(azepan-1-ylsulfonyl)-2-methoxyphenyl)- 2-(4-oxo-3,4-dihydrophthalazin-1-yl)acetamide.
Involved in the TCA cycle. Catalyzes the stereospecific interconversion of fumarate to L-malate.
There are 2 substrate-binding sites: the catalytic A site, and the non-catalytic B site that may play a role in the transfer of substrate or product between the active site and the solvent. Alternatively, the B site may bind allosteric effectors.
Belongs to the uroporphyrinogen decarboxylase family.
Catalyzes the decarboxylation of four acetate groups of uroporphyrinogen-III to yield coproporphyrinogen-III.
Belongs to the multicopper oxidase family.
Mutant is more sensitive to copper (PubMed:23772064, PubMed:24549843). Deletion does not affect virulence in mice (PubMed:24549843).
Overexpression results in copper hyperresistance but not hypervirulence.
Repressed by RicR (PubMed:24549843). Induced by copper (PubMed:23772064, PubMed:24549843).
Required for copper resistance. In vitro, oxidizes organic substrates and Fe(2+). May act in vivo by oxidation of toxic periplasmic Cu(+).
Antitoxin component of a possible type II toxin-antitoxin (TA) system. The cognate toxin is VapC9.
Activity is abolished upon incubation with Chelex and EDTA.
Activity is metal ion dependent and can be restored upon addition of excess Mn(2+).
Belongs to the 4-hydroxy-2-oxovalerate aldolase family.
Exhibits oxaloacetate decarboxylase activity. Lacks any detectable aldolase activity with 4-hydroxy-2-oxopentanoate (HOPA), 4-hydroxy-2-oxohexanoate (HOHA) or other 4-hydroxy-2-oxoacids.
Belongs to the prokaryotic molybdopterin-containing oxidoreductase family.
Binds 1 molybdenum-bis(molybdopterin guanine dinucleotide) (Mo-bis-MGD) cofactor per subunit.
Constitutively expressed; independent of nitrate and nitrate levels.
Increased nitrate reductase activity is seen under hypoxic conditions, however this seems to be due to induction of the probable nitrate/nitrite transporter narK2 rather than increased enzyme activity.
Loss of nitrate reductase activity in aerobic and hypoxic conditions.
One of the activities induced in M.tuberculosis by hypoxia is the dissimilatory reduction of nitrate to nitrite, which serves to provide energy as the bacteria adapt to anaerobiosis.
The alpha chain is the actual site of nitrate reduction (Probable). Supports anaerobic growth of E.coli on glycerol in an E.coli mutant lacking endogenous nitrate reductase.
Contains a N-terminal winged-helix DNA-binding domain and a regulatory C-terminal forkhead-associated (FHA) domain, which mediates binding to a Thr-phosphorylated site in the cognate kinase.
Interacts with RNA polymerase (PubMed:16817899). Co-immunoprecipitates with DarG in the presence and absence of darT (PubMed:32634279).
Phosphorylated on threonine residue(s) by PknH, PknA and PknB. Phosphorylation enhances the DNA-binding activity of EmbR. Dephosphorylated by PstP.
Positively regulates the transcription of the embCAB operon. Exhibits ATPase and GTPase activities.
Belongs to the glycosyltransferase 85 family.
Involved in the biosynthesis of the arabinogalactan (AG) region of the mycolylarabinogalactan-peptidoglycan (mAGP) complex, an essential component of the mycobacterial cell wall. Catalyzes the addition of the first key arabinofuranosyl (Araf) residue from the sugar donor decaprenyl-phospho-arabinose (DPA) on the C-5 of a 6-linked galactofuranosyl (Galf) of the galactan domain, thus 'priming' the galactan for further elaboration by other arabinofuranosyltransferases. It is not able to add an Araf residue to a terminal Galf.
Not inhibited by the anti-tuberculosis drug ethambutol (EMB).
Attempts to disrupt both the Rv3032 gene and glgA in order to create a mutant simultaneously deficient in both alpha-1,4-glucosyltransferases turned out to be unsuccessful. Thus, M.tuberculosis H37Rv requires a functional copy of at least one of these two genes for growth.
Inactivation of glgM affects the production of extracellular alpha-glucan (two-fold reduction), but not that of intracellular glycogen and 6-O-methylglucosyl lipopolysaccharides (MGLP) (PubMed:18808383, PubMed:27513637). Cells lacking this gene are also impaired in their ability to persist in both the spleen and the lungs of mice (PubMed:18808383). Combined inactivation of both glgM and ostA is lethal, potentially due to accumulation of toxic levels of ADP-glucose (PubMed:27513637). Combined inactivation of both glgM and treS results in absence of alpha-glucan (PubMed:27513637).
Involved in the biosynthesis of the maltose-1-phosphate (M1P) building block required for alpha-glucan production by the key enzyme GlgE (PubMed:18808383, PubMed:27513637). Catalyzes the formation of an alpha-1,4 linkage between glucose from ADP-glucose and glucose 1-phosphate (G1P) to yield maltose-1-phosphate (M1P) (PubMed:27513637). Also able to catalyze the elongation of the non-reducing ends of glycogen, maltodextrin and maltoheptaose using ADP-glucose as sugar donor, however the rate of the reaction appears to be too low to be physiologically relevant (PubMed:27513637). GlgM is also able to use UDP-glucose as sugar donor with G1P, however, it is less efficient than with ADP-glucose (PubMed:27513637). UDP-glucose is not used as sugar donor when glycogen is used as acceptor (PubMed:27513637).
Belongs to the thiolase-like superfamily. FabH family.
Catalyzes the condensation reaction of fatty acid synthesis by the addition to an acyl acceptor of two carbons from malonyl-ACP. Catalyzes the first condensation reaction which initiates fatty acid synthesis and may therefore play a role in governing the total rate of fatty acid production. Possesses both acetoacetyl-ACP synthase and acetyl transacylase activities (PubMed:10840036, PubMed:11278743, PubMed:16040614). Possesses a clear preference for long-chain acyl-CoA substrates rather than acyl-ACP primers. Its substrate specificity determines the biosynthesis of mycolic acid fatty acid chain, which is characteristic of mycobacterial cell wall (PubMed:10840036, PubMed:11278743, PubMed:16040614). In vitro, when AcpM (the natural partner) is used as the carrier, malonate incorporation increases with acyl chain length to reach an apparent maximum with primers ranging in length from C:14-CoA to C:20-CoA (PubMed:16040614). However, the initial acylation step shows preference for dodecanoyl-CoA, suggesting a role for AcpM in determining the specificity of the mtFabH reaction (PubMed:18096200). Shows only very weak activity with acetyl-CoA (PubMed:10840036, PubMed:11278743).
Exists in an 'open' form that permits binding of the long chain acyl-coenzyme A substrate and release of the corresponding 3-ketoacyl ACP product. Catalysis and intermediate steps in the process are proposed to occur in a 'closed' form of the enzyme.
Homodimer (PubMed:11278743, PubMed:15713483, PubMed:18096200). Both subunits can react with substrates or inhibitors (PubMed:18096200).
Phosphorylated on Thr-45 in vivo (PubMed:19074144). In vitro, can be phosphorylated by multiple Ser/Thr protein kinases (STPKs), particularly by PknF and PknA, and to a lesser extent by PknD, PknE and PknH (PubMed:19074144). Phosphorylation decreases enzymatic activity (PubMed:19074144). Phosphorylation may fine tune the interactions of mtFabH with the components of the FAS-II system (PubMed:19074144).
Phosphorylation on Thr-45 decreases activity (PubMed:19074144). Sensitive to thiolactomycin and resistant to cerulenin in vitro (PubMed:10840036). Inhibited by decylSSCoA, which modify both of the active site cysteines through disulfide linkage to the decylthio-group (PubMed:18096200).
The last Arg residue of the ACP-binding site is essential for the weak association between ACP/AcpP and FabH.
Citrate synthase is found in nearly all cells capable of oxidative metabolism.
Deletion mutant grows at a normal rate and has a normal cell envelope lipid profile, but shows altered lipid profiles during biofilm maturation (PubMed:31471317). Mutant is attenuated in macrophages, but growth is restored when host CBL is removed (PubMed:30118682).
Interacts with the periplasmic loop domains of the mycolate transporters MmpL3 and MmpL11. Also interacts with secreted cell envelope biosynthetic enzymes such as Ag85A. These interactions are weak and may require a putative mycobacterial adapter protein or molecule (PubMed:31471317). Interacts with human ubiquitin ligase CBL (PubMed:30118682).
Involved in cell envelope biogenesis. May act as a membrane fusion protein, connecting MmpL transporters with periplasmic proteins, and play a role in cell envelope lipid changes during biofilm maturation.
Is also a virulence factor required for intracellular survival (PubMed:30118682). Associates with CBL, a host ubiquitin ligase, and probably blocks the normal functions of CBL and disturbs CBL-mediated antibacterial activity (PubMed:30118682). Interaction counteracts antibacterial defense but causes a reciprocal enhancement of antiviral defense (PubMed:30118676, PubMed:30118682).
Acts as a transcriptional regulator. Probably redox-responsive. The apo- but not holo-form probably binds DNA (By similarity).
May be phosphorylated, possibly on Ser-42.
The apo-form functions as a chaperone, preventing aggregation or helping in correct refolding of a number of substrates; this activity does not require ATP or the ability to bind a Fe-S cluster. Chaperone activity is insensitive to the redox state of its cysteine residues. The apo-form has no protein disulfide reductase activity. The apo-form binds to its own promoter.
The cluster is degraded quickly in the presence of air. Upon cluster removal intramolecular disulfide bonds are formed.
A mycothiol (MSH, N-acetyl-cysteinyl-glucosaminyl-inositol) S-conjugate amidase, it recycles conjugated MSH to the N-acetyl cysteine conjugate and the MSH precursor. Involved in MSH-dependent detoxification of a number of alkylating agents and antibiotics. Activity is specific for the mycothiol moiety. Has a low but measurable deacetylation activity on GlcNAc-Ins (N-acetyl-glucosaminyl-inositol), and thus can also directly contribute to the production of MSH.
Belongs to the MshB deacetylase family. Mca subfamily.
MSH is a glutathione analog and is essential for this organism. As MSH does not exist in its host (human) enzymes that are required for its metabolism (such as this one) are potential therapeutic targets.
Partially inhibited by MSH when MSmB is used as substrate. Competitively inhibited by the GlcNAc-cyclohexyl derivative 5-(4-chlorophenyl)-N-((2R,3R,4R,5S,6R)-2-(cyclohexylthio)-tetrahydro-4,5-dihydroxy-6-(hydroxymethyl)-2H-pyran-3-yl)furan-2-carboxamide, which also inhibits MshB.
Disruption results in the complete loss of diacyltrehalose (DAT) and polyacyltrehalose (PAT) biosynthesis.
Deletion of the gene has no effect on growth in medium containing salicylate or on intra-macrophage replication (PubMed:28061949). Deletion does not affect sensitivity to plumbagin, menadione, nigericin, PAS or CCCP (PubMed:28061949).
Involved in cellular response to chemical stress and may contribute to resistance toward antimicrobial natural compounds as well as drugs (Probable). Catalyzes the methylation and detoxification of the P.aeruginosa toxin 2-heptyl-1-hydroxy-4(1H)-quinolinone (HQNO) to 2-heptyl-1-methoxy-4(1H)-quinolinone (HMOQ) (PubMed:33064871). Can also methylate 3-bromo-2-heptyl-1-hydroxy-4(1H)-quinolinone, and shows much lower activity with 1-hydroxyquinolin-4(1H)-one, quercetin, 4-hydroxyquinolin-2(1H)-one (DHQ) and 4-hydroxyisoquinolin-1(2H)-one (PubMed:33064871). In addition, N-methylates and abolishes the mycobactericidal activity of 3-methyl-1-oxo-2-[3-oxo-3-(pyrrolidin-1-yl)propyl]-1,5-dihydrobenzo[4,5]imidazo[1,2-a]pyridine-4-carbonitrile (compound 14), an inhibitor of DprE1 (PubMed:27432954). Also methylates and reduces the inhibitory effect of TPSA (2-[5-(2-{[4-(2-thienyl)-2-pyrimidinyl]sulfanyl}acetyl)-2-thienyl]acetic acid), an inhibitor of GlmU acetyltransferase (PubMed:31380295).
Is dispensable under in vitro conditions in both axenic and macrophage culture.
It is uncertain whether Met-1 or Met-17 is the initiator.
Repressed by the transcriptional repressor Rv2887 (PubMed:27432954). Induced by salicylate, during iron deprivation (at RNA level), by anaerobiosis and by superoxide generating naphthoquinones such as menadione and plumbagin and by pro-oxidant phenoxyisobutyrates (fibrates) such as gemfibrozil (at protein level). Part of the Rv0560c-Rv0559c operon. Operon induction is slow but is maintained for at least 2 weeks in aerobic culture in the presence of salicylate (PubMed:15528667, PubMed:15644891, PubMed:16175359, PubMed:22485172).
Part of the ABC transporter complex (TC 3.A.1.6.1) involved in sulfate/thiosulfate import.
Part of the ABC transporter complex CysAWTP (TC 3.A.1.6.1) involved in sulfate/thiosulfate import. Probably responsible for the translocation of the substrate across the membrane.
The complex is composed of two ATP-binding proteins (CysA), two transmembrane proteins (CysT and CysW) and a solute-binding protein (CysP).
Belongs to the metallothionein superfamily.
Cells lacking this gene show hypersensitivity to Cu(+) toxicity but not to divalent heavy metals such as Zn(2+). Deficiency of MymT does not impair M.tuberculosis virulence in mice.
It is uncertain whether Met-1 or Met-6 is the initiator. If Met-1 is the initiator, MymT would undergo a first cleavage after Arg-5 followed by processing of the N-terminal methionine.
Metallothioneins are small proteins that have a high content of cysteine residues which allow them to bind heavy metal ions through clusters of thiolate bonds. MymT binds up to seven ions of Cu(+), with a preference for four to six Cu(+) ions, in a solvent-shielded core. MymT protects M.tuberculosis from copper toxicity.
NO and reactive nitrogen intermediates (RNI) can displace Cu(+) from MymT.
Up-regulated by copper, cadmium, cobalt, nickel and zinc, but not manganese. Copper and cadmium salts afford the strongest metal-dependent induction at about 1,000-fold. Also highly up-regulated under conditions that are believed to be attained in phagosomes of interferon-gamma-activated macrophages, including production of nitric oxide and reactive oxygen intermediates, mild acid (pH 5.5), and cell wall perturbation (PubMed:18724363). Repressed by RicR (PubMed:21166899).
Homodimer. Binds DNA as a dimer of dimers.
Mutants exhibit growth defect during infection of mice. They establish a stable infection by three weeks, but the bacterial burden is an order of magnitude less than the wild-type.
Negatively autoregulated (PubMed:22479184). Transcriptionally regulated by the MprB/MprA and PhoP/PhoR two-component systems (PubMed:25536998). Expression is growth phase-dependent, peaking in the stationary phase (PubMed:22479184). Probably induced upon phagocytosis (PubMed:18685700).
The N-terminal domain binds DNA and the C-terminal domain is involved in dimerization. Both domains are required for transcriptional activity and for ESX-1 function.
Virulence regulator that has both architectural and regulatory roles. Impacts cell wall functions and pathogenesis through regulation of multiple genes, including the espACD operon, which is a key ESX-1 component. Influences target gene expression positively or negatively, depending on its binding position relative to the genes it controls. Acts by binding directly to the DNA. May play a central role in regulating virulence gene expression.
Was originally thought to be secreted via the ESX-1 secretion system, but it was probably released in the medium via cell lysis.
Catalyzes the rearrangement of 1-deoxy-D-xylulose 5-phosphate (DXP) to produce the thiazole phosphate moiety of thiamine. Sulfur is provided by the thiocarboxylate moiety of the carrier protein ThiS. In vitro, sulfur can be provided by H(2)S.
Homotetramer. Forms heterodimers with either ThiH or ThiS.
4'-phosphopantetheine is transferred from CoA to a specific serine in each of the two carrier protein domains, leading to their activation from apo to holo forms.
Belongs to the ATP-dependent AMP-binding enzyme family. MbtB subfamily.
Involved in the initial steps of the mycobactin biosynthetic pathway. Putatively couples activated salicylic acid with serine or threonine and cyclizes this precursor to the hydroxyphenyloxazoline ring system present in this class of siderophores. Essential for growth in macrophages.
Modular protein that contains an aryl carrier protein (ArCP) domain which bears a phosphopantetheinyl arm to attach the activated salicylic acid, a condensation/cyclization domain involved in the formation of the oxazoline ring, an adenylation domain which activates the serine or threonine residue into an aminoacyl-AMP ester, a peptidyl carrier protein (PCP) domain which bears a phosphopantetheinyl arm to attach the activated serine or threonine, and a terminal thioesterase domain which assists in the transfer of intermediates from MbtB to ACP1 in MbtD.
The first gene in the probable mtbB-mtbC-mtbD-mtbE-mtbF-mtbG-mtbH operon (Probable). Induced by iron starvation conditions and during infection of human THP-1 macrophages. Transcriptionally repressed by IdeR and iron (PubMed:11722747). Induced 27-fold by iron starvation (0.02 ug Fe/ml versus 8 ug Fe/ml). Probably transcriptionally activated by HupB; deletion of hupB decreases induction 10-fold (PubMed:24610707).
Has strong T-cell and IFN-gamma inducing capacity in human tuberculin skin test positive patients, indicating this might be a good vaccine candidate. Has also been seen to serve as an immunogenic antigen, inducing gamma-interferon responses in whole-blood cultures from M.tuberculosis-exposed adults in Uganda, The Gambia and South Africa, also indicating this might be a good vaccine candidate.
Protease that triggers late cell apoptosis and contributes to the pathogenicity and dissemination of M.tuberculosis (PubMed:36402348). In a mouse model of infection, can induce hepatocyte and lung cell apoptosis and cause pathological damage to the spleen, liver and lungs (PubMed:36402348). Specifically stimulates the secretion of inflammatory cytokines including TNF-alpha, IL-6 and IL-1 beta (PubMed:36402348). Can degrade casein in vitro (PubMed:36402348).
Part of the ESX-5 specialized secretion system, which is responsible for the secretion of EsxN and a number of PE_PGRS and PPE proteins, including PPE41.
Involved in chromosome partition. Localize to both poles of the predivisional cell following completion of DNA replication. Binds to the DNA origin of replication (By similarity).
Belongs to the pseudouridine synthase RluA family.
Belongs to the NADH dehydrogenase family.
Belongs to the OMP decarboxylase family. Type 2 subfamily.
Belongs to the prephenate/arogenate dehydrogenase family.
Catalyzes the NAD(+)-dependent conversion of prephenate to p-hydroxyphenylpyruvate, with the elimination of carbon dioxide. Is a key regulatory enzyme in tyrosine biosynthesis. Displays no chorismate mutase (CM) activity, in contrast to TyrA from E.coli and some other bacteria, that are bifunctional and possess a CM domain.
Is inhibited by NaCl; more than half of the enzyme activity is abolished in the presence of 10 uM of NaCl.
Binds 1 Mg(2+) ion per subunit (PubMed:25295175). Is also active with manganese ions (in vitro) (PubMed:11431477, PubMed:11447108).
Homodimer (PubMed:11447108, PubMed:16403515, PubMed:25295175). Can also exist as monomer (PubMed:16403515, PubMed:25295175).
The structures described in PubMed:16403515 and PubMed:25295175 corresponds to an inactive form, and displays a conformation that alters the position and orientation of the residues that are expected to bind the substrate and the catalytic metal ions.
Guanylyltransferase that catalyzes the activation of phosphoenolpyruvate (PEP) as enolpyruvoyl-2-diphospho-5'-guanosine, via the condensation of PEP with GTP. It is involved in the biosynthesis of coenzyme F420, a hydride carrier cofactor.
Although Co(2+) and Mn(2+) support eight- and fourfold higher catalytic efficiency than Mg(2+), respectively, Mg(2+) is likely the physiologically relevant catalytic divalent metal ion.
Although the enzyme shows affinity to L-glycerol 3-phosphate (sn-glycerol 3-phosphate), it hydrolyzes the substrate with poor efficacy and is therefore not associated with EC 3.1.3.21 / RHEA:11476.
Crystal structures of Rv1692 reveal a unique architecture, a fusion of a predicted haloacid dehalogenase fold with a previously unidentified GCN5-related N-acetyltransferase (GNAT) region. Although not directly involved in acetyl transfer, or regulation of enzymatic activity in vitro, the GNAT region is critical for the solubility of the phosphatase.
Deletion of this gene results in an accumulation of G3P and G3P-containing lipid polar heads.
Dephosphorylates D-glycerol 3-phosphate (sn-glycerol 1-phosphate). Is the final enzyme involved in the recycling/catabolism of glycerophospholipid polar heads. To a lesser extent, is also able to act on glycerol 2-phosphate and D-ribulose 5-phosphate, but cannot use D-glyceraldehyde 3-phosphate, dihydroxyacetone-phosphate, UMP or GMP as substrates.
IGPS catalyzes the conversion of PRFAR and glutamine to IGP, AICAR and glutamate. The HisF subunit catalyzes the cyclization activity that produces IGP and AICAR from PRFAR using the ammonia provided by the HisH subunit (By similarity).
Involved in the galactan polymerization of the arabinogalactan (AG) region of the mycolylarabinogalactan-peptidoglycan (mAGP) complex, an essential component of the mycobacteria cell wall. Thus, successively transfers approximately 28 galactofuranosyl (Galf) residues from UDP-galactofuranose (UDP-Galf) onto the galactofuranosyl-galactofuranosyl-rhamnosyl-GlcNAc-diphospho-decaprenol (Galf-Galf-Rha-GlcNAc-PP-C50) acceptor produced by GlfT1, with alternating 1->5 and 1->6 links, forming a galactan domain with approximately 30 galactofuranosyl residues.
Putative antitoxin component of a possible type II toxin-antitoxin (TA) system. The cognate toxin is VapB14.
Belongs to the LysE/ArgO transporter (TC 2.A.75) family.
Belongs to the TRAFAC class OBG-HflX-like GTPase superfamily. HflX GTPase family.
GTPase that associates with the 50S ribosomal subunit and may have a role during protein synthesis or ribosome biogenesis.
Monomer. Associates with the 50S ribosomal subunit.
Belongs to the fatty acid desaturase type 1 family. AlkB subfamily.
F(1)F(0) ATP synthase produces ATP from ADP in the presence of a proton or sodium gradient. F-type ATPases consist of two structural domains, F(1) containing the extramembraneous catalytic core and F(0) containing the membrane proton channel, linked together by a central stalk and a peripheral stalk. During catalysis, ATP synthesis in the catalytic domain of F(1) is coupled via a rotary mechanism of the central stalk subunits to proton translocation (By similarity).
F-type ATPases have 2 components, F(1) - the catalytic core - and F(0) - the membrane proton channel. F(1) has five subunits: alpha(3), beta(3), gamma(1), delta(1), epsilon(1). F(0) has three main subunits: a(1), b(2) and c(10-14). The alpha and beta chains form an alternating ring which encloses part of the gamma chain. F(1) is attached to F(0) by a central stalk formed by the gamma and epsilon chains, while a peripheral stalk is formed by the delta and b chains (By similarity).
In the C-terminal section; belongs to the ATPase delta chain family.
In the N-terminal section; belongs to the ATPase B chain family.
This fusion protein includes a component of the F(0) channel (subunit b) and of the F(1) subunit (subunit delta). Two copies of subunit b and one of delta together form the peripheral 'stator' stalk which links F(1) to F(0) (By similarity).
Catalyzes the oxidative decarboxylation of 6-phosphogluconate to ribulose 5-phosphate and CO(2), with concomitant reduction of NADP to NADPH.
Binds 1 pyridoxal phosphate per homodimer. This is unusual in the SHMT family, that normally contains 1 pyridoxal phosphate per subunit.
Catalyzes the reversible interconversion of serine and glycine with tetrahydrofolate (THF) serving as the one-carbon carrier. This reaction serves as the major source of one-carbon groups required for the biosynthesis of purines, thymidylate, methionine, and other important biomolecules. Also exhibits THF-independent aldolase activity toward beta-hydroxyamino acids, producing glycine and aldehydes, via a retro-aldol mechanism. Thus, is able to catalyze the cleavage of L-allo-threonine.
Catalyzes the addition of alpha-(1->6)-mannose residue.
Down-regulated upon starvation. Induced by albendazole and thiabendazole, which inhibit the GTPase activity of FtsZ and probably septum formation.
Has been detected in culture filtrate but no signal sequence is predicted by bioinformatic programs.
Contains 7 domains: 2 C (condensation) domains, 2 A (adenylation) domains, 2 T (thiolation) domains, and one R (reduction) domain at its C-terminus. The first T domain likely acts as a lyine-specific peptidyl-carrier protein, and carries a lyine residue that is transferred to it by the first A domain. The C domain catalyzes the condensation of two isonitrile-containing moieties to both amino groups of the lysine bound to the T domain, a rare activity in nonribosomal peptide biosynthesis. Finally, the R domain catalyzes a four-electron thioester reduction, releasing the product from the NRPS and forming a terminal alcohol product.
Nonribosomal peptide synthetase (NRPS) involved in the biosynthesis of a unique class of isonitrile lipopeptides (INLPs) that seem to function as virulence factors in M.tuberculosis and to play a role in metal acquisition (PubMed:28634299). Catalyzes the final step in the pathway, i.e. the condensation of a (3R)-3-isocyanyl-fatty acyl-[ACP] to both amino groups of a lysine, producing isonitrile lipopeptides (By similarity).
Belongs to the lysine N(6)-hydroxylase/L-ornithine N(5)-oxygenase family.
Flavoprotein monooxygenase required for N-hydroxylation of the two acylated lysine residues during mycobactin assembly, thus producing the hydroxamate groups necessary for iron sequestration. Is also able, but less efficiently, to hydroxylate L-lysine (non acylated) in vitro. Shows 5-fold preference for using acetylated lysine over lysine.
Induced by iron starvation conditions and during infection of human THP-1 macrophages. Transcriptionally repressed by ideR and iron (By similarity).
Binds to the N-terminal domain of the chaperone ClpA.
Involved in the modulation of the specificity of the ClpAP-mediated ATP-dependent protein degradation.
Belongs to the pseudouridine synthase RsuA family.
Belongs to the universal ribosomal protein uS5 family.
Located at the back of the 30S subunit body where it stabilizes the conformation of the head with respect to the body.
Part of the 30S ribosomal subunit. Contacts proteins S4 and S8.
The N-terminal domain interacts with the head of the 30S subunit; the C-terminal domain interacts with the body and contacts protein S4. The interaction surface between S4 and S5 is involved in control of translational fidelity.
With S4 and S12 plays an important role in translational accuracy.
Part of the ESX-3 / type VII secretion system (T7SS), which is composed of cytosolic and membrane components.
Part of the ESX-3 specialized secretion system, which is important for iron and zinc uptake or homeostasis (PubMed:19684129, PubMed:24155985). EccA3 exhibits ATPase activity and may provide energy for the export of ESX-3 substrates (By similarity).
Expressed in actively growing cells, positively regulated by alternative sigma factor SigD, probably directly.
Not essential, disruption of rpfC alone has no effect on growth or survival in liquid culture, nor in mouse infection models, although colony size is reduced. Alterations in gene expression are seen. All 5 genes in this family can be deleted without affecting growth in culture, however triple deletion mutants (rpfA-rpfC-rpfB or rpfA-rpfC-rpfD) are not able to resuscitate spontaneously in the presence or absence of O(2), and are attenuated in a mouse infection model.
Belongs to the mycofactocin precursor peptide family.
Mycofactocin is classified as a ribosomally synthesized and post-translationally modified peptide (RiPP).
Precursor peptide that leads to mycofactocin (MFT) after extensive post-translational modifications by enzymes encoded by adjacent genes. Mycofactocin acts as a redox cofactor of nicotinamide-dependent oxidoreductases encoded in the same locus.
The post-translational modifications that lead to mycofactocin involve oxidative decarboxylation of the C-terminal tyrosine residue catalyzed by MftC, introduction of a tyramine-valine cross-link, removal of the modified C-terminal dipeptide by MftE. The released dipeptide then undergoes oxidative deamination by MftD, glycosylation by MftF and methylation by an unknown enzyme.
Belongs to the SecD/SecF family. SecF subfamily.
Forms a complex with SecD. Part of the essential Sec protein translocation apparatus which comprises SecA, SecYEG and auxiliary proteins SecDF. Other proteins may also be involved.
Acts as a chaperone, as it has a significant ability to suppress the thermal denaturation of alcohol dehydrogenase. Cells overexpressing this gene grow more slowly than wild-type cells, and are less susceptible to autolysis following saturation of the culture in vitro, suggesting this protein may slow down the growth rate of M.tuberculosis in culture and by extension during macrophage infection.
Belongs to the small heat shock protein (HSP20) family.
In plasmid DNA-vaccinated mice, subsequent challenge with this protein induces positive levels of antigen-specific IFN-gamma and IL-2, indicating this might be a good vaccine candidate.
Induced by several reactive nitrogen intermediates including S-nitroso glutathione (at protein level). Induced in stationary phase (at protein level). A member of the dormancy regulon. Induced in response to reduced oxygen tension (hypoxia) (at protein level), low levels of nitric oxide (NO) and carbon monoxide (CO). It is hoped that this regulon will give insight into the latent, or dormant phase of infection. Induced in mouse lungs at the same time that adaptive host immunity induces bacterial growth arrest; induction is dependent on interferon gamma. A member of the probable hspX-Rv2030c-pfkB-Rv2028c operon.
Multiple forms of this protein exist in 2D-gels. The differences between them has not been examined.
Strains deleted for this gene show hypervirulence upon intravenous inoculation in BALB/c mice.
Mutants are defective in the secretion of EsxN, PPE41 and PE_PGRS proteins (PubMed:22340629, PubMed:22925462). Mutant is highly sensitive to detergents and hydrophilic antibiotics such as ampicillin, vancomycin and bacitracin (PubMed:22340629). Virulence is attenuated both in macrophages and in the severe combined immune-deficient mouse infection model (PubMed:22340629).
15.5-fold spontaneous mutation frequency increase by rifampicin resistance screening.
Catalyzes the conversion of 8-oxo-dGTP to 8-oxo-dGDP, and 8-oxo-GTP to 8-oxo-GDP (PubMed:23463507, PubMed:16585780). Functions in concert with Rv1700 to detoxify 8-oxo-dGTP to 8-oxo-dGMP and plays an important role in supporting cellular growth under oxidative stress (PubMed:23463507).
Able to hydrolyze geranyl diphosphate (GPP), farnesyl diphosphate (FPP) and geranylgeranyl diphosphate (GGPP) to respectively yield geraniol, farnesol and geranylgeraniol.
Deletion of the gene leads to virulence attenuation in macrophages and mice.
Main aspartate aminotransferase that couples nitrogen assimilation to aspartate synthesis. Has a weak, but significant, side activity toward kynurenine (Kyn). Oxaloacetate and 2-oxoglutarate, but not pyruvate, serve as amino acceptors, while Asp, Glu and Kyn serve as the best amino donors. Essential for axenic growth and survival of M.tuberculosis in macrophages and in mice.
Activity of PfkA is tenfold higher than that of PfkB (PubMed:33540748). Activity with tagatose-6-phosphate suggests that PfkA and/or PfkB may substitute for tagatose-6-phosphate kinase and further support glycolysis (PubMed:33540748).
Belongs to the phosphofructokinase type A (PFKA) family. Mixed-substrate PFK group III subfamily.
Catalyzes the phosphorylation of D-fructose 6-phosphate to fructose 1,6-bisphosphate by ATP, the first committing step of glycolysis (PubMed:33540748). Can also catalyze the phosphorylation of tagatose-6-phosphate. Both sugar phosphates can function equivalently as substrates (PubMed:33540748). Cannot catalyze the reverse gluconeogenic reaction (PubMed:33540748).
Inhibited by high concentrations of the substrates fructose 6-phosphate and ATP, and by the reaction products, fructose 1,6-bisphosphate and ADP. Allosterically inhibited by phosphoenolpyruvate (PEP), guanosine diphosphate (GDP) and citrate.
Magnesium may play a role in formation and maintaining of proper enzyme conformation and multimerization.
Antitoxin component of a type II toxin-antitoxin (TA) system (PubMed:30315706, PubMed:30792174). Neutralizes the activity of cognate toxin MbcT by blocking access to the toxin active site (PubMed:30792174).
Essential, it cannot be deleted (PubMed:28096490). Deletion of the mbcT-mbcA operon has no visible phenotype (PubMed:30792174).
Heterotetramer with 2 subunits each of MbcT and MbcA; the tetramers further assemble into trimers with 3-fold symmetry.
Induced by hypoxia (PubMed:18231589). Expression probably induced in both active and resting C57BL/6 mouse macrophages (PubMed:20628579). Induced in persister cells (PubMed:21673191). Induced by Ethambutol, Isoniazid and streptomycin treatment and by starvation, repressed by rifampicin treatment (PubMed:28724903). Probably part of the mbcT-mbcA operon (PubMed:30792174).
Exported by the Tat system (PubMed:26933057). The position of the signal peptide cleavage has not been experimentally proven (PubMed:26933057).
Monomer. Interacts with RpfB and PBP1A (ponA1) via residues 448-472 of RipA, interacts with RpfE (PubMed:17919286, PubMed:20686708, PubMed:20826344, PubMed:21864539). Interacts with the chaperone MoxR1 (PubMed:26933057). RipA-MoxR1 interaction in the cytoplasm leads to proper folding of RipA, resulting in its secretion (PubMed:26933057). Also interacts with Mce2B (PubMed:26933057).
MoxR1-mediated folding is critical for secretion via the TAT system (PubMed:26933057). The synergistic effects on peptidoglycan degradation of RipA plus RpfB are inhibited by addition of PBP1A (ponA1) (PubMed:20686708).
Peptidoglycan endopeptidase that cleaves the bond between D-glutamate and meso-diaminopimelate. Binds and degrades high-molecular weight peptidoglycan from a number of Actinobacteria; activity is increased in the presence of RpfB and inhibited by PBP1A (ponA1). Required for normal separation of daughter cells after cell division and for cell wall integrity. Required for host cell invasion and intracellular survival in host macrophages.
The role of the N-terminal domain is controversial. A recent paper (PubMed:21864539) found it had no effect on enzyme activity, while another (PubMed:20826344) reported that it had an inhibitory role and had to be cleaved off for full enzyme activity.
Belongs to the complex I subunit 2 family.
Catalyzes the transfer of the enolpyruvyl moiety of phosphoenolpyruvate (PEP) to the 5-hydroxyl of shikimate-3-phosphate (S3P) to produce enolpyruvyl shikimate-3-phosphate and inorganic phosphate.
Is irreversibly inactivated by the beta-lactams carbapenems via the formation of a covalent adduct resulting from enzyme acylation; imipenem is the most efficient drug for in vitro LdtMt4 inactivation.
Belongs to the folylpolyglutamate synthase family.
Catalyzes the addition of a glutamate residue to dihydropteroate (7,8-dihydropteroate or H2Pte) to form dihydrofolate (7,8-dihydrofolate monoglutamate or H2Pte-Glu) (PubMed:23118010). Also catalyzes successive additions of L-glutamate to tetrahydrofolate, leading to folylpolyglutamate derivatives (By similarity).
Is folded into two distinct domains, an N-terminal ATPase domain and a C-terminal Rossmann-fold domain, which are joined by a flexible linker.
Is involved in the bioactivation of the antituberculous drug para-aminosalicylic acid (PAS). Is able to use hydroxy-dihydropteroate (H2PtePAS) as substrate, which is the product formed by the action of DHPS (FolP1) on PAS, leading to hydroxy-dihydrofolate (H2PtePAS-Glu). This compound inhibits dihydrofolate reductase DHFR (DfrA), the next enzyme in the folate pathway, and thus disrupts the folate-dependent metabolic pathways.
Mutations within this gene in the H2Pte binding pocket are responsible for PAS resistance in M.tuberculosis clinical isolates and laboratory strains. FolC-linked PAS resistance is mediated by altered substrate specificity that results in the failure to generate levels of H2PtePAS-Glu that are necessary to inhibit DHFR (DfrA); therefore, a blockage of PAS bioactivation causes PAS resistance.
Belongs to the universal ribosomal protein uS13 family.
Located at the top of the head of the 30S subunit, it contacts several helices of the 16S rRNA. In the 70S ribosome it contacts the 23S rRNA (bridge B1a) and protein L5 of the 50S subunit (bridge B1b), connecting the 2 subunits; these bridges are implicated in subunit movement. Contacts the tRNAs in the A and P-sites.
Part of the 30S ribosomal subunit. Forms a loose heterodimer with protein S19. Forms two bridges to the 50S subunit in the 70S ribosome.
To M.tuberculosis Rv1510 and M.bovis Mb3654.
Belongs to the bacterial ribosomal protein bL12 family.
Forms part of the ribosomal stalk which helps the ribosome interact with GTP-bound translation factors. Is thus essential for accurate translation.
Homodimer. Part of the ribosomal stalk of the 50S ribosomal subunit. Forms a multimeric L10(L12)X complex, where L10 forms an elongated spine to which 2 to 4 L12 dimers bind in a sequential fashion. Binds GTP-bound translation factors.
Activates lipidic moieties required for mycobactin biosynthesis (PubMed:16461464). Converts medium- to long-chain aliphatic fatty acids into acyl adenylate, which is further transferred on to the phosphopantetheine arm of the carrier protein MbtL (PubMed:16461464).
Disruption of the gene decreases growth in the liver, but not in the lungs or spleen.
May play a role in virulence by supporting bacterial growth in the liver.
Activated by a monovalent cation that binds near, but not in, the active site. The most likely occupant of the site in vivo is potassium. Ion binding induces a conformational change that may alter substrate affinity.
Belongs to the carbohydrate kinase PfkB family. Ribokinase subfamily.
Catalyzes the phosphorylation of ribose at O-5 in a reaction requiring ATP and magnesium. The resulting D-ribose-5-phosphate can then be used either for sythesis of nucleotides, histidine, and tryptophan, or as a component of the pentose phosphate pathway.
Requires a divalent cation, most likely magnesium in vivo, as an electrophilic catalyst to aid phosphoryl group transfer. It is the chelate of the metal and the nucleotide that is the actual substrate.
A member of the dormancy regulon. Induced in response to reduced oxygen tension (hypoxia), low levels of nitric oxide (NO) and carbon monoxide (CO). It is hoped that this regulon will give insight into the latent, or dormant phase of infection. Induction by hypoxia is independent of nitrate and nitrate levels.
Increased nitrate reductase activity is seen under hypoxic conditions, however this seems to be due to induction of the probable nitrate/nitrite transporter narK2 rather than increased enzyme activity of the probable nitrate reductase NarGHJI.
Involved in excretion of nitrite produced by the dissimilatory reduction of nitrate.
Permits nitrate and nitrate transport into E.coli.
Wild-type levels of nitrite production in aerobic cultures, but hypoxic cultures show no increase in nitrite production.
Antitoxin component of a type II toxin-antitoxin (TA) system. Upon expression in E.coli neutralizes the effect of cognate toxin ParE1.
Could be involved in insertion of integral membrane proteins into the membrane.
Part of the high-affinity ATP-driven potassium transport (or Kdp) system, which catalyzes the hydrolysis of ATP coupled with the electrogenic transport of potassium into the cytoplasm. This subunit binds the extracellular potassium ions and delivers the ions to the membrane domain of KdpB through an intramembrane tunnel.
The system is composed of three essential subunits: KdpA, KdpB and KdpC.
In vitro, the reduced form of Rv2466c catalyzes the reduction and activation of TP053, which is a thienopyrimidine derivative drug that can kill both replicating and non-replicating M.tuberculosis.
Binding of inhibitors to EthR induces a conformational change in this repressor, which is then unable to bind its DNA operator, consequently allowing for increased transcription of EthA and bioactivation of ethionamide (ETH).
Cells lacking this gene leads to ETH hypersentivity.
Inhibited by tert-butyl 4-(3-thiophen-2-yl-1,2,4-oxadiazol-5-yl) piperidine-1-carboxylate (RF1) and 1-(thiophen-2-ylacetyl)-4-(3-thiophen-2-yl-1,2,4-oxadiazol-5-yl)piperidine (RF3).
Involved in the repression of the monooxygenase EthA which is responsible of the formation of the active metabolite of ethionamide (ETH).
Toxic component of a type II toxin-antitoxin (TA) system. An RNase (By similarity). Upon expression in M.smegmatis inhibits colony formation. Its toxic effect is neutralized by coexpression with cognate antitoxin VapB31 (By similarity).
Belongs to the helicase family. UvrD subfamily.
DNA-dependent ATPase, stimulated equally by ss- and dsDNA. Has both ATPase and helicase activities, and translocates along ssDNA displacing bound streptavidin. Its essentiality for growth does not depend on its helicase activity.
Essential for growth; the 100 C-terminal residues are not required for growth.
Belongs to the glycosyl hydrolase 13 family. GlgE subfamily.
Essential maltosyltransferase that uses maltose 1-phosphate (M1P) as the sugar donor to elongate linear or branched alpha-(1->4)-glucans. Maltooligosaccharides with a degree of polymerization (DP) superior or equal to 4 are efficient acceptors, with DP5 being optimal in the GlgE-catalyzed polymerization with M1P. Is specific for the alpha-anomer of M1P as substrate, since the beta-anomer of M1P gives no activity. Exhibits an alpha-retaining catalytic mechanism. Is also able to catalyze the reverse reaction in vitro, releasing M1P from glycogen in the presence of inorganic phosphate. Also catalyzes disproportionation reactions through maltosyl transfer between maltooligosaccharides. Is involved in a branched alpha-glucan biosynthetic pathway from trehalose, together with TreS, Mak and GlgB.
GlgE inactivation causes rapid death of M.tuberculosis in vitro and in mice through a self-poisoning accumulation of maltose 1-phosphate, driven by a self-amplifying feedback stress response.
The unique combination of maltose 1-phosphate toxicity and gene essentiality within a synthetic lethal pathway validates GlgE as a distinct potential drug target that exploits new synergistic mechanisms to induce death in M.tuberculosis.
Belongs to the peroxidase family. Peroxidase/catalase subfamily.
Bifunctional enzyme with both catalase and broad-spectrum peroxidase activity, oxidizing various electron donors including NADP(H) (PubMed:9006925, PubMed:18178143). Protects M.tuberculosis against toxic reactive oxygen species (ROS) including hydrogen peroxide as well as organic peroxides and thus contributes to its survival within host macrophages by countering the phagocyte oxidative burst (PubMed:8658136, PubMed:15165233). Also displays efficient peroxynitritase activity, which may help the bacterium to persist in macrophages (PubMed:10080924).
Bifunctional enzyme with both catalase and broad-spectrum peroxidase activity.
Binds 1 heme b (iron(II)-protoporphyrin IX) group per subunit.
By treatment with H(2)O(2) (PubMed:8658136). Repressed by FurA (PubMed:11401695).
Catalyzes the oxidative activation of the antitubercular pro-drug isoniazid (INH) to generate an isonicotinoyl radical that then reacts nonenzymatically with NAD to form an isonicotinoyl-NAD adduct which inhibits InhA.
Cells lacking this gene are devoid of catalase activity, supersensitive to H(2)O(2) exposure and highly resistant to the antitubercular drug isoniazid (INH) in vitro. This mutant strain is markedly attenuated for virulence in mice and displays impaired growth in infected macrophages, but its growth and survival is indistinguishable from wild-type in macrophages lacking the ROS-generating NADPH oxidase (Phox).
Consists of two related domains. The catalase-peroxidase activity is associated with the N-terminal domain but no definite function has been assigned to the C-terminal domain, although it may play a role in substrate binding.
Formation of the three residue Trp-Tyr-Met cross-link is important for the catalase, but not the peroxidase activity of the enzyme (By similarity). The formation of the Trp-Tyr-Met cross-link is autocatalytic (PubMed:15840564).
Formation of the three residue Trp-Tyr-Met cross-link is important for the catalase, but not the peroxidase activity of the enzyme.
In contrast to the Synechocystis sp. enzyme, no Trp radical is formed on the distal Trp residue (Trp-91).
Many isoniazid-resistant clinical isolates contain mutations in katG, leading to abolition or reduction of catalase/peroxidase activity which results in lack of INH activation, or to a reduced affinity for INH. Other mechanisms of INH resistance include deletion of the katG gene, and down-regulation of katG expression due to mutations in the furA-katG intergenic region.
Might be involved in DNA repair. Partly complements recA-deficient E.coli cells exposed to UV radiation, mitomycin C or hydrogen peroxide. Increases resistance to mitomycin C in E.coli cells deficient for either uvrA, uvrB or uvrC.
Although related to the lipase family, lacks the conserved His active site at position 344 which is replaced by a Gln residue, suggesting it is inactive.
Belongs to the AB hydrolase superfamily. Lipase family.
Plays a role in the regulation of phosphate uptake. In this role, it may bind, possibly as a chaperone, to PhoR, PhoP or a PhoR-PhoP complex to promote dephosphorylation of phospho-PhoP, or inhibit formation of the PhoR-PhoP transitory complex (By similarity).
Component of a biotin-dependent acyl-CoA carboxylase complex. This subunit transfers the CO2 from carboxybiotin to the CoA ester substrate (PubMed:25695631). When associated with the alpha1 subunit AccA1, is involved in branched amino-acid catabolism with methylcrotonyl coenzyme A as the substrate (PubMed:25695631). Shows residual with propionyl-CoA and acetyl-CoA (PubMed:25695631).
C-terminal domain binds DNA and interacts with MtrB.
Divalent cation. Ca(2+) and Mg(2+) have both been seen in crystal structures. Optimal DNA-binding requires Ca(2+).
Expressed in culture (at protein level). Constitutively expressed in infected human blood-derived macrophages and mouse macrophage cell line J774A. Autoregulates its own expression.
Member of the two-component regulatory system MtrA/MtrB. Binds direct repeat motifs of sequence 5'-GTCACAGCG-3', phosphorylation confers higher affinity. Overexpression decreases bacteria viability upon infection of human THP-1 macrophage cell line, due at least in part to impaired blockage of phagosome-lysosome fusion (upon infection bacteria usually remain in phagosomes). Infecting C57BL/6 mice with an overexpressing strain leads to an attentuated infection in both spleen and lungs. The level of dnaA mRNA increases dramatically. Binds the promoter of dnaA, fbpD, ripA and itself, as well as oriC, which it may regulate. Upon co-overexpression of MrtA and MtrB growth in macrophages is partially restored, dnaA expression is not induced, although mouse infections are still attenuated, suggesting that bacterial growth in macrophages requires an optimal ratio of MtrB to MtrA.
Phosphorylated by MtrB (Probable). Autophosphorylates very slowly. Phosphorylated protein binds DNA better than unphosphorylated.
Probably a monomer when inactive, phosphorylation may permit it to oligomerize. It can oligomerize, and interacts with MrtB (PubMed:20702407, PubMed:21295603). Co-immunoprecipitates with DarG in the presence and absence of darT (PubMed:32634279).
Pupylated at Lys-207 by the prokaryotic ubiquitin-like protein Pup, which leads to its degradation by the proteasome.
DNA-dependent ATPase, acting on dsDNA with a 3'-ssDNA tail, unwinding with 3'-to 5'-polarity. A minimal tail of 18 nt is required for activity. Also highly efficient on nicked DNA. Involved in the post-incision events of nucleotide excision repair, as well as in nitrosative and oxidative stress response and possibly in persistence in the host. Inhibits RecA-mediated DNA strand exchange; this does not require ATPase activity. When combined with UvrA greatly inhibits RecA-mediated DNA strand exchange.
Forms small colonies, liquid growth is unchanged. Increased sensitivity to UV light, mitomycin C, nitrosative and oxidative stress; a double uvrA/uvrD1 mutant is even more sensitive. Single uvrD1 mutant is strongly attenuated in late stages of mouse infection, the double uvrA/uvrD1 mutant is strongly attenuated at all stages of infection.
Mg(2+); Mn(2+), Cu(2+), Ni(2+) or Co(2+) also support ATPase activity.
Belongs to the methylthiotransferase family. MiaB subfamily.
Binds 2 [4Fe-4S] clusters. One cluster is coordinated with 3 cysteines and an exchangeable S-adenosyl-L-methionine.
Catalyzes the methylthiolation of N6-(dimethylallyl)adenosine (i(6)A), leading to the formation of 2-methylthio-N6-(dimethylallyl)adenosine (ms(2)i(6)A) at position 37 in tRNAs that read codons beginning with uridine.
An accessory protein needed during the final step in the assembly of 30S ribosomal subunit, possibly for assembly of the head region. Essential for efficient processing of 16S rRNA. May be needed both before and after RbfA during the maturation of 16S rRNA. It has affinity for free ribosomal 30S subunits but not for 70S ribosomes.
The PRC barrel domain binds ribosomal protein uS19.
Contains an N-terminal DNA-binding domain and a C-terminal ligand-binding regulatory domain (PubMed:26396194). The C-terminal regulatory domain can bind saturated fatty acids (PubMed:26396194).
DNA-binding activity may be regulated by fatty acids.
Disruption of the gene affects the expression of about forty genes (PubMed:35938806). The mutant survives better than the wild-type strain inside macrophages (PubMed:35938806). It also has impaired biofilm formation, due to overexpression of the alkB-rubAB operon (PubMed:35938806). Mutant does not show significant difference in the transcription of mmpL3 and mmpL11 (PubMed:35938806).
Represses the expression of the alkB-rubAB operon, which encodes the alkane hydroxylase AlkB and the rubredoxins RubA and RubB (PubMed:35938806). Acts by binding to the promoter region of the operon (PubMed:35938806). In addition, EMSA analysis show that AlkX can bind to the promoter region of mmpS1 and mmpL3 and to the intragenic region of mmpL11, suggesting that it may participate in the regulatory network that controls the expression of MmpL lipid transporters (PubMed:26396194).
Belongs to the complex I 49 kDa subunit family.
Catalyzes the conversion of 1-hydroxy-2-methyl-2-(E)-butenyl 4-diphosphate (HMBPP) into a mixture of isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP) (PubMed:23091471). Acts in the terminal step of the DOXP/MEP pathway for isoprenoid precursor biosynthesis. Has a reduced activity compared with LytB2 (PubMed:23091471). Is unable to functionally complement the loss of lytB2 in M.tuberculosis (PubMed:26309039).
A putative lipoprotein that seems to be specialized for the initial steps of macrophage infection (PubMed:27220037). A non-acylated fragment (residues 26-185) binds phosphatidyl-myo-inositol mannosides (PIMs) (PubMed:27568926). Limits, in a TLR2-dependent fashion, bacterial uptake by host (mouse); this effect may be mediated by nonacylated fragment 26-185 (PubMed:27220037). Plays a TLR2-dependent role in host phagosome maturation arrest (PubMed:20844580, PubMed:27220037). Plays a TLR2-independent role in chemokine production during the first 24 hours of mouse infection (PubMed:27220037).
A shorter form (about 20 kDa) is secreted; upon overexpression of the whole protein in M.smegmatis the C-terminus of the short form is about residue 187, suggesting it is generated by cleavage of the protein before its C-terminal transmembrane domain (PubMed:27568926).
An extracytoplasmic domain (residues 26-185, without the lipid-anchor, either periplasmic or extracellular) decreases phagocystosis by macrophages; when added exogenously to the deletion mutant initial bacteria uptake by host (mouse) decreases to wild-type levels. When added exogenously however this region is not sufficient to restore phagosome maturation arrest (PubMed:27220037).
Constitutively expressed in culture (at protein level) (PubMed:27220037).
Grows normally in liquid culture. Traffics into host (human and mouse) acidified compartments early after phagocytosis, suggesting it no longer arrests phagosome maturation as well as wild-type (PubMed:20844580, PubMed:27220037). Grows normally in mouse macrophages at 7 days post-infection (PubMed:20844580). Initial uptake (2 hours post-infection) by host (mouse) macrophages is higher than wild-type, but decreased growth in host (mouse) macrophages from 1 to 3 days post-infection, wild-type growth at 4 days (PubMed:27220037). Initial uptake of bacteria is the same in TLR2-/TLR2- mice (PubMed:27220037). Decreased host (mouse) induction of pro-inflammatory chemokines gamma IP-10 (Cxcl10), MCP-1 (Ccl2) and MIP-1-alpha (Ccl3); decreased induction is not TLR2-dependent (PubMed:27220037).
P-type ATPase involved in specific uptake of calcium.
Stimulates the host (mouse) immune response; lipidated protein produced in E.coli stimulates T-cell proliferation in mice previously sensitized with LprN. Spleenocytes from these mice produce increased amounts of TNF-alpha and IFN-gamma, as well as somewhat increased nitric oxide levels, upon subsequent challenge with LprN. Previously sensitized mice infected with M.tuberculosis have an exacerbated disease response, suggesting this lipoprotein may down-regulate the host's immune response.
Copper-sensitive repressor that has a key role in copper homeostasis. It is part of the cso operon involved in the cellular response to increasing concentrations of copper inside the bacterium, which can be highly toxic. In the presence of copper, CsoR fully dissociates from the promoter in the cso operon, leading to the transcription of its genes. Binds to a GC-rich pseudopallindromic sequence, 5'-GTAGCCCACCCCCAGTGGGGTGGGA-3', in the cso promoter region.
This protein has an antiparallel four-helix bundle architecture that represents a novel DNA-binding fold.
A helicase/nuclease that prepares dsDNA breaks (DSB) for recombinational DNA repair. Binds to DSBs and unwinds DNA via a highly rapid and processive ATP-dependent bidirectional helicase activity. Unwinds dsDNA until it encounters a Chi (crossover hotspot instigator) sequence from the 3' direction. Cuts ssDNA a few nucleotides 3' to the Chi site. The properties and activities of the enzyme are changed at Chi. The Chi-altered holoenzyme produces a long 3'-ssDNA overhang and facilitates RecA-binding to the ssDNA for homologous DNA recombination and repair. Holoenzyme degrades any linearized DNA that is unable to undergo homologous recombination. In the holoenzyme this subunit contributes ATPase, 3'-5' helicase, exonuclease activity and loads RecA onto ssDNA.
Heterotrimer of RecB, RecC and RecD. All subunits contribute to DNA-binding. Interacts with RecA (By similarity). Co-immunoprecipitates with DarG in the presence and absence of darT (PubMed:32634279).
The C-terminal domain has nuclease activity and interacts with RecD. It interacts with RecA, facilitating its loading onto ssDNA.
The N-terminal DNA-binding domain is a ssDNA-dependent ATPase and has ATP-dependent 3'-5' helicase function. This domain interacts with RecC.
Belongs to the AAC(2')-I acetyltransferase family.
May catalyze the coenzyme A-dependent acetylation of the 2' hydroxyl or amino group of a broad spectrum of aminoglycosides and confer resistance to aminoglycosides (By similarity). In vitro assays show no significant increase of resistance to aminoglycosides, possibly due to low expression in a heterologous system (PubMed:9159528).
Autophosphorylates in the presence of Mg(2+) and/or Ca(2+), but only Mg(2+) ions promote phosphotransfer to MtrA.
Ca(2+) ions inhibit the phosphotransfer from MtrB to MtrA.
Interacts with MrtA. Interacts with LpqB, probably extracytoplasmically via MtrB's sensor domain.
Member of the two-component regulatory system MtrA/MtrB. Probably functions as a membrane-associated protein kinase that phosphorylates MtrA in response to environmental signals. Autophosphorylates and transfers phosphate to MtrA in vitro. Overexpression of MtrA alone decreases bacterial virulence in mouse infection; co-expression of MtrA and MtrB restores normal bacterial growth, suggesting that bacterial growth in macrophages requires an optimal ratio of MtrB to MtrA. Probably plays a role in cell division.
Not essential for growth in liquid culture.
The C-terminal domain (residues 234-567) autophosphorylates.
Belongs to the purine nucleoside phosphorylase YfiH/LACC1 family.
Purine nucleoside enzyme that catalyzes the phosphorolysis of adenosine and inosine nucleosides, yielding D-ribose 1-phosphate and the respective free bases, adenine and hypoxanthine. Also catalyzes the phosphorolysis of S-methyl-5'-thioadenosine into adenine and S-methyl-5-thio-alpha-D-ribose 1-phosphate. Also has adenosine deaminase activity.
Toxic component of a type II toxin-antitoxin (TA) system. An RNase (By similarity). Upon expression in M.smegmatis inhibits colony formation. Its toxic effect is neutralized by coexpression with cognate antitoxin VapB26.
Ref.1 (CAA41963) sequence was wrongly assigned to be a thymidylate synthase.
Inhibited by fructose 1,6-bisphosphate (FBP).
Key enzyme in the regulation of glycerol uptake and metabolism. Catalyzes the phosphorylation of glycerol to yield sn-glycerol 3-phosphate.
Pupylated at Lys-280 by the prokaryotic ubiquitin-like protein Pup, which probably leads to its degradation by the proteasome.
Belongs to the protoporphyrinogen/coproporphyrinogen oxidase family. Coproporphyrinogen III oxidase subfamily.
Involved in coproporphyrin-dependent heme b biosynthesis. Catalyzes the oxidation of coproporphyrinogen III to coproporphyrin III.
An essential GTPase which binds GTP, GDP and possibly (p)ppGpp with moderate affinity, with high nucleotide exchange rates and a fairly low GTP hydrolysis rate. Plays a role in control of the cell cycle, stress response, ribosome biogenesis and in those bacteria that undergo differentiation, in morphogenesis control (By similarity). GTPase activity is not inhibited by ATP or GDP. Overexpression decreases cell growth starting in late log phase and continuing into stationary phase (PubMed:21352546).
Autophosphorylates using GTP but not ATP; autophosphorylation requires Mg(2+), is inhibited by cold GTP and to a lesser extent GDP but not by ATP.
Belongs to the TRAFAC class OBG-HflX-like GTPase superfamily. OBG GTPase family.
Expression increases about 5-fold from early log phase to stationary phase, dropping in late stationary phase (at protein level).
Monomer (By similarity). Interacts with anti-sigma-F factor RsbW, was not seen to interact with RelA (PubMed:21352546).
Belongs to the fluoride channel Fluc/FEX (TC 1.A.43) family.
Fluoride-specific ion channel. Important for reducing fluoride concentration in the cell, thus reducing its toxicity.
Na(+) is not transported, but it plays an essential structural role and its presence is essential for fluoride channel function.
Binds 2 Zn(2+) or Co(2+) ions per subunit.
Catalyzes the hydrolysis of N-succinyl-L,L-diaminopimelic acid (SDAP), forming succinate and LL-2,6-diaminoheptanedioate (DAP), an intermediate involved in the bacterial biosynthesis of lysine and meso-diaminopimelic acid.
Belongs to the class-I aminoacyl-tRNA synthetase family. IleS type 2 subfamily.
Catalyzes the attachment of isoleucine to tRNA(Ile). As IleRS can inadvertently accommodate and process structurally similar amino acids such as valine, to avoid such errors it has two additional distinct tRNA(Ile)-dependent editing activities. One activity is designated as 'pretransfer' editing and involves the hydrolysis of activated Val-AMP. The other activity is designated 'posttransfer' editing and involves deacylation of mischarged Val-tRNA(Ile) (By similarity).
Confers high-level resistance to the antibiotic mupirocin (pseudomonic acid A), an Ile-analog that competitively inhibits activation by Ile-tRNA synthetase, thus inhibiting protein biosynthesis.
IleRS has two distinct active sites: one for aminoacylation and one for editing. The misactivated valine is translocated from the active site to the editing site, which sterically excludes the correctly activated isoleucine. The single editing site contains two valyl binding pockets, one specific for each substrate (Val-AMP or Val-tRNA(Ile)) (By similarity).
Probably part of the ABC transporter complex Rv1217c-Rv1218c involved in the resistance to a wide range of structurally unrelated drugs (PubMed:23143285). Probably responsible for the translocation of the substrate across the membrane (Probable).
Antitoxin component of a type II toxin-antitoxin (TA) system. Upon expression in M.smegmatis neutralizes the effect of cognate toxin VapC32.
Belongs to the NrnA oligoribonuclease family.
Bifunctional enzyme which has both oligoribonuclease and pAp-phosphatase activities. Degrades RNA oligonucleotides with a length of 5 nucleotides and shorter, with a preference for 2-mers. Also degrades 24-mers. Converts 3'(2')-phosphoadenosine 5'-phosphate (PAP) to AMP.
In accordance with its dual activities, is able to complement both orn and cysQ mutants in E.coli.
Toxic component of a type II toxin-antitoxin (TA) system. An RNase (By similarity). Upon expression in M.smegmatis inhibits colony formation. Its toxic effect is neutralized by coexpression with cognate antitoxin VapB43.
Belongs to the FtsQ/DivIB family. FtsQ subfamily.
Belongs to the type 2 tetrahydrodipicolinate N-succinyltransferase family.
Catalyzes the conversion of the cyclic tetrahydrodipicolinate (THDP) into the acyclic N-succinyl-L-2-amino-6-oxopimelate using succinyl-CoA.
Is activated by Mg(2+), Ca(2+) and Mn(2+), and inhibited by Zn(2+) and Co(2+). Is not inhibited by EDTA in vitro.
Belongs to the peroxiredoxin family. AhpC/Prx1 subfamily.
Homodimer; disulfide-linked, upon oxidation. 6 homodimers assemble to form a ring-like dodecamer (PubMed:11171096, PubMed:15886207). Identified in a complex with AhpD, DlaT and Lpd (PubMed:11799204).
Induced in isoniazid (INH)-resistant, KatG-deficient strains as well as in INH-sensitive strains when challenged with the drug. Increased expression in these strains probably compensates for loss of katG activity in detoxification of organic peroxides. A possible member of the dormancy regulon. Induced in response to reduced oxygen tension (hypoxia). It is hoped that this regulon will give insight into the latent, or dormant phase of infection.
The active site is a conserved redox-active cysteine residue, the peroxidatic cysteine (C(P)), which makes the nucleophilic attack on the peroxide substrate. The peroxide oxidizes the C(P)-SH to cysteine sulfenic acid (C(P)-SOH), which then reacts with another cysteine residue, the resolving cysteine (C(R)), to form a disulfide bridge. The disulfide is subsequently reduced by an appropriate electron donor to complete the catalytic cycle. In this typical 2-Cys peroxiredoxin, C(R) is provided by the other dimeric subunit to form an intersubunit disulfide (PubMed:15178486, PubMed:15886207). The disulfide can subsequently be reduced through a mixed disulfide with the C-terminal cysteine of AhpD, resolved by its second cysteine (PubMed:15178486) or by thioredoxin (TrxC) (PubMed:14871480).
Thiol-specific peroxidase that catalyzes the reduction of hydrogen peroxide and organic hydroperoxides to water and alcohols, respectively. Plays a role in cell protection against oxidative stress by detoxifying peroxides. Together with AhpD, DlaT and Lpd, constitutes an NADH-dependent peroxidase active against hydrogen and alkyl peroxides as well as serving as a peroxynitrite reductase, thus protecting the bacterium against reactive nitrogen intermediates and oxidative stress generated by the host immune system. Does not however seem to play a role in detoxification of isoniazid.
Disruption of this gene causes no major change in the fatty acid and lipid contents of the mutant strain in vitro; the mutant produces all the major methyl-branched fatty acid containing lipids, including DIM, in similar amounts to the wild-type strain. The replication of this mutant is unaffected in mouse bone-marrow macrophages. However, the mutant strain displays severe growth defects in mice, since it multiplies much less extensively than does the parental strain during the acute phase of infection in the lungs and spleen of mice infected via the respiratory route.
Is expressed in bacteria grown axenically (7H9 medium) and inside macrophages.
Is organized in a condensing KS-AT and a modifying DH-PsiKR-ER-KR region, followed by a flexibly tethered ACP domain.
Polyketide synthase likely involved in the biosynthesis of a polymethyl-branched fatty acid (PMB-FA) that might only be produced during host infection. Is required for the full virulence of M.tuberculosis during host infection.
An article reported the phosphorylation of PbpA by PknB, but this paper was later retracted as some figures were modified prior to publication.
Deletion of the gene does not impact in vitro growth, but it leads to aberrations in the cell length. Deletion mutant shows much higher sensitivity to oxacillin and clavulanic acid. Mutant shows compromised bacterial virulence in the host.
Inhibited by the antibiotics imipenem, penicillin G, and ceftriaxone.
The apo form can adopt multiple conformations (PubMed:22365933). The beta5-alpha11 loop near the active site is a flexible region that can adopt a variety of conformations in the acylated state of PBPA and appears important for acylation (PubMed:22365933).
Transpeptidase that catalyzes cross-linking of the peptidoglycan cell wall (Probable). Required for the regulation of cell length. Plays critical roles for the survival of the pathogen inside the host. Required for both bacterial survival and formation of granuloma structures in a guinea pig infection model (PubMed:29530985).
Belongs to the NAD(P)-dependent epimerase/dehydratase family. Fucose synthase subfamily.
Catalyzes the two-step NADP-dependent conversion of GDP-4-dehydro-6-deoxy-D-mannose to GDP-fucose, involving an epimerase and a reductase reaction.
Catalyzes the activation of long-chain fatty acids as acyl-adenylates (acyl-AMP), which are then transferred to the multifunctional polyketide synthase PpsA for further chain extension (PubMed:15042094, PubMed:15749014, PubMed:20553505). Catalyzes the adenylation of the long-chain fatty acids eicosanoate (C20) or docosanoate (C22), and potentially the very-long-chain fatty acid lignocerate (C24) (PubMed:15749014, PubMed:20553505). Involved in the biosynthesis of phthiocerol dimycocerosate (DIM A) and phthiodiolone dimycocerosate (DIM B) (PubMed:11279114, PubMed:20553505).
Disruption of the gene abolishes the production of phthiocerol dimycocerosate (DIM) on the cell envelope (PubMed:11279114). Mutant is attenuated in BALB/c mice. Mutant induces less pneumonia and larger delayed-type hypersensitivity (DTH) reactions. It also induces lower but progressive production of IFN-gamma, IL-4 and TNF-alpha (PubMed:15958066).
Vaccination with the fadD26 mutant protects against progressive tuberculosis more efficiently than does Bacille Calmette-Guerin (BCG). It suggests that inactivation of DIM synthesis can increase the immunogenicity of live vaccines, and increase their ability to protect against tuberculosis, indicating that fadD26 mutant could be a potential vaccine candidate (PubMed:15958066). A double unmarked sigE fadD26 mutant is more attenuated and more protective than BCG and is also a promising new prime TB vaccine candidate (PubMed:31591165).
Belongs to the malate synthase family. GlcB subfamily.
By bromopyruvate, oxalate, and phosphoenolpyruvate. Malate inhibits the activity to 50% at 1 mM concentration. Glycolate inhibits only at fairly high concentrations.
Involved in the glycolate utilization. Catalyzes the condensation and subsequent hydrolysis of acetyl-coenzyme A (acetyl-CoA) and glyoxylate to form malate and CoA.
Mg(2+). Mn(2+) is able to replace Mg(2+).
Belongs to the isochorismate synthase family.
Catalyzes the conversion of chorismate to isochorismate.
A potent antigen in animals immunized with live bacteria, it induces a strong delayed-type hypersensitivity (DTH) in immunized animals (PubMed:10531201). Elicits a mostly Th1 type of T-cell response in healthy humans; induces IFN-gamma production from CD4(+) and CD8(+) cells (PubMed:12654810). Functions as an adhesin, binds to mouse macrophages via mannose residues (PubMed:10531201, PubMed:25359607). Might interact via host CD209 (PubMed:16092920).
Glycosylated, with mannose residues (PubMed:8626314, PubMed:10542234, PubMed:10531201, PubMed:25359607). The secreted protein has from 0 to 9 mannose residues, the majority have 6, 7, or 8 mannose residues (22, 24 and 17% respectively) (PubMed:10531201). Deglycosylated molecules had a significantly lower capacity to elicit a DTH reaction in guinea pigs in vivo or to activate specific T lymphocytes in vitro (PubMed:10531201). Pretreating mouse macrophages with mannan decreases binding of M.tuberculosis (PubMed:25359607). The non-glycosylated form stimulates IFN-gamma production however, so glycosylation is not essential (PubMed:12654810).
Major immunodominant antigen that has potential as a vaccine against tuberculosis (PubMed:10542234, PubMed:10531201, PubMed:12654810). Can be used as a DNA vaccine in guinea pigs (PubMed:12654810). Apa-ELISA could be used in diagnosis.
Runs as 45 and 47 kDa protein, the nature of the difference between the 2 forms is not known but is still seen after alpha-mannosidase treatment (PubMed:10531201).
Was originally thought to be involved in molybdenum transport.
Upon expression in E.coli has a weak triacylglycerol synthase function, making triacylglycerol (TG) from diolein and long-chain fatty acyl-CoA. Also functions weakly as a wax synthase, as it incorporates palmityl alcohol into wax esters in the presence of palmitoyl-CoA.
A wide array of epitopes was recognized on Rv1985c in TB patients. Those epitopes could specifically discriminate TB infection from BCG vaccination. These results indicate that the peptide pools selected from Rv1985c have the potential to diagnose TB infection by a method that may be routinely used in clinical laboratories.
Contains an N-terminal DNA binding domain (DBD) and a C-terminal regulatory domain (RD).
Homodimer (PubMed:20036253). Two types of dimers are identified from the crystal packing: a DBD-type dimer, where the dimer is mainly stabilized by the coiled-coil linker helices, and a RD-type dimer, where RDs contact each other in an antiparallel, side-by-side alignment (PubMed:20036253).
Positively regulates the expression of the exporter LysE and represses its own expression. Activity requires the presence of a coinducer, lysine or histidine. Acts by binding to lysG-lysE promoter region. Also up-regulates the expression of ppsB, ppsC and ppsD, by binding to the upstream region of ppsB.
A disrupted strain immunizes mice against subsequent infection with wild-type H37Rv as well as the M.bovis vaccine strain BCG.
A fragment of the mature protein (residues 41-60) prevents uptake of M.tuberculosis by a human macrophage-like cell line; lesser effects are seen on bacterial uptake by a human lung epithelial cell line.
A host TLR2 agonist (PubMed:10426995, PubMed:11441098, PubMed:12874328). Plays a complicated role in bacterial interactions with the host immune system; some effects favor the host (induces interleukin 1-beta and IL-12 p40 (IL12B), both increase the host's immune response) while others favor the bacteria (increases growth in monocyte-derived macrophages and decreases host MHC class II (MHC-II) expression and antigen processing) (PubMed:16177361). Induces host (human and mouse) IL-12 p40 (IL12B, a pro-inflammatory cytokine) release by monocyte cell lines via TLR2 and CD14 (PubMed:10426995). Induces host (human) monocytes to produce TNF-alpha, IL-6 and IL-12 p40; LpqH is a more potent inducer than PstS1 (PubMed:16622205). Inhibits MHC-II expression and antigen processing in host (mouse) macrophages via TLR2 (independently of TLR4) probably via the lipid modification (PubMed:11441098). Stimulates host (human) dendritic cell maturation to become MHC-II-positive antigen presenting cells via TLR2, which depends on lipidation; nonlipidated protein does not stimulate maturation (PubMed:11160304). Inhibits host (human and mouse) IFN-gamma signaling in macrophages via TLR2; decreases IFN-gamma stimulated MHC-II antigen processing as well as decreasing IFN-gamma-mediated up-regulation of immunoglobulin gamma Fc receptor (FCGR1A), enabling the bacteria to evade the immune system (PubMed:12874328). In resting human CD4+ T-cells lipidated (but probably not nonlipidated protein) is a costimulatory ligand (with anti-CD3 and anti-CD28) for T-cell proliferation and IFN-gamma and IL-2 production (PubMed:21078852). Human CD4+ T-cells probably use TLR1/TLR2 heterodimers to respond to mycobacterial lipoproteins (PubMed:21078852). Acting via TLR2 enhances expression of host peroxisome proliferator-activated receptor gamma (PPARG), a regulator of inflammation and immunoregulation, and increases p38 MAPK phosphorylation, IL-6 and TNF-alpha expression (PubMed:25504154). Native or nonlipidated recombinant protein missing the first 4 residues have been shown to induce apoptosis in the human macrophage cell line THP-1 and human monocyte-derived macrophages in a TLR2, caspase-3 and caspase-8-dependent manner (PubMed:12594264). Protein overexpressed in M.smegmatis (lipidated and probably glycosylated) induces apoptosis in human macrophages via TLR2 in a caspase-3/caspase-8-mediated manner, but also in a caspase-independent manner where mitochondrial apoptosis-inducing factor (AIFM1) translocates to the nucleus (PubMed:23316255). Another study found mature, native (lipidated) protein did not induce apoptosis in THP-1 macrophage cell line (PubMed:12874328). Functions as an adhesin, binds to human and mouse macrophages (PubMed:25359607).
Based on its structure might be involved in ligand transport (Ref.25) (By similarity).
Belongs to the mycobacterial 19 kDa antigen family.
Expressed in cell culture; expressed at a steady level for 4 days following infection of human mononuclear phagocytes.
Forms a U-shaped beta-half-barrel with a large hydrophobic cavity.
No visible phenotype in culture. Grows less well than wild-type in human monocyte-derived macrophages (MDM) over 7 days; increased human monocyte MHC class II expression, decreased interleukin 1-beta secretion from monocytes and MDM (PubMed:16177361). No growth in C57BL/6 mice over 40 days, even in mice lacking gamma interferon (PubMed:17804126).
Triacylated with a thioether-linked diacylglycerol with C16 and C19 on Cys-22 and an amide-linked C16 fatty acid (PubMed:24093492). Modified by Lgt on Cys-22 with an S-linked diacylglycerol with a mixture of C16, C18 and C19 fatty acids (palmitic, stearic and tuberculostearic acid), signal peptide is removed by LspA, modifed by Lnt with an amide-linked mixture of C16 and C19 fatty acids, expressed in M.bovis (PubMed:24093492). Upon expression in M.smegmatis the protein is glycosylated (possibly by mannose, detected by concanavalin A (conA) binding) within the first 20 residues of the mature protein; altering the probably glycosylated Thr residues alters processing of the mature protein in M.smegmatis and slightly differently in M.vaccae (PubMed:8670858). Glycosylation may protect this region of the protein from proteolysis, which would release the lipoprotein from the cell surface (PubMed:8670858). Mannosylated upon expression in M.smegmatis; treatment with alpha-D-mannosidase decreases its apparent molecular weight (PubMed:16098710). Native protein binds conA (PubMed:16098710).
Allosterically activated by GTP, when glutamine is the substrate; GTP has no effect on the reaction when ammonia is the substrate. The allosteric effector GTP functions by stabilizing the protein conformation that binds the tetrahedral intermediate(s) formed during glutamine hydrolysis. Inhibited by the product CTP, via allosteric rather than competitive inhibition (By similarity). Is inhibited by the EthA-activated metabolites of compounds 7947882 (5-methyl-N-(4-nitrophenyl)thiophene-2-carboxamide) and 7904688 (3-phenyl-N-[(4-piperidin-1-ylphenyl)carbamothioyl]propanamide), that have been shown to have anti-tubercular activity against M.tuberculosis in its replicating, non-replicating, and intracellular states; active metabolites of 7947882 correspond to the S-dioxide and S-monoxide derivatives (PubMed:26097035). One active metabolite was shown to behave as a competitive inhibitor toward the ATP-binding site of PyrG (PubMed:26097035). Direct inhibition of PyrG decreases CTP levels, leading to disruption of the nucleotide metabolic network, characterized by increased levels of several intermediates in the biosynthesis of pyrimidines and purines (PubMed:26097035).
CTPSs have evolved a hybrid strategy for distinguishing between UTP and CTP. The overlapping regions of the product feedback inhibitory and substrate sites recognize a common feature in both compounds, the triphosphate moiety. To differentiate isosteric substrate and product pyrimidine rings, an additional pocket far from the expected kinase/ligase catalytic site, specifically recognizes the cytosine and ribose portions of the product inhibitor.
Catalyzes the ATP-dependent amination of UTP to CTP with either L-glutamine or ammonia as the source of nitrogen. Is essential for M.tuberculosis growth in vitro and ex vivo (PubMed:26097035). Regulates intracellular CTP levels through interactions with the four ribonucleotide triphosphates (By similarity).
Toxic component of a type II toxin-antitoxin (TA) system. An RNase. Its cognate antitoxin is VapB36 (By similarity).
Not essential, no effect on the SOS response genes, no change in resistance to DNA-damaging agents including mitomycin C.
Sigma factors are initiation factors that promote the attachment of RNA polymerase to specific initiation sites and are then released. Extracytoplasmic function (ECF) sigma factors are held in an inactive form by a cognate anti-sigma factor until released, although no anti-sigma factor is known for this protein. May be involved in host intracellular survival after infection (strains H37Rv and CDC 1551). A role in the SOS response is controversial; it has been seen in strain CDC 1551 (PubMed:18039768) but not in H37Rv (PubMed:21169493).
The sigma-70 factor domain-2 mediates sequence-specific interaction with the -10 element in promoter DNA, and plays an important role in melting the double-stranded DNA and the formation of the transcription bubble. The sigma-70 factor domain 2 mediates interaction with the RNA polymerase subunits RpoB and RpoC (By similarity).
Very poorly expressed in exponential phase; further repressed at room temperature. Up-regulated 10-fold 7 days after infection of human macrophages. Induced by DNA-damaging agents but not by surface stress (detergent).
Belongs to the uracil-DNA glycosylase (UDG) superfamily. UNG family.
Excises uracil residues from the DNA which can arise as a result of misincorporation of dUMP residues by DNA polymerase or due to deamination of cytosine.
Cells lacking this gene are unable to grow using either propionate or cholesterol as a primary carbon source and the transcript levels of both prpD and prpC are dramatically reduced regardless of carbon source. When the mutant grows on medium containing glucose or acetate as a sole carbon source, there is no significant difference in growth compared to the wild-type.
Plays a key role in regulating expression of enzymes involved in the catabolism of short chain fatty acids (SCFA) via both the glyoxylate (acetyl degradation route) and the methylcitrate cycle (propionate degradation route) (PubMed:22916289, PubMed:24705740). Required for intracellular growth in macrophages and for the assimilation of cholesterol-derived propionate (PubMed:22365605). PrpR acts as a transcriptional activator of prpDC and icl genes when propionate is the main carbon source, and as a ramB repressor (PubMed:22916289). During growth on propionate, PrpR also acts as a transcriptional repressor of dnaA, which encodes the DnaA initiator protein responsible for initiating chromosomal replication (PubMed:24705740). It is possibly involved in the regulation of genes responsible for controlling cholesterol utilization (PubMed:22365605).
Belongs to the LeuD family. LeuD type 1 subfamily.
Belongs to the glycosyltransferase 39 family.
Transfers mannose from Dol-P-mannose to Ser or Thr residues on proteins (Probable). Mannosylates an artificial substrate, probably on a Thr residue, upon expression in M.smegmatis. Glycosylation probably requires the Sec-translocation system.
Interacts with cognate antitoxin VapB27.
Probably the toxic component of a type II toxin-antitoxin (TA) system. An RNase (By similarity). Its cognate antitoxin is VapB27.
Toxic component of a type II toxin-antitoxin (TA) system. An RNase. Its cognate antitoxin is VapB44 (By similarity).
Binds 4 Mn(2+); 2 Mn(2+) for polymerase/primase activity, 1 each for 3-phosphoesterase and ligase.
In conjunction with endogenous or Mycobacterium phage Omega Ku (AC Q853W0) can reconstitute NHEJ in Saccharomyces cerevisiae.
In the C-terminal section; belongs to the ATP-dependent DNA ligase family.
In the N-terminal section; belongs to the LigD polymerase family.
In the central section; belongs to the LigD 3'-phosphoesterase family.
It is not clear whether there is a 5- to 3'-exonuclease activity associated with the enzyme.
LigD has variable architecture; domain order can be permutated, domains can be independently encoded, while some bacteria lack the 3'-phosphoesterase domain entirely.
Monomer. Component of the NHEJ repair enzyme with mKu. Interacts with Ku in the absence of DSB via the Pol domain. In structures of the Pol domain with template DNA 2 Pol domains are bound to microhomologous DNA complexes to form an end-bridging complex. Probably interacts with Mycobacterium phage Omega and Corndog Ku homologs (AC Q853W0, AC Q856K7). Interacts with Sir2; may form a trimeric complex with LigD during NHEJ.
Not essential for growth, 80% reduction in NHEJ (in strain Erdman).
The C-terminal ligase domain (Lig) binds dsDNA and functions as an independent domain (PubMed:14985346, PubMed:16023671).
The N-terminal Mn(2+)-dependent polymerase/primase domain (Pol) functions as an independent domain, binds DNA, is sufficient for DNA-directed and non-DNA-directed DNA synthesis (PubMed:15778718) and interacts with Ku (PubMed:16023671).
The central 3'-phosphoesterase domain (PE) has exonuclease activity probably constituted of 3'-ribonuclease and 3'-phosphatase activity (PubMed:15499016). It does not function as an independent domain (PubMed:16023671).
The polymerase, exonuclease and ligase activities are stimulated by Ku. Polymerase activity is inhibited by EDTA.
The preference of the polymerase domain for rNTPs over dNTPs may be advantageous in dormant cells, where the dNTP pool is limiting.
With Ku forms a non-homologous end joining (NHEJ) repair enzyme which repairs DNA double-strand breaks (DSB) with reduced fidelity. Recognizes, processes and reseals DSBs, including repairs on incompatible DSB which require 3'-resection, gap filling and ligation. Anneals the 3' overhanging strands from opposing breaks to form a gapped intermediate, which then can be extended in trans by using the termini as primers for extension of the annealed break. Binds to the recessed 5'-phosphate moiety of the downstream DNA strand forming a stable synaptic complex even when the 3'-protruding ends of the template DNA strands are not complementary. Has numerous activities; gap filling copies the template strand, and prefers a 5'-phosphate in the gap and rNTPS (PubMed:17174332, PubMed:17947582), DNA-directed DNA or RNA polymerase on 5'-overhangs, terminal transferase (extending ssDNA or blunt dsDNA in a non-templated fashion, preferentially with rNTPs), DNA-dependent RNA primase (synthesizes short RNAs on unprimed closed ssDNA) and 3'- to 5'-exonuclease on ssDNA (PubMed:15499016). Isolated Pol domain (and presumably the holoenzyme) is able to form complexes between 2 noncompatible protruding 3'-ends DNA ends via microhomologous DNA strands, in a end-bridging function to which it adds a templated nucleotide (PubMed:17947582). Minimal primer length is 2 nucleotides (PubMed:21255731).
Belongs to the nitrite and sulfite reductase 4Fe-4S domain family.
Catalyzes the reduction of sulfite to sulfide, a step in the biosynthesis of sulfur-containing amino acids and cofactors.
Belongs to the sigma-70 factor family. RpoD/SigA subfamily.
Constitutively expressed under all conditions tested except for 3-fold reduction in stationary phase, standing culture and upon growth in H(2)O. 2-fold induced by starvation. Half-life of over 40 minutes.
Interacts transiently with the RNA polymerase catalytic core formed by RpoA, RpoB, RpoC and RpoZ (2 alpha, 1 beta, 1 beta' and 1 omega subunit) to form the RNA polymerase holoenzyme that can initiate transcription. Interacts with WhiB3 and probably with RbpA probably via its sigma-2 region.
Sigma factors are initiation factors that promote the attachment of RNA polymerase to specific initiation sites and are then released. This sigma factor is the primary sigma factor during exponential growth (Probable).
Nucleoside triphosphate pyrophosphatase. May have a dual role in cell division arrest and in preventing the incorporation of modified nucleotides into cellular nucleic acids.
Involved in the degradation of cholesterol. Catalyzes the introduction of a 9a-hydroxyl moiety into 1,4-androstadiene-3,17-dione (ADD) to yield the 9alpha-hydroxy-1,4-androstadiene-3,17-dione (9OHADD) intermediate which spontaneously form 3-hydroxy-9,10-seconandrost-1,3,5(10)-triene-9,17-dione (HSA) via the meta-cleavage of ring B with concomitant aromatization of ring A. KSH is also able to use 4-androstene-3,17-dione (AD), 3-oxo-23,24-bisnorcholesta-4-en-22-oate (4-BNC), 3-oxo-23,24-bisnorcholesta-1,4-dien-22-oate (1,4-BNC), 3-oxo-23,24-bisnorcholesta-4-en-22-oyl-coenzyme A thioester (4-BNC-CoA) and 3-oxo-23,24-bisnorcholesta-1,4-dien-22-oyl-coenzyme A thioester (1,4-BNC-CoA) as substrates.
Monomer. The two-component system 3-ketosteroid-9-alpha-monooxygenase is composed of an oxygenase component KshA and a reductase component KshB.
Belongs to the ketol-acid reductoisomerase family.
Inhibited by N-hydroxy-N-isopropyloxamate (IpOHA).
Involved in the biosynthesis of branched-chain amino acids (BCAA). Catalyzes an alkyl-migration followed by a ketol-acid reduction of (S)-2-acetolactate (S2AL) to yield (R)-2,3-dihydroxy-isovalerate. In the isomerase reaction, S2AL is rearranged via a Mg-dependent methyl migration to produce 3-hydroxy-3-methyl-2-ketobutyrate (HMKB). In the reductase reaction, this 2-ketoacid undergoes a metal-dependent reduction by NADPH to yield (R)-2,3-dihydroxy-isovalerate. It is also able to use 3-hydroxypyruvate (HP).
Autophosphorylated on threonine and serine residues. Dephosphorylated by PstP.
Deletion causes hypervirulence during the chronic phase of infection in BALB/c mice. Mutant displays increased resistance to acidified nitrite stress. Does not affect sensitivity to ethambutol.
Inhibited by the kinase inhibitors staurosporine and H-7.
May regulate bacterial growth in response to external signals to facilitate adaptation to the host environment. In vitro, phosphorylates several substrates such as EmbR, DevR (DosR), DacB1 and Rv0681.
Repressed by low pH and heat shock. Up-regulated inside the host macrophages.
Deletion mutant does not secrete EsxN and shows a minor reduction of PPE41 secretion.
Part of the ESX-5 / type VII secretion system (T7SS), which is composed of cytosolic and membrane components.
Part of the ESX-5 specialized secretion system, which is responsible for the secretion of EsxN and a number of PE_PGRS and PPE proteins, including PPE41 (PubMed:22340629, PubMed:22925462). EccA5 exhibits ATPase activity and may provide energy for the export of ESX-5 substrates (By similarity).
Adenine glycosylase active on G:A and C:A mispairs, as well as processing 7,8-dihydro-8-oxoguanine:A (8-oxoG) mismatches. Minor activity against 8-oxoG:G and 8-oxo:T mismatches is also seen. Bind dsDNA oligonucleotides containing the above mismatches.
Binds 1 [4Fe-4S] cluster. The cluster does not appear to play a role in catalysis, but is probably involved in the proper positioning of the enzyme along the DNA strand.
Binding to DNA is inhibited by zinc ions.
Induced by zinc. Negatively autoregulated.
Transcriptional regulator involved in zinc homeostasis. Represses the expression of the smtB-zur operon in the absence of zinc. Could act as the metal sensor that controls the expression of zur in response to zinc availability.
Antitoxin component of a type II toxin-antitoxin (TA) system. Upon expression in M.smegmatis neutralizes the effect of cognate toxin VapC19.
Disruption of the gene reduces the ability of M.tuberculosis to bind to host cells. Disruption does not reduce virulence in a mouse model of infection (PubMed:17030567). Invasion of the infant human brain microvascular endothelial-cell monolayer is significantly decreased in transposon mutant (PubMed:16586367).
Probably part of an ABC transporter complex involved in host cell binding either through secretion of an adherence factor or through maintaining the architecture and integrity of the mycobacterial cell envelope (PubMed:17030567). Could be required for host endothelial-cell invasion and/or intracellular survival (PubMed:16586367).
Belongs to the antibiotic biosynthesis monooxygenase family.
Catalyzes the oxidative degradation of the heme macrocyclic porphyrin ring in the presence of a suitable electron donor such as ascorbate or NADPH--cytochrome P450 reductase, with subsequent release of free iron.
MhuD has the ability to bind 2 heme molecules per monomer but only the monoheme-protein complex is active.
Cells lacking this gene result in a decreased permeability and fluidity of the cell envelope due to a drastic difference in the mycolates pattern. The parent strain makes three types of mycolates (alpha-mycolate, methoxymycolates and ketomycolates), but the mutant contains most exclusively alpha-mycolates. The mutated strain grows more slowly in the lungs, spleen and liver of mouse and is cleared more rapidly from the liver than the wild-type strain. Cells lacking this gene show also an increased production of interleukin-12p40 which probably mediated by the mycolate-containing glycolipid trehalose 6,6'-dimycolate (TDM), which is known to be secreted as a potential immunomodulator into the cytosol of infected macrophages. Inactivation of MmaA4 confers a strong TAC resistance.
Inhibited by S-adenosyl-N-decyl-aminoethyl (SADAE).
Involved in the biosynthesis of hydroxymycolate, a common precursor of oxygenated mycolic acids (methoxy-mycolate and keto-mycolate). Probably transfers a methyl group from the S-adenosylmethionine (SAM) cofactor and, subsequently or simultaneously, a water molecule onto the double bound of ethylene substrates, leading to the formation of the hydroxylated product at the distal position. Involved in the activation of the antitubercular drug thiacetazone (TAC).
Susceptibility of M.tuberculosis to the second-line antitubercular drug thiacetazone (TAC) requires primary activation by the monooxygenase, EthA, but is not sufficient to hit the lethal target. TAC must be secondarily modified (methylation) to its lethal form which causes growth arrest. MmaA4 activates TAC by interacting directly with TAC or with EthA to produce lethal TAC, but the methylation of the drug appears independent of MmaA4.
Catalyzes the synthesis of 5,6-dihydrouridine (D), a modified base found in the D-loop of most tRNAs, via the reduction of the C5-C6 double bond in target uridines.
The revised start codon for this protein is ATA.
Antitoxin component of a type II toxin-antitoxin (TA) system. Upon expression in E.coli and M.smegmatis neutralizes the effect of cognate toxin MazF3. Overexpression of MazE3 alone decreased persister cells formation in M.smegmatis upon challenge with gentamicin or kanamycin.
Forms a complex with cognate toxin MazF3, possibly with 1:1 stoichiometry.
Mildly induced (about 4-fold) when grown in a non-replicating state.
Activity is increased about twofold by 10 mM manganese. ADP, at 10 mM concentration, inhibits the formation of trehalose-P by 70% with either UDP-glucose or GDP-glucose as substrate, but GDP, also at 10 mM, only inhibits the reaction with UDP-glucose (50%) but not with GDP-glucose.
Belongs to the glycosyltransferase 20 family.
Combined inactivation of both glgM and ostA is lethal, potentially due to accumulation of toxic levels of ADP-glucose. Combined inactivation of otsA and glgC results in a loss of alpha-glucans and maltose-1-phosphate (M1P).
Involved in the production of glycogen and alpha-glucan via the TreS-Pep2 branch involved in the biosynthesis of maltose-1-phosphate (M1P), and probably in the osmoprotection via the biosynthesis of trehalose (PubMed:12473104, PubMed:27513637). Catalyzes the transfer of glucose from UDP-glucose (UDP-Glc) to D-glucose 6-phosphate (Glc-6-P) to form trehalose-6-phosphate (PubMed:12473104). Is specific for the glucosyl acceptor (Glc-6-P cannot be replaced by either mannose-6-P, fructose-6-P or glucosamine-6-P), but any of the glucose sugar nucleotides can be used as glucosyl donors (PubMed:12473104). It is more active with the purine sugar nucleotides than with the pyrimidine sugar nucleotides (PubMed:12473104).
Catalyzes the deacetylation of 1D-myo-inositol 2-acetamido-2-deoxy-alpha-D-glucopyranoside (GlcNAc-Ins) in the mycothiol (MSH) biosynthesis pathway. Shows some amidase activity toward S-conjugates of mycothiol.
Partially inhibited by MSH when MSmB is used as substrate. Competitively inhibited by the GlcNAc-cyclohexyl derivative 5-(4-chlorophenyl)-N-((2R,3R,4R,5S,6R)-2-(cyclohexylthio)-tetrahydro-4,5-dihydroxy-6-(hydroxymethyl)-2H-pyran-3-yl)furan-2-carboxamide, which also inhibits Mca.
Belongs to the universal ribosomal protein uL24 family.
One of the proteins that surrounds the polypeptide exit tunnel on the outside of the subunit.
One of two assembly initiator proteins, it binds directly to the 5'-end of the 23S rRNA, where it nucleates assembly of the 50S subunit.
Protective antigen that could be included in novel subunit tuberculosis vaccines. Expressed and presented to the immune system throughout the different stages of the infection (PubMed:18822333).
Belongs to the bacterial ribosomal protein bL20 family.
Binds directly to 23S ribosomal RNA and is necessary for the in vitro assembly process of the 50S ribosomal subunit. It is not involved in the protein synthesizing functions of that subunit (By similarity).
Required for the formation of a threonylcarbamoyl group on adenosine at position 37 (t(6)A37) in tRNAs that read codons beginning with adenine. Catalyzes the conversion of L-threonine, HCO(3)(-)/CO(2) and ATP to give threonylcarbamoyl-AMP (TC-AMP) as the acyladenylate intermediate, with the release of diphosphate.
PPIases accelerate the folding of proteins. It catalyzes the cis-trans isomerization of proline imidic peptide bonds in oligopeptides (By similarity).
Belongs to the TPP enzyme family. MenD subfamily.
Catalyzes the thiamine diphosphate-dependent decarboxylation of 2-oxoglutarate and the subsequent addition of the resulting succinic semialdehyde-thiamine pyrophosphate anion to isochorismate to yield 2-succinyl-5-enolpyruvyl-6-hydroxy-3-cyclohexene-1-carboxylate (SEPHCHC).
Mutants are defective in the secretion of EsxN, PPE41 and PE_PGRS proteins.
Was originally thought to be the product of two separate ORFs, eccCa5 and eccCb5.
Belongs to the myo-inositol 1-phosphate synthase family.
Key enzyme in myo-inositol biosynthesis pathway that catalyzes the conversion of glucose 6-phosphate to 1D-myo-inositol 3-phosphate in a NAD-dependent manner.
Pupylated at Lys-73 by the prokaryotic ubiquitin-like protein Pup, which leads to its degradation by the proteasome.
An intermediate of this reaction is the autophosphorylated ppk in which a phosphate is covalently linked to a histidine residue through a N-P bond.
Belongs to the polyphosphate kinase 1 (PPK1) family.
Catalyzes the reversible transfer of the terminal phosphate of ATP to form a long-chain polyphosphate (polyP).
Belongs to the ferredoxin--NADP reductase type 1 family.
Transports electrons between ferredoxin and NADPH. May supply electrons to P450 systems (PubMed:12071965). The enzyme can use both NADPH and NADH as a reductant, but the catalytic efficiency is two orders of magnitude higher with NADPH (PubMed:12071965).
Belongs to the gamma-glutamyl phosphate reductase family.
Catalyzes the NADPH-dependent reduction of L-glutamate 5-phosphate into L-glutamate 5-semialdehyde and phosphate. The product spontaneously undergoes cyclization to form 1-pyrroline-5-carboxylate.
Toxic component of a type II toxin-antitoxin (TA) system. Upon expression in E.coli inhibits cell growth and colony formation. Its toxic effect is neutralized by coexpression with cognate antitoxin ParD1.
Belongs to the diacylglycerol/lipid kinase family.
Binds 1 Mg(2+) ion per subunit. This ion appears to have a structural role and is required for catalytic activity.
Catalyzes the phosphorylation of diacylglycerol (DAG) into phosphatidic acid. Is involved in the biosynthesis of phosphatidylinositol mannosides (PIMs), probably via a role in the biosynthesis of phosphatidylinositol (PI), a PIM precursor, which is derived from phosphatidic acid.
Belongs to the binding-protein-dependent transport system permease family. OppBC subfamily.
Binds 2 heme b groups per subunit. Heme 1 is located at the cytoplasmic interface, heme 2 is located at the extracellular interface. Electrons are transferred from the extracellular to the cytoplasmic heme.
Does not seem to have nitrate reductase activity.
In the C-terminal section; belongs to the nitrate reductase gamma subunit family.
In the N-terminal section; belongs to the nitrate reductase alpha subunit family.
In the central section; belongs to the NarJ/NarW family.
This protein serves as an immunogenic antigen, inducing gamma-interferon responses in whole-blood cultures from M.tuberculosis-exposed adults in Uganda and South Africa, indicating this might be a good vaccine candidate.
Belongs to the GTP cyclohydrolase I family.
Toroid-shaped homodecamer, composed of two pentamers of five dimers.
Belongs to the radical SAM superfamily. Biotin synthase family.
Binds 1 [2Fe-2S] cluster. The cluster is coordinated with 3 cysteines and 1 arginine.
Catalyzes the conversion of dethiobiotin (DTB) to biotin by the insertion of a sulfur atom into dethiobiotin via a radical-based mechanism.
Toxic component of a type II toxin-antitoxin (TA) system. An RNase. Its cognate antitoxin is VapB38 (By similarity).
Plays a major role in the integrity and stability of the capsule.
Antitoxin component of a type II toxin-antitoxin (TA) system. Antitoxin that counteracts the effect of its cognate VapC4 toxin. Upon expression in situ, in M.smegmatis or E.coli neutralizes the effect of cognate toxin VapC4.
The C-terminal domain (residues 55-85) is sufficient to interact with and neutralize VapC4; exchanging the N-terminus (residues 1-54) with VapB5 allows neutralization, while exchanging the C-terminal domain (residues 55-85) does not. Many single residue mutations in the C-terminal domain construct but not in full-length protein prevent toxin neutralization, they are not all annotated here.
Belongs to the universal ribosomal protein uS19 family.
Protein S19 forms a complex with S13 that binds strongly to the 16S ribosomal RNA.
In the C-terminal section; belongs to the dienelactone hydrolase family.
Belongs to the class-II pyridine nucleotide-disulfide oxidoreductase family.
Essential thiol-reducing enzyme that protects the cell from thiol-specific oxidizing stress. Plays a minor role in defense against oxidative and nitrosative stress. Is essential to establish and maintain infection in mice.
Essential, a deletion mutant cannot be isolated. TrxB depletion inhibits mycobacterial growth and causes lytic death of the cells. Depletion affects growth-essential processes, including sulfur and DNA metabolism. Partially depleted cells are highly susceptible to thiol-specific oxidizing stress, but not to peroxide and reactive nitrogen species. Depleted cells are highly susceptible to the cell wall biosynthesis inhibitors vancomycin and moenomycin. In vivo, depletion of TrxB results in clearance of M.tuberculosis during both the acute and chronic phases of infection.
Expressed following oxidative stress under control of SigH.
Required for the biosynthesis of sulfolipid-1 (SL-1), a major mycobacterial cell wall lipid (PubMed:17259623, PubMed:17592143, PubMed:22194604). Catalyzes the acylation of trehalose-2-sulfate by adding the palmitoyl group at the 2'-position to yield the intermediate trehalose-2-sulfate-2'-palmitate (SL659) (PubMed:17592143, PubMed:22194604).
Cells lacking this gene have no growth defect in media containing different nitrogen sources. Total glutamine synthetase (GS) activity in culture filtrates is markedly reduced in the mutant, although activity in cell-free extracts remains normal. Virulence is unaffected in both in vitro and in vivo model systems of infection.
Has four distinct domains: an N-terminal nucleotidyltransferase (NT) domain responsible for UTase activity, a central HD domain that encodes UR activity, and two C-terminal ACT domains that seem to have a role in glutamine sensing.
Modifies, by uridylylation and deuridylylation, the PII regulatory protein (GlnB), in response to the nitrogen status of the cell that GlnD senses through the glutamine level. Under low glutamine levels, catalyzes the conversion of the PII protein and UTP to PII-UMP and PPi, while under higher glutamine levels, GlnD hydrolyzes PII-UMP to PII and UMP (deuridylylation). Thus, controls uridylylation state and activity of the PII protein, and plays an important role in the regulation of nitrogen assimilation and metabolism (Probable).
Slightly up-regulated in a low ammonia medium.
Uridylyltransferase (UTase) activity is inhibited by glutamine, while glutamine activates uridylyl-removing (UR) activity.
Functions in inorganic phosphate uptake, is probably the main carrier for phosphate uptake, it is the most highly expressed of the 3 PstS proteins under phosphate starvation (PubMed:20933472). Binds phosphate; probably able to bind both H(2)PO(4)(-) and HPO(4)(2-) (PubMed:24615888). Part of the ABC transporter complex PstSACB involved in phosphate import (Probable). Probably plays a role in host phagosome maturation arrest (PubMed:20844580).
Grows normally in liquid culture, traffics into host (human and mouse) acidified compartments early after phagocytosis, suggesting it no longer arrests phagosome maturation as well as wild-type, impaired growth in mouse macrophages (PubMed:20844580). No growth phenotype in phosphate-rich medium (3.6 mM Pi), nor in restricted medium (Sauton), but in phosphate-free Sauton medium dies faster than wild-type when pre-exposed to complete starvation (PubMed:20933472).
Monomer (PubMed:24615888). The complex is composed of two ATP-binding proteins (PstB), two transmembrane proteins (PstC and PstA) and a solute-binding protein (PstS).
Transcription induced 6-fold by phosphate starvation, protein levels increase after 24 hours starvation (at protein level) (PubMed:20933472). Part of the pstS3-pstC2-pstA1 operon.
Catalyzes the transfer of the first rhamnosyl residue on p-hydroxybenzoic acid or phenolphthiocerol derivatives to form, after O-methylation at position 2 of the sugar unit, mono-O-methyl-glycosyl-p-hydroxybenzoic acid derivative (p-HBAD I) and 2-O-methyl-rhamnosyl-phenolphthiocerol dimycocerosate (also called mycoside B) during p-hydroxybenzoic acid derivatives (p-HBAD) and glycosylated phenolphthiocerol dimycocerosates (PGL) biosynthesis.
Disruption of the gene leads to significantly reduced bacterial growth in macrophages and in mice.
Esterase activity is significantly inhibited by the serine modifier phenylmethylsulfonyl fluoride (PMSF). Completely inhibited by diethyl pyrocarbonate.
Esterase that preferentially hydrolyzes short-chain fatty acids, particularly pNP-acetate (C2) and pNP-butyrate (C4). Has also weak activity with pNP-hexanoate (C6) and pNP-octanoate (C8). It can also hydrolyze short-chain tryglycerides such as triacetin and tributyrin (PubMed:31001637). Important for intracellular survival (PubMed:31001637).
Belongs to the AB hydrolase superfamily. HsaD family.
Catalyzes the hydrolysis of a carbon-carbon bond in 4,5: 9,10-diseco-3-hydroxy-5,9,17-trioxoandrosta-1(10),2-diene-4-oate (4,9-DSHA) to yield 9,17-dioxo-1,2,3,4,10,19-hexanorandrostan-5-oate (DOHNAA) and 2-hydroxy-hexa-2,4-dienoate (HHD). Is also able to catalyze the hydrolysis of 2-hydroxy-6-oxo-6-phenylhexa-2,4-dienoic acid (HOPDA) and the synthetic analog 8-(2-chlorophenyl)-2-hydroxy-5-methyl-6-oxoocta-2,4-dienoic acid (HOPODA).
Toxic component of a type II toxin-antitoxin (TA) system. Upon expression in M.smegmatis inhibits colony formation. Its toxic effect is neutralized by coexpression with cognate antitoxin Rv2654c.
Belongs to the succinate/malate CoA ligase beta subunit family.
Succinyl-CoA synthetase functions in the citric acid cycle (TCA), coupling the hydrolysis of succinyl-CoA to the synthesis of either ATP or GTP and thus represents the only step of substrate-level phosphorylation in the TCA. The beta subunit provides nucleotide specificity of the enzyme and binds the substrate succinate, while the binding sites for coenzyme A and phosphate are found in the alpha subunit.
Belongs to the arginine deiminase family.
A penicillin-binding domain is found between residues 420-820.
Cell wall formation. Synthesis of cross-linked peptidoglycan from the lipid intermediates. The enzyme has a penicillin-insensitive transglycosylase N-terminal domain (formation of linear glycan strands) and a penicillin-sensitive transpeptidase C-terminal domain (cross-linking of the peptide subunits) (By similarity). Has little peptidoglycan hydrolytic activity; however it inhibits the synergistic peptidoglycan hydrolysis of RipA plus RpfB.
In the C-terminal section; belongs to the transpeptidase family.
In the N-terminal section; belongs to the glycosyltransferase 51 family.
Interacts with RipA via its transpeptidase domain (residues 561-820).
Belongs to the GTP-binding SRP family. SRP54 subfamily.
Composed of three domains: the N-terminal N domain, which is responsible for interactions with the ribosome, the central G domain, which binds GTP, and the C-terminal M domain, which binds the RNA and the signal sequence of the RNC.
Involved in targeting and insertion of nascent membrane proteins into the cytoplasmic membrane. Binds to the hydrophobic signal sequence of the ribosome-nascent chain (RNC) as it emerges from the ribosomes. The SRP-RNC complex is then targeted to the cytoplasmic membrane where it interacts with the SRP receptor FtsY (By similarity). Most of the substrate proteins are involved in stress regulation, lipid metabolism, intermediary metabolism, and cell wall processes (PubMed:29361248). Shows GTPase activity (PubMed:22534010).
Part of the signal recognition particle protein translocation system, which is composed of SRP and FtsY (PubMed:29361248). SRP is a ribonucleoprotein composed of Ffh and a 4.5S RNA molecule (PubMed:22534010). Can interact with FtsY in the absence of 4.5S RNA (PubMed:29361248).
The SRP-FtsY complex formation results in mutual stimulation of their GTP hydrolysis activity.
Cell division protein that is part of the divisome complex and is recruited early to the Z-ring. Probably stimulates Z-ring formation, perhaps through the cross-linking of FtsZ protofilaments. Its function overlaps with FtsA.
Deletion results in increased susceptibility to isoniazid and accumulation of intracellular ethidium bromide.
Forms multimeric structures containing a central pore.
Participates in the development of tolerance to both isoniazid and ethambutol. May function through a MDR-pump like mechanism, although it does not appear to directly transport isoniazid from the cell.
A possible member of the dormancy regulon. Slightly induced in response to reduced oxygen tension (hypoxia) and by low levels of nitric oxide (NO). It is hoped that this regulon will give insight into the latent, or dormant phase of infection.
Upon expression in E.coli functions as a triacylglycerol synthase, making triacylglycerol (TG) from diolein and long-chain fatty acyl-CoA. Also functions as a wax synthase, incorporating palmityl alcohol into wax esters in the presence of palmitoyl-CoA.
Toxic component of a type II toxin-antitoxin (TA) system. An RNase. Its cognate antitoxin is VapB49 (By similarity).
Global transcriptional regulator that complexes with cAMP and binds to specific DNA promoter sites, causing DNA-bending, to regulate transcription. cAMP improves binding to specific DNA sequences, probably by altering protein conformation. The CRP regulon is predicted to contain about 115 genes. Some genes are activated by CRP (rpfA, whiB1) while others are repressed (fadD10). There are 2 CRP-binding sites in the promoter of whiB1, at low concentrations of CRP with or without cAMP transcription of whiB1 is enhanced via site CRP1, then repressed as site CRP2 is filled.
Grows more slowly in aerobic liquid culture and on plates, severely impaired growth in unactivated mouse bone marrow-derived macrophages and in infected mice.
Homodimer; in the absence of cAMP the DNA-binding domains are asymmetric in one structure; upon cAMP binding the dimer becomes symmetric, preparing it to bind DNA.
Carboxylase activity of the AccA3/AccD5 complex is stimulated by interaction with the epsilon subunit AccE5 (PubMed:16354663, PubMed:16385038). Activity of the AccA3/AccD6 complex is inhibited by interaction with AccE5 and by dimethyl itaconate, C75, haloxyfop, cerulenin, and 1,2-cyclohexanedione (PubMed:17114269).
Component of a biotin-dependent acyl-CoA carboxylase complex. This subunit catalyzes the ATP-dependent carboxylation of the biotin carried by the biotin carboxyl carrier (BCC) domain, resulting in the formation of carboxyl biotin (PubMed:16354663, PubMed:16385038, PubMed:17114269). When associated with the beta5 subunit AccD5, is involved in the carboxylation of acetyl-CoA and propionyl-CoA, with a preference for propionyl-CoA (PubMed:16354663, PubMed:16385038). When associated with the beta6 subunit AccD6, is involved in the carboxylation of acetyl-CoA and propionyl-CoA, with a preference for acetyl-CoA (PubMed:17114269). When associated with the beta4 subunit AccD4, the beta5 subunit AccD5 and the epsilon subunit AccE5, forms the LCC complex, which is involved in the carboxylation of long chain acyl-CoA (PubMed:16354663, PubMed:28222482). The LCC complex can use C16-C24 substrates, the highest specific activity is obtained with carboxy-C20-CoA (PubMed:28222482).
Homodimer (PubMed:28469974). The biotin-dependent acyl-CoA carboxylase complex is composed of AccA3, which contains the biotin carboxylase (BC) and biotin carboxyl carrier protein (BCCP) domains, and an AccD protein, which contains the carboxyl transferase (CT) domain (PubMed:16354663, PubMed:16385038, PubMed:17114269, PubMed:28222482). Can interact with AccD4, AccD5 and AccD6 (PubMed:16354663, PubMed:16385038, PubMed:17114269, PubMed:28222482). The AccA3/AccD5 complex forms a dodecamer, and can associate with the epsilon subunit AccE5 (Rv3280), which stimulates carboxylation by the complex (PubMed:16354663, PubMed:16385038). The AccA3/AccD6 complex forms a dodecamer. Interaction of AccA3/AccD6 with the epsilon subunit AccE5 (Rv3280) decreases carboxylation by the complex (PubMed:17114269). The long-chain acyl-CoA carboxylase (LCC) complex is composed of AccA3, AccD4, AccD5 and AccE5. The four subunits are essential for activity, but AccD5, together with AccE5, probably plays a structural role rather than a catalytic one (PubMed:28222482).
Catalyzes the formation of tuberculosinyl diphosphate from geranylgeranyl diphosphate (GGPP). It could also react with (14R/S)-14,15-oxidoGGPP to generate 3alpha- and 3beta-hydroxytuberculosinyl diphosphate.
Strongly inhibited by 15-aza-dihydrogeranylgeraniol and 5-isopropyl-N,N,N,2-tetramethyl-4-(piperidine-1-carbonyloxy)benzenaminium chloride (Amo-1618). Inhibited by GGPP concentrations higher than 50 uM.
Degradation of inorganic polyphosphates (polyP). Releases orthophosphate processively from the ends of the polyP chain. Prefers long-chain length polyphosphates as substrates (By similarity). Can also hydrolyze ATP and ADP substrates, but lacks GTPase activity. Cannot hydrolyze pppGpp to ppGpp (PubMed:22880033).
Involved in the biosynthesis of the arabinogalactan (AG) region of the mycolylarabinogalactan-peptidoglycan (mAGP) complex, an essential component of the mycobacterial cell wall. Catalyzes the transfer of arabinofuranosyl (Araf) residues from the sugar donor decaprenyl-phospho-arabinose (DPA) to the arabinan domain to form terminal beta-(1->2)-linked Araf residues, which marks the end point for AG arabinan biosynthesis before decoration with mycolic acids.
Belongs to the UPF0073 (Hly-III) family.
GTP-dependent RNA ligase that is involved in tRNA splicing and RNA repair. Joins RNA with 2',3'-cyclic-phosphate or 3'-phosphate ends to RNA with 5'-hydroxy ends.
Ligation proceeds through 3 nucleotidyl transfer steps, with 2',3'-cyclic phosphate termini being hydrolyzed to 3'-P termini in a step that precedes 3'-P activation with GMP. In the first nucleotidyl transfer step, RtcB reacts with GTP to form a covalent RtcB-histidine-GMP intermediate with release of PPi; in the second step, the GMP moiety is transferred to the RNA 3'-P; in the third step, the 5'-OH from the opposite RNA strand attacks the activated 3'-P to form a 3',5'-phosphodiester bond and release GMP.
Possibly the antitoxin component of a type II toxin-antitoxin (TA) system. Its cognate toxin is VapC36.
Catalyzes the condensation of (S)-aspartate-beta-semialdehyde [(S)-ASA] and pyruvate to 4-hydroxy-tetrahydrodipicolinate (HTPA).
Is insensitive to feedback inhibition by (S)-lysine.
Was originally thought to be a dihydrodipicolinate synthase (DHDPS), catalyzing the condensation of (S)-aspartate-beta-semialdehyde [(S)-ASA] and pyruvate to dihydrodipicolinate (DHDP). However, it was shown in E.coli that the product of the enzymatic reaction is not dihydrodipicolinate but in fact (4S)-4-hydroxy-2,3,4,5-tetrahydro-(2S)-dipicolinic acid (HTPA), and that the consecutive dehydration reaction leading to DHDP is not spontaneous but catalyzed by DapB.
Contains an N-terminal winged-helix-turn-helix (wHTH) DNA-binding domain and a C-terminal alpha helix, which is mainly involved in dimerization (PubMed:30266832). Binding of cadmium causes subtle conformational changes in all key metal-binding residues and conserved DNA-binding residues (PubMed:30266832).
May have transcription regulation and metal-detoxifying functions through which it may enhance intracellular survival of mycobacteria. Binds to its own promoter region and to the Rv1999c promoter region. It displays strong affinity for cadmium ions, but can also bind zinc, manganese and nickel. Expression increases the intracellular survival of recombinant M. smegmatis in murine macrophage cell line and increases its tolerance to cadmium ions.
Belongs to the IS21/IS1162 putative ATP-binding protein family.
Probable antitoxin component of a type II toxin-antitoxin (TA) system. Its putative cognate toxin is VapC37.
Catalyzes the conversion of L-glutamate to alpha-N-acetyl-L-glutamate. L-glutamine is a significantly better substrate compared to L-glutamate.
Cargo protein of a type 1 encapsulin nanocompartment possibly involved in protection against oxidative stress.
Cleaved by the mycobacterial serine protease Hip1 (PubMed:24830429). Hip1-dependent cleavage of multimeric GroEL2 results in release of cleaved monomeric GroEL2 into the extracellular milieu (PubMed:24830429).
Cleaved, monomeric GroEL2 is biologically relevant and significantly contributes to Hip1-mediated dampening of macrophage responses during M.tuberculosis (Mtb) infection (PubMed:24830429). Within macrophage, the cleaved form is able to detach from the bacterial surface and crosses the phagosomal membrane towards mitochondria organelles where it interacts with the host stress-70 protein (HSPA9 or mortalin) and blocks macrophage apoptosis, which promotes Mtb survival in the hostile macrophage environment (PubMed:28288970). The cleaved form is poorly immunostimulatory and is unable to promote DC maturation and antigen presentation. Proteolytic cleavage of GroEL2 allows Mtb to prevent optimal DC-T-cell cross talk during infection (PubMed:29133346).
Conditions that promote oligomer formation increase the ATPase activity (PubMed:22834700). Chaperone activity is fundamentally influenced by the interdomain communication, even if oligomerization and the ability to recognize the substrates are retained (PubMed:26553853).
Each subunit is composed of an apical domain, an intermediate domain and an equatorial domain (PubMed:26553853). The two hinges that connect the equatorial and intermediate domains (EI hinge) and the apical and intermediate domains (AI hinge) play a significant role in the chaperonin activity (PubMed:26553853). The N-terminus is important in determining the oligomerization status (PubMed:22834700).
Forms a cylinder of 14 subunits composed of two heptameric rings stacked back-to-back (Probable). Also exists as lower oligomers, including monomeric, dimeric, tetrameric and heptameric forms (PubMed:15327959, PubMed:22834700, PubMed:15547284, PubMed:21802426, PubMed:24830429). Forms monomers under standard conditions but oligomerizes in the presence of high concentrations of ammonium salts and either ATP or ADP (PubMed:22834700). Interacts with the co-chaperonin GroES (By similarity). Interacts with the serine protease Hip1 (PubMed:24830429). Interacts with host CD43 (PubMed:20633027).
Induced in response to heat shock (45 degrees Celsius), pH 10, hyperosmolarity and starvation (PubMed:18227175). Repressed by WhiB1, activated by Cmr (PubMed:22464736).
Mediates association of bacteria with macrophages (PubMed:19470749, PubMed:20633027). Acts as an adhesin that binds CD43 on the host macrophage surface (PubMed:20633027). The full-length protein elicits robust pro-inflammatory responses from dendritic cells (DCs) and promotes DC maturation and antigen presentation to T-cells. DCs exposed to full-length GroEL2 induce strong antigen-specific gamma interferon (IFN-gamma), interleukin-2 (IL-2), and IL-17A cytokine responses from CD4(+) T-cells (PubMed:29133346). Recombinant extracellular protein activates expression of NF-kappa-B in immortalized human dermal endothelial cells in a TLR4-dependent, TLR2-independent manner. Activation occurs via MYD88-dependent and -independent pathways and requires TIRAP, TRIF, TRAM and MD-2 (some experiments done in mouse cells, mice do not usually catch tuberculosis) (PubMed:15809303).
Monomer (PubMed:24830429). Hip1-dependent proteolytic cleavage converts multimeric GroEL2 to a monomeric form (PubMed:24830429). Interacts with host mitochondrial mortalin (PubMed:28288970).
Purified 65 kDa antigen can elicit a strong delayed-type hypersensitivity reaction in experimental animals infected with M.tuberculosis. This protein is one of the major immunoreactive proteins of the mycobacteria (PubMed:3029018). It contains epitopes that are common to various species of mycobacteria (PubMed:7699930).
Together with its co-chaperonin GroES, plays an essential role in assisting protein folding. The GroEL-GroES system forms a nano-cage that allows encapsulation of the non-native substrate proteins and provides a physical environment optimized to promote and accelerate protein folding (By similarity). Prevents aggregation of substrate proteins and promotes their refolding (PubMed:15327959, PubMed:18227175, PubMed:22834700). In vitro, activity may be independent of the presence or absence of the GroES co-chaperonin or ATP (PubMed:15327959). Shows weak ATPase activity (PubMed:15327959, PubMed:21802426).
When coexpressed at high levels of expression with the co-cheperonin GroES, can complement the E.coli groEL mutant.
Belongs to the class-I aminoacyl-tRNA synthetase family. MshC subfamily.
Catalyzes the ATP-dependent condensation of GlcN-Ins and L-cysteine to form L-Cys-GlcN-Ins.
Binds to its own promoter and probably autoregulates its expression.
DNA-binding activity is increased in the presence of L-arabinose and inhibited by the small molecule I-OMe-Tyrphostin.
Deletion mutant is compromised for survival upon exposure to oxidative stress and infection in guinea pigs (PubMed:36507689). Deletion of the gene does not affect colony morphology, growth pattern, biofilm formation and sensitivity to isoniazid, rifampicin, levofloxacin and ethambutol (PubMed:36507689). About 200 genes are differentially expressed in the mutant strain in comparison to the wild-type strain (PubMed:36507689).
The N-terminal domain binds DNA and the C-terminal region plays a pivotal role in dimer formation.
Transcriptional regulator required for survival in oxidative stress and for establishing infection in host tissues (PubMed:36507689). Regulates the expression of a subset of genes involved in oxidative stress adaptation and virulence, enabling the bacteria to adapt and persist in host tissues (PubMed:36507689).
Antitoxin component of a possible type II toxin-antitoxin (TA) system. The cognate toxin is VapC34.
Slightly induced by phosphate starvation, part of the pstB3-pstS2-pstC1-pstA2 operon.
Could also transport the mycolic acid-containing lipids monomeromycolyl diacylglycerol (MMDAG) and mycolate ester wax (WE) to the bacterial surface.
Inactivation increases mouse survival. Mutants show growth patterns similar to the wild-type strain during the active growth phase, but they are attenuated for survival in the chronic stages of infection.
Part of a heme-iron acquisition system. Receives heme from the heme-binding protein Rv0203 and transports it into the mycobacterial cell. Contributes to virulence.
Represses a number of genes involved in the response to DNA damage (SOS response), including recA and lexA. Has been shown to bind to the 14 bp palindromic sequence 5'-CGAACNNNNGTTCG-3'. In the presence of single-stranded DNA, RecA interacts with LexA causing an autocatalytic cleavage which disrupts the DNA-binding part of LexA, leading to derepression of the SOS regulon and eventually DNA repair.
An RNase that has 5'-3' exonuclease and possible endonuclease activity. Involved in maturation of rRNA and in some organisms also mRNA maturation and/or decay (By similarity). Has both beta-lactamase and RNase activity, but the physiological relevance of the beta-lactamase activity, i.e. whether it confers antibiotic resistance, has not been shown (PubMed:21568871).
Belongs to the metallo-beta-lactamase superfamily. RNA-metabolizing metallo-beta-lactamase-like family. Bacterial RNase J subfamily.
Binds up to 2 Zn(2+) ions per subunit. It is not clear if Zn(2+) or Mg(2+) is physiologically important.
Both beta-lactamase and RNase activities are inhibited by chaperone DnaJ2.
Homodimer, may be a subunit of the RNA degradosome (By similarity). Interacts with chaperone DnaJ2.
Assembles into a homotetramer formed by a dimer of dimers (By similarity). Interacts with DNA-binding protein HU (hupB) (PubMed:35521527) (Probable).
Binds 2 Zn(2+) ions per homotetramer. Zinc ions are bound between subunits.
Endoribonuclease that plays a central role in RNA processing and decay. Plays a major role in pre-16S rRNA maturation, probably generating the mature 5'-end, and a minor role in pre-5S and pre-23S rRNA maturation. Probably also processes tRNA (By similarity). RNase E and HupB jointly contribute to cellular adaptation to changing growth conditions and survival during antibiotic treatment and in the host (PubMed:35521527).
Essential, it cannot be deleted. Depletion experiments show a decrease in growth rate, decreased processing of furA-katG operon mRNA and decreased expression levels of many transcripts, accounting for the metabolic decrease. Cells are more sensitive to isoniazid (INH). Murine macrophage infection is impaired.
Monomer. Binds 30S ribosomal subunits, but not 50S ribosomal subunits or 70S ribosomes.
One of several proteins that assist in the late maturation steps of the functional core of the 30S ribosomal subunit. Associates with free 30S ribosomal subunits (but not with 30S subunits that are part of 70S ribosomes or polysomes). Required for efficient processing of 16S rRNA. May interact with the 5'-terminal helix region of 16S rRNA.
Disruption mutant is sensitive to oxidative stress and exposure to toxic transition metals (PubMed:35745538). In a human monocyte (THP-1) cell infection model, mutant shows reduced uptake and intracellular survival and increased expression of pro-inflammatory molecules, including IL-1 beta, IP-10, and MIP-1 alpha (PubMed:35745538). In a guinea pig model of pulmonary infection, mutant displays growth attenuation in the lungs (PubMed:35745538). Knockdown of the gene leads to increased sensitivity to peroxides such as cumene hydroperoxide and hydrogen peroxide (PubMed:27818650).
Interaction with PknI increases the peroxidase activity by several folds.
Interacts with the serine/threonine-protein kinase PknI (PubMed:26546727, PubMed:27818650). The PknI-Rv2159c interaction is mediated through phosphorylation independent physical interaction (PubMed:27818650).
Involved in protection against oxidative stresses (PubMed:27818650, PubMed:35745538). May play a significant role in maintaining the cellular homeostasis during stress and virulence of M.tuberculosis (PubMed:27818650, PubMed:35745538). In vitro, catalyzes the decomposition of cumene hydroperoxide (CHP) to acetophenone (PubMed:27818650).
Though the Rv2159c protein is a peroxidase, it does not form disulfide bridges between the two catalytic site cysteines.
Belongs to the monovalent cation:proton antiporter 1 (CPA1) transporter (TC 2.A.36) family.
Catalyzes the phosphorylation of glucose using polyphosphate or ATP as the phosphoryl donor (PubMed:8617763). Polyphosphate, rather than ATP, seems to be the major phosphate donor for the enzyme in M.tuberculosis (By similarity).
The poly(P)- and ATP-dependent glucokinase reactions both follow an ordered Bi-Bi mechanism, with glucose being the second substrate to bind and glucose 6-phosphate being released last. The mechanism of poly(P) utilization is not strictly processive and is most likely nonprocessive, where there is dissociation of poly(P) prior to complete utilization.
Alternative, nonproton pumping NADH:quinone oxidoreductase that delivers electrons to the respiratory chain by oxidation of NADH and reduction of quinones.
Deletion of the gene does not affect virulence in mice (PubMed:29382761). Deletion of the gene does not induce any major redox perturbation in M.tuberculosis (PubMed:29382761). Non-essential, can be deleted without causing any adverse effects in vitro (PubMed:25128581). The ndh-ndhA double knockout could not be obtained, suggesting that at least one type II NADH dehydrogenase is required for M.tuberculosis growth (PubMed:29382761).
Belongs to the 'phage' integrase family.
Integrase is necessary for integration of the phage into the host genome by site-specific recombination. In conjunction with excisionase, integrase is also necessary for excision of the prophage from the host genome (By similarity).
Deletion of the gene triggers a stress response under physiological conditions that results in the up-regulation of a number of gene products, including sigE, and a subset that are regulated by SigE (PubMed:20061478). Deletion mutant shows attenuated virulence in a mouse model of infection (PubMed:18479146).
Each subunit is composed of an N-terminal cytoplasmic domain, a transmembrane domain, a catalytic serine protease domain, and a single C-terminal PDZ domain (PubMed:18479146, PubMed:21445360). The protease domains form the central core of the trimer and the PDZ domains extend to the periphery (PubMed:18479146). PDZ domain is required for protease activity (PubMed:20061478).
Homotrimer (PubMed:18479146). Interacts with numerous proteins, including the 35 kDa antigen PspA (PubMed:21445360).
Probably regulates its own activity by autocleavage, which removes the PDZ domain (PubMed:18479146). Inhibited by the serine protease inhibitor diisopropylfluorophosphate (DFP) (PubMed:20061478). Inhibited by fluoroquinolone such as ciprofloxacin, moxifloxacin and ofloxacin and their analogs (PubMed:23440996).
Required for virulence (PubMed:18479146). Acts both as a protease, which degrades and/or refolds damaged substrate targets, and as a chaperone (PubMed:18479146, PubMed:20061478). Plays an important role in the stress response network mediated through the two-component regulatory system MprAB and SigE signaling networks (PubMed:20061478). May utilize its PDZ domain to recognize and process misfolded proteins at the cell membrane, leading to activation of the MprAB and SigE signaling pathways and subsequent establishment of a positive feedback loop that facilitates bacterial adaptation (PubMed:20061478). Interacts with and potentially cleaves several proteins, including the 35 kDa antigen PspA (PubMed:21445360). Proteolytic cleavage of PspA may help to maintain cell envelope homeostasis in Mycobacterium and regulate specific stress response pathways during periods of extracytoplasmic stress (PubMed:21445360). In vitro, exhibits proteolytic activity against the artificial substrate beta-casein (PubMed:18479146, PubMed:20061478).
Transcribed from three distinct promoters, one that is located in the intergenic region between mprB and pepD, one that overlaps with the translational start site for mprA, and one upstream of mprA that resides in a predicted SigE-regulated promoter region.
Deletion mutants fail to secrete EsxA and EsxB, and are as attenuated as ESX-1 mutants in virulence assays (PubMed:16030141). Bacteria no longer translocate from the phagolysosome to the cytosol of host (human) cells; bacteria replicate in phagolysosome (PubMed:17604718). Host (human) cells no longer produce cytokine IP-10 (CXCL10) upon infection, but continue to produce IL-1 beta (IL1B) (PubMed:26048138).
Has been postulated to mediate virulence through maintenance of mycobacterial cell surface integrity (PubMed:20585630), but studies of detergent sensitivity of various strains and mutants indicate that EspACD and ESX-1 deficiency does not impact the cell surface integrity (PubMed:24078612).
Homodimer; disulfide-linked (PubMed:20585630). An artificial EsxB-EsxA heterodimer interacts with EspA (PubMed:19854905).
Maintenance of wild-type levels of EspA requires both EspC and EspD.
Required for secretion of EsxA (ESAT-6) and EsxB (CFP-10) and for virulence. Involved in translocation of bacteria from the host (human) phagolysosome to the host cytoplasm (PubMed:17604718).
Catalyzes the decarboxylative condensation of pimeloyl-[acyl-carrier protein] and L-alanine to produce 8-amino-7-oxononanoate (AON), [acyl-carrier protein], and carbon dioxide.
In the C-terminal section; belongs to the class-II pyridoxal-phosphate-dependent aminotransferase family. BioF subfamily.
Catalyzes the activation of medium/long-chain fatty acids as acyl-coenzyme A (acyl-CoA), which are then transferred to the multifunctional polyketide synthase (PKS) type III for further chain extension (PubMed:15042094, PubMed:15984864, PubMed:19182784). Also involved in the degradation of cholesterol via the degradation of the side chains of C-24 branched-chain sterols. Catalyzes the ATP-dependent CoA thioesterification of the sterol 3-oxocholest-4-en-26-oate to yield 3-oxocholest-4-en-26-oyl-CoA. It can also use 3beta-hydroxy-5-cholesten-26-oate (PubMed:24244004).
Catalyzes the deamidation of nicotinamide (NAM) into nicotinate (PubMed:18201201). Likely functions in the cyclical salvage pathway for production of NAD from nicotinamide (By similarity).
Is inhibited by Cu(2+), Zn(2+) and Fe(3+).
Is involved in the activation of the first-line antituberculous drug pyrazinamide (PZA) by converting it into the active form, pyrazinoic acid.
Most pyrazinamide-resistant clinical M.tuberculosis isolates contain mutations in the pncA gene, causing lack or reduction of PZAase activity.
PncA contains Mn(2+) and Fe(2+) in a molecular ratio of 1:1. PncA has only one metal center. It is believed that PncA binds iron in the natural state, although both metals can support enzymatic activity.
Homotrimer (PubMed:19234303). The two-component system 3-ketosteroid-9-alpha-monooxygenase is composed of an oxygenase component KshA and a reductase component KshB (PubMed:21987574).
Belongs to the glutaminase PdxT/SNO family.
Catalyzes the hydrolysis of glutamine to glutamate and ammonia as part of the biosynthesis of pyridoxal 5'-phosphate. The resulting ammonia molecule is channeled to the active site of PdxS.
In the presence of PdxS, forms a dodecamer of heterodimers. Only shows activity in the heterodimer.
Antitoxin component of a type II toxin-antitoxin (TA) system. Upon expression in M.smegmatis neutralizes the effect of cognate toxin Rv0299.
Catalyzes the hydrolysis of 10-formyltetrahydrofolate (formyl-FH4) to formate and tetrahydrofolate (FH4).
Toxic component of a type II toxin-antitoxin (TA) system. An RNase. The cognate antitoxin is VapB7 (By similarity).
Belongs to the phosphoglycerate mutase family. BPG-dependent PGAM subfamily.
Catalyzes the interconversion of 2-phosphoglycerate and 3-phosphoglycerate.
Belongs to the IspD/TarI cytidylyltransferase family. IspD subfamily.
Catalyzes the formation of 4-diphosphocytidyl-2-C-methyl-D-erythritol from CTP and 2-C-methyl-D-erythritol 4-phosphate (MEP).
Belongs to the thioester dehydratase family.
Heterodimer composed of ChsH1 and ChsH2. Two heterodimers combine to form an heterotetramer (PubMed:25203216). The complex interacts with Ltp2 via the DUF35 C-terminal region of ChsH2 (PubMed:29109182, PubMed:31568719). The ChsH1-ChsH2-Ltp2 protein complex is composed of two protomers that form a heterohexameric structure through the Ltp2 dimerization interface (PubMed:31568719).
In the absence of the Ltp2 aldolase, ChsH1/ChsH2 can hydrate only about 30% of the 3-OPDC-CoA substrate. Complete turnover requires the presence of Ltp2.
Involved in cholesterol side chain degradation (PubMed:22045806, PubMed:25203216). Catalyzes the hydration of 3-oxo-4,17-pregnadiene-20-carboxyl-CoA (3-OPDC-CoA) to form 17-hydroxy-3-oxo-4-pregnene-20-carboxyl-CoA (17-HOPC-CoA), in the modified beta-oxidation pathway for cholesterol side chain degradation (PubMed:25203216, PubMed:31568719). Can also use octenoyl-CoA and decenoyl-CoA, with lower efficiency (PubMed:25203216).
The DUF35 C-terminal region is not required for hydratase activity (PubMed:25203216). This region is involved in interaction with LtpA and is required for optimal LtpA aldolase activity (PubMed:29109182).
Belongs to the glycosyltransferase 4 family. MraY subfamily.
Catalyzes the initial step of the lipid cycle reactions in the biosynthesis of the cell wall peptidoglycan: transfers peptidoglycan precursor phospho-MurNAc-pentapeptide from UDP-MurNAc-pentapeptide onto the lipid carrier undecaprenyl phosphate, yielding undecaprenyl-pyrophosphoryl-MurNAc-pentapeptide, known as lipid I.
Positively regulated by alternative sigma factor SigD, probably directly.
A double darT-darG deletion shows no change in growth in culture, upon infection of mice or upon exposure to a variety of stresses (PubMed:32634279). Another group finds the double knockout gives a competitive advantage over wild-type cells in liquid culture growth experiments (PubMed:34408320).
Belongs to the DarT ADP-ribosyltransferase family.
Forms a complex with cognate antitoxin DarG; this complex neutralizes the toxic effect of DarT.
The NAD(+)-binding element stabilizes the ADP-ribosylating turn-turn (ARTT) loop which confers substrate specificity; both domains contribute to ssDNA-binding.
Toxic component of a hybrid type II/IV toxin-antitoxin (TA) system. Its toxic effect is neutralized by cognate antitoxin DarG (PubMed:27939941). ADP-ribosylates ssDNA, preferentially in the motif TTTW. Uncontrolled expression of DarT leads to ADP-ribosylation of the origin of chromosomal replication DNA in cells (in vitro the most heavily modified motifs are TTTT/A in the OriC lower strand) and growth arrest (PubMed:34408320). Is very toxic to E.coli, it cannot be expressed in E.coli (PubMed:27939941). Experiments in situ in which antitoxin DarG levels are depleted (similar to overexpression of DarT) lead to cell death; expression of wild-type DarG protein from M.tuberculosis or T.aquaticus restores growth. Cells with decreased levels of DarG are more sensitive to bedaquilline (targets respiration), DNA-damaging drugs (mitomycin C, netropsin) and transcription-targeted drugs (rifabutin and rifampicin). When DarG is depleted, a DNA-damage response is induced and mutability is increased, suggesting ADP-ribosylation of DNA is the toxic effect (PubMed:32634279).
Converts molybdopterin precursor Z into molybdopterin. This requires the incorporation of two sulfur atoms into precursor Z to generate a dithiolene group. The sulfur is provided by MoaD (By similarity).
Heterotetramer of 2 MoaD subunits and 2 MoaE subunits. Also stable as homodimer. The enzyme changes between these two forms during catalysis (By similarity).
Inactivation leads to the attenuation of the recombinant strain, in spite of strong EsxA (ESAT-6) secretion and generation of specific T-cell responses. Mutant has lower amounts of PPE68.
Interacts specifically with ESX-1-dependent PE/PPE proteins (By similarity). Interacts with PPE68 (PubMed:17433643).
Belongs to the CRISPR-associated protein Cas6/Cse3/CasE family.
CRISPR (clustered regularly interspaced short palindromic repeat) is an adaptive immune system that provides protection against mobile genetic elements (viruses, transposable elements and conjugative plasmids). CRISPR clusters contain sequences complementary to antecedent mobile elements (spacers) and target invading nucleic acids. CRISPR clusters are transcribed and processed into CRISPR RNA (crRNA). The type III-A Csm effector complex binds crRNA and acts as a crRNA-guided RNase, DNase and cyclic oligoadenylate synthase; binding of target RNA cognate to the crRNA is required for all activities (Probable). This CRISPR-Cas system protects bacteria against transformation with plasmids containing DNA homologous to its spacer regions (PubMed:29979631).
Ca(2+) and Mn(2+) stimulate processing of pre-crRNA.
Deletion of this gene alone blocks maturation of pre-crRNA (PubMed:29979631). Deletion of the entire CRISPR-Cas locus (cas6 to cas2, Rv2824c to Rv2816c) decreases resistance to plasmids encoding spacer elements about 6-fold (PubMed:29979631).
Pre-crRNA processing is inhibited by EDTA.
Processes pre-crRNA into individual crRNA units; accurate cleavage of pre-crRNA depends on a 3' stem-loop and the sequence of the bases in the stem. The mature crRNA is unusual for type III-A systems as it does not undergo 3' processing after Cas6 cleavage. Mature crRNA is about 71 nucleotides (nt long) with an 8 nt 5' handle and 28 nt repeat with a 10 nt stem-loop at the 3' end.
Belongs to the TRAFAC class translation factor GTPase superfamily. Classic translation factor GTPase family. EF-Tu/EF-1A subfamily.
This protein promotes the GTP-dependent binding of aminoacyl-tRNA to the A-site of ribosomes during protein biosynthesis.
Belongs to the FAD-dependent oxidoreductase 2 family. 3-oxosteroid dehydrogenase subfamily.
Deletion mutant is unable to use cholesterol as a source of carbon and energy, and has a limited ability to multiply in resting human macrophages following infection, reflecting a failure of the mutant to inhibit the TLR2-dependent bactericidal activity of resting macrophages.
Involved in the degradation of cholesterol (PubMed:18031290, PubMed:21987574). Catalyzes the elimination of the C-1 and C-2 hydrogen atoms of the A-ring from the polycyclic ring structure of 3-ketosteroids (PubMed:18031290). Has a clear preference for 3-ketosteroids with a saturated A-ring, displaying highest activity on 5alpha-AD (5alpha-androstane-3,17-dione) and 5alpha-T (5alpha-testosterone, also known as 17beta-hydroxy-5alpha-androstane-3-one) (PubMed:18031290). Is also involved in the formation of 3-keto-1,4-diene-steroid from 3-keto-4-ene-steroid (PubMed:21987574). Catalyzes the conversion of 3-oxo-23,24-bisnorchol-4-en-22-oyl-coenzyme A thioester (4-BNC-CoA) to 3-oxo-23,24-bisnorchola-1,4-dien-22-oyl-coenzyme A thioester (1,4-BNC-CoA) (PubMed:21987574).
Mice immunized with recombinant bacteria carrying a DNA vaccine encoding HtpX were significantly protected from challenge with M.tuberculosis, indicating this might be a good vaccine candidate.
Belongs to the inorganic phosphate transporter (PiT) (TC 2.A.20) family.
Belongs to the universal ribosomal protein uL1 family.
Binds directly to 23S rRNA. The L1 stalk is quite mobile in the ribosome, and is involved in E site tRNA release.
Protein L1 is also a translational repressor protein, it controls the translation of the L11 operon by binding to its mRNA.
Belongs to the thioesterase PaaI family.
Esterase that can hydrolyze short-chain esters with the carbon chain containing 2 to 12 carbon atoms. In vitro, pNP-butyrate is the preferred substrate.
Inhibited by ionic detergents SDS (anions) and CTAB (cationic). Strongly inhibited by Zn(2+).
Involved in the biosynthesis of methyl-branched alkylpyrones (PubMed:23615910). Pks11 catalyzes the extension of medium- and long-chain aliphatic acyl-CoA substrates by using malonyl-CoA and methylmalonyl-CoA as extender molecules to synthesize polyketide products (PubMed:12941968, PubMed:23615910). Palmitoyl-CoA or a similar long chain fatty acid derivative is the likely substrate in vivo (PubMed:23615910).
The expression is almost identical during the mid-exponential and extended stationary phase.
Couples transcription and DNA repair by recognizing RNA polymerase (RNAP) stalled at DNA lesions. Mediates ATP-dependent release of RNAP and its truncated transcript from the DNA, and recruitment of nucleotide excision repair machinery to the damaged site.
In the C-terminal section; belongs to the helicase family. RecG subfamily.
In the N-terminal section; belongs to the UvrB family.
Interacts with the RNA polymerase subunit beta (RpoB).
Belongs to the class-I aminoacyl-tRNA synthetase family. TyrS type 1 subfamily.
Catalyzes the attachment of tyrosine to tRNA(Tyr) in a two-step reaction: tyrosine is first activated by ATP to form Tyr-AMP and then transferred to the acceptor end of tRNA(Tyr).
Belongs to the mer family. Phthiodiolone/phenolphthiodiolone dimycocerosates ketoreductase subfamily.
Catalyzes the reduction of the keto moiety of phthiodiolone dimycocerosates (DIM B) and glycosylated phenolphthiodiolone dimycocerosates to form the intermediate compounds phthiotriol and glycosylated phenolphthiotriol dimycocerosates during phthiocerol dimycocerosates (DIM A) and glycosylated phenolphthiocerol dimycocerosates (PGL) biosynthesis.
Belongs to the isocitrate and isopropylmalate dehydrogenases family. LeuB type 2 subfamily.
Catalyzes the oxidation of 3-carboxy-2-hydroxy-4-methylpentanoate (3-isopropylmalate) to 3-carboxy-4-methyl-2-oxopentanoate. The product decarboxylates to 4-methyl-2 oxopentanoate.
Catalyzes the interconversion of L-alanine and D-alanine. D-alanine plays a key role in peptidoglycan cross-linking.
Inhibited by the antituberculous drug D-cycloserine (DCS), which is a structural analog of D-alanine.
Cells lacking this gene do not produce mycolipanoic acids, mycolipenic (phthienoic) or mycolipodienoic acids, the major constituents of polyacyltrehaloses, but synthesize all of the other classes of lipids. The absence of the major acyl chains that anchor the surface-exposed acyltrehaloses causes a novel growth morphology.
Polyketide synthase involved in the biosynthesis of methyl-branched fatty acids such as mycolipanoic, mycolipenic (phthienoic) and mycolipodienoic acids required for the synthesis of a major class of polyacylated trehaloses. Catalyzes the elongation of CoA esters of long-chain fatty acids by incorporation of three methylmalonyl (but not malonyl) residues, to form trimethyl-branched fatty-acids.
The previously assigned stop codon (TAA) of pks3 (Rv1180) is found to be a Tyr codon (TAC), and with this change, pks3 and pks4 become a single open reading frame designated msl3 (PubMed:12207710). Large scale proteomics studies identify protein sequence that extends N-terminal to the initially annotated start site of Rv1181, more evidence that a single protein is translated from this locus.
Glutamine synthetase (GS) is an unusual multitasking protein that functions as an enzyme, a transcription coregulator, and a chaperone in ammonium assimilation and in the regulation of genes involved in nitrogen metabolism. It catalyzes the ATP-dependent biosynthesis of glutamine from glutamate and ammonia. Feedback-inhibited GlnA also interacts with and regulates the activity of the transcriptional regulator TnrA. During nitrogen limitation, TnrA is in its DNA-binding active state and turns on the transcription of genes required for nitrogen assimilation. Under conditions of nitrogen excess, feedback-inhibited GlnA forms a stable complex with TnrA, which inhibits its DNA-binding activity. In contrast, feedback-inhibited GlnA acts as a chaperone to stabilize the DNA-binding activity of GlnR, which represses the transcription of nitrogen assimilation genes.
Oligomer of 12 subunits arranged in the form of two hexagons. In its feedback-inhibited form, interacts with TnrA in order to block its DNA-binding activity.
Belongs to the class-V pyridoxal-phosphate-dependent aminotransferase family. NifS/IscS subfamily.
Catalyzes the removal of elemental sulfur from cysteine to produce alanine (Probable). Participates in the biosynthesis of metalloclusters by providing the inorganic sulfur required for Fe-S core formation. One acceptor is Whib3, on which this enzyme assembles a 4Fe-4S cluster. It can use both L-cysteine and L-selenocysteine as substrates.
Cells lacking this gene are microaerophilic and hypersensitive to oxidative stress. Moreover, they show impaired Fe-S cluster-dependent enzyme activity.
Homodimer. It interacts with Whib3, Acn, SdhB, FdhF and SirA, other S acceptors.
IscU is absent from the mycobacterial ISC operon.
Toxic component of a type II toxin-antitoxin (TA) system. An RNase. Its cognate antitoxin is VapB42 (By similarity).
Belongs to the 2-oxoadipate dioxygenase/decarboxylase family.
Catalyzes the decarboxylation and hydroxylation of 2-oxoadipate (2OA) to form D-2-hydroxyglutarate (D-2-HGA).
Forms a homooligomeric, either hexameric or heptameric, ring-like structure which stacks co-axially with the proteasomal alpha-rings.
Interacts with the core proteasome alpha-subunit (PrcA) through its C-terminal hydrophobic-tyrosine-X motif (HbYX motif). Interaction of Bpa with the proteasome stimulates proteasomal peptidase and casein degradation activity, which suggests Bpa could play a role in the removal of non-native or damaged proteins by influencing the conformation of the proteasome complex upon interaction. Can inhibit degradation of Pup-tagged substrates in vitro by competing with Mpa for association with the proteasome.
Abolishes the production of phthiocerol dimycocerosate (DIM) on the cell envelope.
Could catalyze the elongation of hydroxybenzoyl-CoA as well as elongation of the aliphatic precursor involved in the synthesis of phthiocerol dimycocerosate (DIM).
May bind long-chain fatty acids, such as palmitate, and may play a role in lipid transport or fatty acid metabolism.
Diadenylate cyclase activity is inhibited by the interaction with RadA.
Has also diadenylate cyclase activity, catalyzing the condensation of 2 ATP molecules into cyclic di-AMP (c-di-AMP). c-di-AMP likely acts as a signaling molecule that may couple DNA integrity with a cellular process. To a lesser extent, can also use ADP as substrate to produce c-di-AMP. Does not convert GTP to c-di-GMP. Also exhibits residual ATPase and ADPase activities in vitro.
Magnesium. Can also use Mn(2+), and, to a lesser extent, Co(2+). Cannot use Ni(2+), Ca(2+) and Fe(2+).
Participates in a DNA-damage check-point. DisA forms globular foci that rapidly scan along the chromosomes searching for lesions.
The N-terminal catalytic domain contributes to tetramerization and the C-terminal domain provides additional dimerization. Both domains are required for full catalytic activity. The C-terminal domain may play a role in stabilizing the active conformation.
Belongs to the heat shock protein 90 family.
Molecular chaperone. Has ATPase activity.
Involved in cell division and chromosome segregation.
Contains an N-terminal nucleotide-binding domain (NBD) and a C-terminal regulatory domain (RD).
Monomer. Homodimerizes in the presence of ATP (PubMed:32092417). The complex is composed of two ATP-binding proteins (SugC), two transmembrane proteins (SugA and SugB) and a solute-binding protein (LpqY) (PubMed:21118978).
Part of the ABC transporter complex LpqY-SugA-SugB-SugC, which is highly specific for uptake of trehalose. Involved in the recycling of extracellular trehalose released from trehalose-containing molecules synthesized by M.tuberculosis. Trehalose uptake is essential for virulence (PubMed:21118978). Responsible for energy coupling to the transport system (PubMed:32092417).
Involved in the biosynthesis of methoxymycolic acid. It catalyzes the O-methylation of the hydroxy group of the hydroxymycolate to form a methyl ether.
Efflux activity is inhibited by carbonyl cyanide m-chlorophenylhydrazone (CCCP) and verapamil.
Induced in the presence of ethambutol or isoniazid.
Involved in resistance to ethambutol and isoniazid.
May have a role in host tissue attachment, whereby ligands may include the serum protein fibronectin and small sugars.
Converts cobyric acid to cobinamide by the addition of aminopropanol on the F carboxylic group.
Belongs to the CobB/CobQ family. GatD subfamily.
The lipid II isoglutaminyl synthase complex catalyzes the formation of alpha-D-isoglutamine in the cell wall lipid II stem peptide. The GatD subunit catalyzes the hydrolysis of glutamine to glutamate and ammonia. The resulting ammonia molecule is channeled to the active site of MurT.
Carboxylase activity of the AccA3/AccD5 complex is stimulated by interaction with AccE5.
Component of a biotin-dependent acyl-CoA carboxylase complex. This subunit transfers the CO2 from carboxybiotin to the CoA ester substrate (PubMed:16354663, PubMed:16385038, PubMed:28222482). When associated with the alpha3 subunit AccA3, is involved in the carboxylation of acetyl-CoA and propionyl-CoA, with a preference for propionyl-CoA (PubMed:16354663, PubMed:16385038, PubMed:28222482). Is also required for the activity of the long-chain acyl-CoA carboxylase (LCC) complex (PubMed:28222482).
Forms homohexamers (PubMed:16492739, PubMed:17157300). The biotin-dependent acyl-CoA carboxylase complex is composed of AccA3, which contains the biotin carboxylase (BC) and biotin carboxyl carrier protein (BCCP) domains, and AccD5, which contains the carboxyl transferase (CT) domain (PubMed:16354663, PubMed:16385038). The AccA3/AccD5 complex forms a dodecamer, and can associate with the epsilon subunit AccE5 (Rv3280), which stimulates carboxylation by the complex (PubMed:16354663, PubMed:16385038). Is also part of the long-chain acyl-CoA carboxylase (LCC) complex, which is composed of AccA3, AccD4, AccD5 and AccE5. The four subunits are essential for activity, but AccD5, together with AccE5, probably plays a structural role rather than a catalytic one (PubMed:28222482).
Required for the formation of a threonylcarbamoyl group on adenosine at position 37 (t(6)A37) in tRNAs that read codons beginning with adenine. Is involved in the transfer of the threonylcarbamoyl moiety of threonylcarbamoyl-AMP (TC-AMP) to the N6 group of A37, together with TsaE and TsaB. TsaD likely plays a direct catalytic role in this reaction.
Binds 1 [2Fe-2S] cluster per subunit. This cluster acts as a Lewis acid cofactor.
Functions in the biosynthesis of branched-chain amino acids. Catalyzes the dehydration of (2R,3R)-2,3-dihydroxy-3-methylpentanoate (2,3-dihydroxy-3-methylvalerate) into 2-oxo-3-methylpentanoate (2-oxo-3-methylvalerate) and of (2R)-2,3-dihydroxy-3-methylbutanoate (2,3-dihydroxyisovalerate) into 2-oxo-3-methylbutanoate (2-oxoisovalerate), the penultimate precursor to L-isoleucine and L-valine, respectively. Is specific for the (R) isomer of 2,3-dihydroxy-3-methylbutanoate, with no catalytic activity against the (S) isomer.
Is competitively inhibited by aspterric acid in vitro, which is thus a potential new lead compound for the design of novel anti-TB drugs.
Belongs to the universal ribosomal protein uL29 family.
Belongs to the methyltransferase superfamily. EgtD family.
Catalyzes the SAM-dependent triple methylation of the alpha-amino group of histidine to form hercynine, a step in the biosynthesis pathway of ergothioneine.
Induced at acidic pH. Negatively autoregulated.
Mutant displays altered colony morphology and cell wall structure, reduced contents and altered composition of mycolic acids along with the accumulation of saturated C24 and C26 fatty acids, and enhanced susceptibility to antibiotics, detergents and acidic pH. Also impairs ability to survive in activated macrophages, but not in resting macrophages.
Phosphorylated by PknK. Phosphorylation increases affinity for the mymA promoter.
Regulates the expression of the mymA operon (Rv3083-Rv3089).
Does not seem to have metal cofactors; no metal ions were found via inductively coupled plasma atomic emission spectroscopy, and the residues that bind metal in homologs are not conserved.
It is not clear if Met-1 or Met-10 is the start codon.
Probably specifically methylates an O atom of its substrate.
Toxic component of a type II toxin-antitoxin (TA) system. An RNase (By similarity). Upon expression in M.smegmatis inhibits colony formation. Its toxic effect is neutralized by coexpression with cognate antitoxin VapB41.
Enhances mycobacterial intracellular survival, probably via altering host macrophage cytokine profiling and attenuating the cell apoptosis (PubMed:27987050). Could be required for host endothelial-cell invasion (PubMed:16586367).
Expression in Mycobacterium smegmatis, a nonpathogenic species naturally deficient in PE_PGRS genes, results in alteration of the production of host cytokines, including IL-6, IL-1beta, IL-10 and IL-12p40, as well as enhanced survival within macrophages largely via attenuating the apoptosis of macrophages.
Binds 2 Mg(2+) ions per subunit. Mn(2+) and Fe(2+) ions also support activity.
Catalyzes the condensation of isopentenyl pyrophosphate (IPP) with geranyl diphosphate (GPP) to yield (2E,6E)-farnesyl diphosphate (E,E-FPP). May be used for squalene and possibly sterol biosynthesis.
Dithiothreitol increases the enzyme activity by 2.5-fold.
This enzyme is unique in that it is the first reported eubacterial E,E-FPP synthase that does not have four amino acids between the aspartate residues of the first aspartate-rich motif (FARM) and that has the features of the archaeal chain length-determining (CLD) region.
Belongs to the aspartate-semialdehyde dehydrogenase family.
Catalyzes the NADPH-dependent formation of L-aspartate-semialdehyde (L-ASA) by the reductive dephosphorylation of L-aspartyl-4-phosphate (PubMed:15752328). Is essential for the growth and pathogenicity of M.tuberculosis, and for the generation of the bacterial cell wall (PubMed:26437401).
Deletion of this gene inhibits bacterial growth. The mutant cells lose an average of 77.8% of their cell wall materials, exhibit altered morphology, and have a reduced capacity to infect macrophages.
No difference in growth in culture up to 120 days. Increased sensitivity to 10 and 20 mM H(2)O(2), no difference in response to growth at 53 degrees Celsius, pH 4.0, 10% ethanol or 0.05% sodium dodecyl sulfate (surface stress). No detectable difference in spleen or lungs of infected BALB/c mice during 15 weeks growth.
Sigma factors are initiation factors that promote the attachment of RNA polymerase to specific initiation sites and are then released. Extracytoplasmic function (ECF) sigma factors are held in an inactive form by an anti-sigma factor until released, although no anti-sigma factor is known for this protein (By similarity). Regulates the promoter of SigI, may not be autoregulated.
Undetectable expression in log phase, 18-fold induced by 30 days, decreasing slightly after (at protein level). Up-regulated 2.4-fold 7 days after infection of human macrophages.
Binds 1 Mg(2+) ion per subunit (PubMed:19237750, PubMed:19121323, Ref.7, Ref.8, PubMed:23485416). Can also use Co(2+) ion to a lesser extent (Ref.8) (PubMed:23485416).
Catalyzes the last two sequential reactions in the de novo biosynthetic pathway for UDP-N-acetylglucosamine (UDP-GlcNAc). The C-terminal domain catalyzes the transfer of acetyl group from acetyl coenzyme A to glucosamine-1-phosphate (GlcN-1-P) to produce N-acetylglucosamine-1-phosphate (GlcNAc-1-P), which is converted into UDP-GlcNAc by the transfer of uridine 5-monophosphate (from uridine 5-triphosphate), a reaction catalyzed by the N-terminal domain.
In the C-terminal section; belongs to the transferase hexapeptide repeat family.
In the N-terminal section; belongs to the N-acetylglucosamine-1-phosphate uridyltransferase family.
Phosphorylated at the C-terminal domain by PknB. The phosphorylation is required for acetyltransferase activity, but does not affect uridyltransferase activity.
Member of the three-protein two-component system HK1/HK2/TcrA.
Catalyzes the dephosphorylation of inositol 1-phosphate (I-1-P) to yield free myo-inositol, a key metabolite in mycobacteria.
Catalyzes the synthesis of GMP from XMP.
Inhibited by tetrahydrolipstatin (THL), a specific lipase inhibitor, and by derivatives of THL (PubMed:19169353, PubMed:20656688, PubMed:21384024). Inhibited by high concentrations of paraoxon (PubMed:19225166). Also inhibited by a Furan-based urea derivative, 1-(3,5-difluorophenyl)-3-(furan-2-ylmethyl)urea (PubMed:31741730).
Shows esterase and phospholipase A activities (PubMed:19169353, PubMed:19225166, PubMed:20656688, PubMed:29247008). May be involved in cell wall biosynthesis and/or maintenance (PubMed:19169353, PubMed:19225166, PubMed:20656688). Can hydrolyze various substrates, including the p-nitrophenol-linked aliphatic esters pNP-laurate (C12), pNP-myristate (C14), pNP-palmitate (C16), pNP-stearate (C18), pNP-butyrate (C4), phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, 4-methylumbelliferyl heptanoate and palmitic acid and arachidonic acid containing phospholipids (PubMed:19169353, PubMed:19225166, PubMed:20656688). Does not exhibit cutinase activity (PubMed:19225166).
The essential nature of the cell wall protein Culp6 makes it a promising target for drug development.
Both the PE domain and the non-PGRS C-terminal domain possess independent cell wall localization signals. The PGRS domain is responsible for polar localization of PE_PGRS30 (PubMed:24530527, PubMed:25390359). PE and PGRS domains are necessary for the cytokine-modulating function (PubMed:27129781). The non-PGRS C-terminal domain is not exposed on the surface and is not required for full virulence in vivo (PubMed:22050772, PubMed:25390359).
Deletion mutant is attenuated in vivo during murine tuberculosis, specifically during the chronic steps of infection. On day 28 post infection, shows a slight reduction of the bacterial burden. On day 70, shows a strong reduction of the bacterial burden. Mice infected with the mutant show smaller, non-confluent tubercules. Mutant shows impaired ability to survive and multiply within murine macrophages. It is unable to inhibit phago-lysosome fusion in THP-1 cells.
Infection of human THP-1 macrophages with M.smegmatis expressing PE_PGRS30 results in reduced production of IL-12, TNF-alpha and IL-6, as compared to infection with vector control M.smegmatis. No differential effects are observed on bacterial persistence inside macrophages or on macrophage mortality upon infection (PubMed:27129781). However, expression of this gene in M.smegmatis is sufficient to enhance the ability to persist intracellularly and induce murine J774 macrophages death (PubMed:22050772). Differential response of the human and murine macrophages could be due to cell-specific processes (Probable).
Mediates suppression of pro-inflammatory immune response in macrophages via modulation of host cytokine response (PubMed:27129781). Required for full virulence. Involved in inhibition of phago-lysosome fusion (PubMed:22050772).
Ferredoxin that is the redox partner of cytochrome CYP51, a sterol 14alpha-demethylase encoded by an adjacent gene.
There is a positive driving force (of about 95 mV) for electron transfer from NADPH through the redox chain (FprA and Fdx) to CYP51. Thus, the overall process is thermodynamically favorable.
Belongs to the mannose-6-phosphate isomerase type 1 family.
Methylates precorrin-2 at the C-20 position to produce precorrin-3A.
Belongs to the transaldolase family. Type 2 subfamily.
Transaldolase is important for the balance of metabolites in the pentose-phosphate pathway.
Putative antitoxin component of a possible type II toxin-antitoxin (TA) system. The cognate toxin is VapC23.
Putative antitoxin component of a possible type II toxin-antitoxin (TA) system. The cognate toxin is VapC17.
Belongs to the class I-like SAM-binding methyltransferase superfamily. rRNA adenine N(6)-methyltransferase family. RsmA subfamily.
Specifically dimethylates two adjacent adenosines (A1518 and A1519) in the loop of a conserved hairpin near the 3'-end of 16S rRNA in the 30S particle. May play a critical role in biogenesis of 30S subunits.
Catalyzes the F420H(2)-dependent reduction of biliverdin-IXalpha at C10 position, leading to bilirubin-IXalpha, a potent antioxidant. As biliverdin-IXalpha is produced in high amounts in macrophages infected with M.tuberculosis, its reduction by Rv2074 may play a role in protecting mycobacteria against oxidative stress, aiding the persistence of M.tuberculosis infection.
Belongs to the universal ribosomal protein uS14 family. Zinc-binding uS14 subfamily.
Cells lacking this gene do not show a detectable glutamine synthetase activity and is auxotrophic for L-glutamine. This mutant is also attenuated for intracellular growth in human THP-1 macrophages and avirulent in the highly susceptible guinea pig model of pulmonary tuberculosis.
Involved in nitrogen metabolism via ammonium assimilation. Catalyzes the ATP-dependent biosynthesis of glutamine from glutamate and ammonia (PubMed:7937767, PubMed:12819079). Also able to use GTP (PubMed:7937767). D-glutamate is a poor substrate, and DL-glutamate shows about 50% of the standard specific activity (PubMed:7937767). Also plays a key role in controlling the ammonia levels within infected host cells and so contributes to the pathogens capacity to inhibit phagosome acidification and phagosome-lysosome fusion (PubMed:7937767, PubMed:12819079). Involved in cell wall biosynthesis via the production of the major component poly-L-glutamine (PLG) (PubMed:7937767, PubMed:10618433). PLG synthesis in the cell wall occurs only in nitrogen limiting conditions and on the contrary high nitrogen conditions inhibit PLG synthesis (Probable).
Oligomer of 12 subunits arranged in the form of two hexagons.
Repressed by phosphorothioate modified antisense oligodeoxyribonucleotides (PS-ODNs), which acts against the mRNA of glutamine synthetase.
When cellular nitrogen levels are high, the C-terminal adenylyl transferase (AT) of GlnE inhibits GlnA by covalent transfer of an adenylyl group from ATP to Tyr-406 (PubMed:15037612). Conversely, when nitrogen levels are low, the N-terminal adenylyl removase (AR) of GlnE activates GlnA by removing the adenylyl group by phosphorolysis (PubMed:15037612). The fully adenylated enzyme complex is inactive (Probable). Also inhibited by the diketopurine analog 1-[(3,4-dichlorophenyl)methyl]-3,7-dimethyl-8-morpholin-4-yl-purine-2,6-dione, EDTA, and by L-methionine-SR-sulfoximine (MSO) (PubMed:7937767, PubMed:12496196, PubMed:19695264).
Cells lacking this gene lead to irreversible loss of viability.
Involved in the biosynthesis of the mycolylarabinogalactan-peptidoglycan (mAGP) complex, an essential component of the mycobacterial cell wall. Catalyzes the transfer of the rhamnosyl moiety from dTDP-rhamnosyl (dTDP-Rha) onto the decaprenyl-pyrophosphoryl-GlcNAc (C50-PP-GlcNAc), yielding rhamnosyl-decaprenyl-pyrophosphoryl-GlcNAc (Rha-C50-PP-GlcNAc).
Catalyzes the reversible adenylation of nicotinate mononucleotide (NaMN) to nicotinic acid adenine dinucleotide (NaAD).
Component of the Rv3654c-Rv3660c operon that is highly up-regulated during M.tuberculosis infection of macrophages.
Effector protein that participates in the suppression of macrophage apoptosis by blocking the extrinsic pathway. Interferes with caspase-8 activation and binds to the host E3 ubiquitin-protein ligase RNF213, whose fusion partners have anti-apoptotic function.
Interacts with human E3 ubiquitin-protein ligase RNF213.
Heptamer of 7 subunits arranged in a domed ring (Ref.11, PubMed:12837792). 2 rings join in their base to form a spherical cage-like structure; both heptamers and tetradecamers exist in solution (PubMed:12837792). Interacts with RimI (PubMed:27353550).
Induced in response to heat shock (45 degrees Celsius), pH 4, pH 10, ethanol, H(2)O(2), hyperosmolarity and starvation (PubMed:18227175).
Together with the chaperonin GroEL, plays an essential role in assisting protein folding. The GroEL-GroES system forms a nano-cage that allows encapsulation of the non-native substrate proteins and provides a physical environment optimized to promote and accelerate protein folding. GroES binds to the apical surface of the GroEL ring, thereby capping the opening of the GroEL channel.
Mg(2+). Mn(2+) can substitute for Mg(2+) for PAP phosphatase and IMPase activities, but is less efficient (50%-60% of the activity observed with Mg(2+)).
PAP phosphatase and IMPase activities are inhibited by Li(+). To a lesser extent, PAP hydrolysis is also inhibited by Na(+) and K(+), with IC50 values of 150 and 250 mM, respectively, so much higher than IC50 with Li(+) (0.5 mM). Exhibits about 50% residual IMPase activity at 5 mM Li(+) and about 10% at 30 mM Li(+). Na(+) and K(+) have no significant effect on IMPase activity between 0 and 200 mM.
Phosphatase with a broad specificity. Its primary physiological function is to dephosphorylate 3'-phosphoadenosine 5'-phosphate (PAP) and 3'-phosphoadenosine 5'-phosphosulfate (PAPS). Thus, plays a role in mycobacterial sulfur metabolism, since it can serve as a key regulator of the sulfate assimilation pathway by controlling the pools of PAP and PAPS in the cell. To a lesser extent, is also able to hydrolyze inositol 1-phosphate (I-1-P), fructose 1,6-bisphosphate (FBP) (to fructose 6-phosphate (F-6-P)) and AMP in vitro, but this might not be significant in vivo. Glucose-1-phosphate (G-1-P), p-nitrophenyl phosphate (pNPP), and beta-glycerol phosphate (beta-GP) are also good substrates, compared to I-1-P. With much lower efficiency, can also hydrolyze inositol 2-phosphate (I-2-P) and glucose-6-phosphate (G-6-P) in vitro, but not fructose-6-phosphate (F-6-P) and trehalose-6-phosphate (T-6-P).
Strains lacking this gene show normal growth, do not require exogenous inositol for growth, and show no differences in levels of phosphatidylinosotol mannosides (PIMs), lipomannan (LM), lipoarabinomannan (LAM) or mycothiol (in the absence of exogenous inositol).
Probable toxic component of a type II toxin-antitoxin (TA) system. An RNase. Upon expression in M.smegmatis inhibits colony formation. The putative cognate antitoxin is VapB37.
Deletion of the gene leads to cytoplasmic Mn(2+) accumulation and a decrease in secreted Mn(2+)-bound proteins (PubMed:23482562). Mutant is hypersensitive to zinc and oxidative stress (PubMed:21925112, PubMed:23482562). It exhibits an impaired growth in human macrophages (PubMed:21925112).
High affinity, slow turnover Mn(2+) transporting ATPase, which is required for virulence. Controls the Mn(2+) cytoplasmic quota and is involved in the uploading of Mn(2+) into secreted metalloproteins (PubMed:23482562). Required for tolerance to Zn(2+) and oxidative stress (PubMed:23482562). Plays a crucial role in the ability to resist zinc poisoning in human macrophages (PubMed:21925112). Shows a preference for Mn(2+), but Zn(2+), Co(2+) and Cu(2+) can act as alternative substrates although at slower turnover rates (PubMed:23482562).
Induced by zinc and during infection of human macrophages (PubMed:21925112, PubMed:23482562). Transcriptionally regulated by iron (PubMed:9514635).
Cell wall hydrolase that modulates cell division process (PubMed:22094151, PubMed:16942606). Probably acts by modulating FtsZ ring assembly (PubMed:16942606, PubMed:22094151). Murein hydrolase activity is targeted to sites of nascent peptidoglycan (PG) synthesis (PubMed:16942606). Overproduction compromises midcell localization of FtsZ rings, but has no effect on the intracellular levels of FtsZ (PubMed:16942606).
Interacts with the cell division proteins FtsI and FtsQ.
Mutants have stable FtsZ rings (PubMed:22094151). Deletion mutant is more sensitive to DNA damage (PubMed:16942606). Deletion of the gene causes a 10% increase in average cell length (PubMed:16942606). Loss of the gene does not influence the growth of M.tuberculosis in mice lungs and spleen (PubMed:22094151).
Up-regulated in the presence of nitric oxide, reactive oxygen intermediates, mitomycin C, cephalexin or during growth in macrophages (PubMed:16942606). Expression is strongly DNA damage inducible independently of RecA (PubMed:16885473). Down-regulated under hypoxic growth conditions (PubMed:16942606).
Belongs to the class-I aminoacyl-tRNA synthetase family. MetG type 2B subfamily.
Is required not only for elongation of protein synthesis but also for the initiation of all mRNA translation through initiator tRNA(fMet) aminoacylation.
Lacks the Zn(2+) binding motif and the C-terminal dimerization appendix that are found in MetRSs from several organisms including E.coli MetRS.
Activity is competitively inhibited by substituted ribitylpurinetrione compounds such as 3-(1,3,7,9-tetrahydro-9-D-ribityl-2,6,8-trioxopurin-7-yl)propane 1-phosphate, with inhibition constants in the 4-5 nM range.
Catalyzes the formation of 6,7-dimethyl-8-ribityllumazine by condensation of 5-amino-6-(D-ribitylamino)uracil with 3,4-dihydroxy-2-butanone 4-phosphate. This is the penultimate step in the biosynthesis of riboflavin.
Probably part of the ABC transporter complex DrrABC involved in doxorubicin resistance. Probably responsible for the translocation of the substrate across the membrane.
Disruption of only this gene, or of the lrpG-Rv1410c operon leads to increased levels of many triacylglyceride alkylforms; up to 100-fold increase depending on the exact form (PubMed:26751071). Cells grow more slowly on lipid carbon sources, conditions thought to mimic infection, and grow more slowly in infected mice (PubMed:26751071). Disruption of the preceeding gene lprG leads to loss of expression of Rv1410c due to polar effects; in infected BALB/c mice 1.5 and 2.5 log decrease in bacterial load 15 and 35 days after infection (PubMed:14998516). The single lprG mutant increases sensitivity to malachite green, sodium dodecyl sulfate (SDS), isoniazid, ethambutal and ethidium bromide, alters the permeability of the cell wall; both genes are required to fully restore the phenotypes (PubMed:21762531). Single lprG deletion mutant (probably without Rv1410c) has decreased surface-exposed glycolipid lipoarabinomannan (LAM), although cellular LAM content is normal (PubMed:25232742, PubMed:25356793). It also forms smaller colonies on agar (PubMed:25232742). Loss of surface LAM has several consequences; bacteria enter mouse macrophages with reduced efficiency and block mouse macrophage phagosome-lysosome fusion less efficiently than wild-type (PubMed:25232742). Reduced efficiency of mouse macrophage phagosome-lysosome fusion was seen in another study (PubMed:25356793). C57BL/6 mice infected with mutant bacteria have 10-fold less bacterial burden after 10 days and about 2700-fold less burden after 70 days; attenuation of mutant is not rescued in macrophages or mice impaired for reactive oxygen or nitrogen generation (disruption of Ncf1 or iNOS) (PubMed:25232742, PubMed:26751071).
In association with lipoprotein LprG probably transports triacylglycerides (TAG) across the inner cell membrane into the periplasm; TAG probably regulates lipid metabolism and growth regulation (PubMed:26751071). Confers resistance to ethidium bromide, possibly acting as an efflux pump, requires LprG lipoprotein for normal function (PubMed:18156250). With LprG maintains cell wall permeability (PubMed:21762531). Probably required with LprG for normal surface localization of LAM (PubMed:25232742, PubMed:25356793). Overexpression of LprG and Rv1410c leads to increased levels of TAG in the culture medium (PubMed:26751071).
Inhibited by reserpine (PubMed:18156250).
Belongs to the cation transport ATPase (P-type) (TC 3.A.3) family. Type IA subfamily.
Part of the high-affinity ATP-driven potassium transport (or Kdp) system, which catalyzes the hydrolysis of ATP coupled with the electrogenic transport of potassium into the cytoplasm. This subunit is responsible for energy coupling to the transport system and for the release of the potassium ions to the cytoplasm.
Autophosphorylated at serine and threonine residues.
Dimerization of the C-terminal extracellular sensor domain activates kinase autophosphorylation activity.
Expression decreases during infection of human macrophages.
Mutants show increased growth within macrophages and a hypervirulence phenotype in severe combined immunodeficiency mice.
Plays an important role in slowing down the growth of mycobacteria within the infected host (PubMed:19341393). Activates the peroxidase activity of Rv2159c in a phosphorylation independent manner during oxidative stress conditions and thereby maintains the cellular homeostasis (PubMed:27818650).
Probably functions as a dimer in the regulation of M.tuberculosis growth (PubMed:28712808). In the absence of stimuli, exists in a monomer-dimer equilibrium: a monomer form with no activity and a domain-swapped dimer form with a basic level of autophosphorylation activity (PubMed:28712808). The presence of stimuli results in a shift in the monomer-dimer equilibrium, leading to the formation of more dimeric PknI (PubMed:28712808). Specifically interacts with two peroxidase proteins, Rv2159c and Rv0148 (PubMed:26546727, PubMed:27818650). The PknI-Rv2159c interaction is mediated through phosphorylation independent physical interaction (PubMed:27818650).
Several structural motifs known to be critical for the activity of eukaryotic-like Ser/Thr protein kinases (ePKs) are severely degraded in PknI (PubMed:28054744). No kinase activity was detected by Lisa et al. for the catalytic domain of PknI, against different substrates and in various experimental conditions, suggesting that PknI may rely on unconventional mechanism(s) for kinase activity and/or it could play alternative role(s) in mycobacterial signaling (PubMed:28054744).
Antitoxin component of a type II toxin-antitoxin (TA) system.
Forms a complex with cognate toxin MazF1.
An anti-sigma factor for extracytoplasmic function (ECF) sigma factor SigK. ECF sigma factors are held in an inactive form by an anti-sigma factor until released by regulated intramembrane proteolysis (RIP). RIP occurs when an extracytoplasmic signal triggers a concerted proteolytic cascade to transmit information and elicit cellular responses. The membrane-spanning regulatory substrate protein is first cut extracytoplasmically (site-1 protease, S1P), then within the membrane itself (site-2 protease, S2P, Rip1), while cytoplasmic proteases finish degrading the regulatory protein, liberating the sigma factor.
Belongs to the anti-sigma-K factor family.
Interacts with ECF RNA polymerase sigma factor SigK; this inhibits the interaction of SigK with the RNA polymerase catalytic core and leads to a decreased expression of SigK-regulated genes, such as mpt70 and mpt83.
The cytosolic domain interacts with sigma factor SigK.
Possibly the antitoxin component of a type II toxin-antitoxin (TA) system. Its cognate toxin is VapC24.
Cells lacking both glpX and gpm2 grow as well as wild-type on glucose, but are unable to grow on any of the gluconeogenic carbon sources tested (glycerol, acetate and butyrate); the growth defect on gluconeogenic carbon sources is fully complemented by restoring expression of either GlpX or Gpm2. This double mutant lacks detectable FBPase activity and accumulates FBP. It is also severely attenuated in a mouse model of infection, as it fails to replicate in mouse lungs during the first 10 days of infection and begins to die thereafter.
In contrast to classical FBPases, is resistant to inhibition by lithium.
Phosphatase with a broad specificity. Can dephosphorylate a variety of substrates including phosphorylated sugars like fructose-6-phosphate (F6P) (PubMed:16672613). Is able to function in vivo as a fructose-1,6-bisphosphatase (FBPase) and to maintain gluconeogenesis when the classical FBPase GlpX is absent (PubMed:26258286). Shows negligible phosphoglycerate mutase activity (PubMed:16672613). Has no phosphatase activity against 3-phosphoglycerate, 2,3-bisphosphoglycerate, or hydrophobic substrates such as alpha-napthyl phosphate (PubMed:16672613).
Acetylates and succinylates nucleoid-associated, DNA-binding protein HupB.
A nucleoid-associated protein (NAP) required for septum formation and normal cell division as well as for DNA segregation. Binds about 135 sites across the chromosome, most of which are genes involved in virulence; most DNA-binding sites are immediately upstream of transcription start sites. When mIHF is depleted most of the genes are down-regulated (PubMed:30242166). Binds supercoiled and linear dsDNA in a concentration-dependent manner, probably non-sequence specifically. Binding compacts DNA, protecting it from degradation. Initial binding to supercoiled DNA opens it fully, followed by bending and compaction. Bends and thus compacts linear DNA (PubMed:23922883). Binds DNA via 2 sites, forms left-handed loops on linear DNA; at low concentrations unwinds larger cosmids (42.6 kb) then collapses and condenses DNA as protein levels rise. Forms mostly left-handed loops on condensing cosmid DNA (PubMed:31846718).
Belongs to the actinobacterial IHF (aIHF) family.
Essential, it cannot be deleted. Depletion of mIHF is bactericidal, and compromises DNA, RNA and protein synthesis. Cells depleted of mIHF are about 2.3-fold longer than wild-type, have no septa and only 1 nucleoid. Regulation of many genes is altered (both up- and down-regulation occurs).
Expressed at all stage of growth (at protein level).
Forms a globular protein with 5 short alpha-helies and an extended N-terminus.
Homodimer in solution (Probable). Binds DNA as a monomer (By similarity).
Was identified as a novel immunogenic protein with the potential to reduce the severity of M.bovis infection when used alone as a subunit vaccine.
Responsible for the release of ribosomes from messenger RNA at the termination of protein biosynthesis. May increase the efficiency of translation by recycling ribosomes from one round of translation to another.
The Rv2743c-Rv2742c double mutation reduces intracellular ATP levels under surface-stress conditions to less than 60% of wild-type levels.
Binds 1 pyruvoyl group covalently per subunit.
Catalyzes the pyruvoyl-dependent decarboxylation of aspartate to produce beta-alanine.
Heterooctamer of four alpha and four beta subunits.
Is synthesized initially as an inactive proenzyme, which is activated by self-cleavage at a specific serine bond to produce a beta-subunit with a hydroxyl group at its C-terminus and an alpha-subunit with a pyruvoyl group at its N-terminus. Cleavage is not necessary for tetramerization upon expression in E.coli; protein expressed in E.coli is fully process in vitro after 48 hours at 37 degrees Celsius (PubMed:12182836).
Overexpression of wild-type protein confers resistance to pyrazinoic acid (POA), the active form of the anti-tuberculosis prodrug pyrazinamide (PZA).
Pantothenate, pantetheine and beta-alanine containing compounds (all part of the panthothenate/coenzyme A biosynthetic pathway) antagonize PZA and POA antitubercular activity. However cultivation of the double panD and panC mutant with low levels of pantetheine (an intermediate between pantothenate and coenzyme A, at pH 5.8) restores sensitivity to PZA, suggesting PanD is not the PZA target.
Simultaneous disruption of panD and panC gives a mutant unable to grow in the absence of panothenate. The double mutant has a highly attenuated disease response in BALB/c and SCID mice; immunocompromised BALB/c SCID mice survive on average 36 weeks as opposed to 5 weeks for mice infected with wild-type bacteria, while immunocompetent BALB/c mice survive indefinitely. In wild-type mice bacteria grow for 3 weeks then undergo a steady decline, bacteria persist over 8 months in SCID mice (PubMed:12219086). The double mutant is sensitive to PZA but not POA in liquid culture, beta-alanine but not pantothenate antagonize the effect of PZA at pH 5.8 (PubMed:25246400).
Subcutaneous immunization with the double panD and panC bacterial disruption mutant protects mice for over a year against subsequent virulent M.tuberculosis (strain Erdman) infections; mice show mild lung inflammation and fibrosis despite a chronic bacterila infection. This is a promising attenuated vaccine strain.
Disruption does not attenuate growth in macrophages.
Phosphorylates the FHA domains of the ABC transporter Rv1747, the heat-shock protein GroEL 1, and Rv0020c. May play a role in the regulation of glucose transport, cell growth and septum formation.
Interacts with the Mce1 and Mce4 accessory subunits Rv0199/OmamA, Rv0177/Mam1C and Rv3492c/Mam4B.
Mutant is unable to utilize both fatty acids and cholesterol during infection in macrophages.
Required for the import of both fatty acids and cholesterol during growth in macrophages and in axenic culture. Facilitates the uptake of these lipids by stabilizing protein subunits of the Mce1 and Mce4 multi-subunit transporters, which transport fatty acids and cholesterol, respectively. Required for full virulence in vivo.
Increased susceptibility to detergent and heat shock, slighty decreased resistance to oxidative stress. Poor growth in both human and mouse macrophage-derived cell lines. Attenuated infection in both SCID and BALB/c mice. 13-fold decreased transcription of sigB, no change in its own transcript in culture. The sigE mutant induced the up-regulation of human and mouse macrophage gene expression, which correlated with an increased innate immune response.
Interacts transiently with the RNA polymerase catalytic core formed by RpoA, RpoB, RpoC and RpoZ (2 alpha, 1 beta, 1 beta' and 1 omega subunit) to form the RNA polymerase holoenzyme that can initiate transcription. Interacts (via sigma-70 factor domain 4) with cognate anti-sigma-E factor RseA under reducing conditions, which stops the sigma factor from functioning. Inhibition is specific; RsaH and RsaL (anti-sigma-H and -L factors) do not inhibit SigE.
Produced following oxidative stress and heat shock. Able to interact with RseA. Shown by mutagenesis of the start codon and subsequent loss of translationally fused LacZ.
Produced following oxidative stress and heat shock. Shown by mutagenesis of the start codon and subsequent loss of translationally fused LacZ.
Sigma factors are initiation factors that promote the attachment of RNA polymerase to specific initiation sites and are then released. Extracytoplasmic function (ECF) sigma factors are held in an inactive form by an anti-sigma factor until released. Responds to heat shock and surface stress (detergent exposure). When combined with isolated core RNA polymerase from M.smegmatis is able to guide initiation from the sigB promoter. Required for full expression of sigB, and for sigB induction after detergent exposure but not after heat shock. Controls a regulon of about 38 genes in culture (PubMed:11489128) and about 16 genes during macrophage infection (PubMed:18657035), most of which have decreased expression in a disruption mutant. Probably down regulates the host immune response to mycobacterial infection.
Unlike many sigma factors not directly autoregulated. Expressed from 3 promoters. P1 is 55 nucleotides upstream of the major start codon, used during normal growth, repressed by surface stress, P2 is at the start codon, under control of MprAB and is induced following surface stress and alkaline pH leading to a leader-less RNA, while P3 is 63 nucleotides downstream of the major start codon, transcribed from a SigH-responsive promoter under conditions of oxidative stress and heat shock. Expressed in exponential phase; further induced by detergent (6-fold) and heat shock (3-fold, 45 degrees Celsius) under control of SigH. Positively regulated by MprAB, as is induction by detergent. 6-fold induced by starvation, not known by which promoter.
Forms a complex with cognate antitoxin MazE7.
Toxic component of a type II toxin-antitoxin (TA) system. Upon expression in E.coli and M.smegmatis inhibits cell growth and colony formation. Its toxic effect is neutralized by coexpression with cognate antitoxin MazE7 (PubMed:19016878, PubMed:20011113). Probably an endoribonuclease (By similarity).
90% of activity is inhibited by nickel, zinc and calcium ions. Magnesium, cobalt, copper and manganese ions inhibit between 50 and 80% of activity.
Belongs to the neutral ceramidase family.
Catalyzes the cleavage of the N-acyl linkage of the ceramides (Cers) to yield sphingosine (Sph) and free fatty acid. Also catalyzes the synthesis of Cers from Sph and fatty acid. Cers containning C6-C24 fatty acids are well hydrolyzed, and Cers with mono unsaturated fatty acids are much more hydrolyzed than those with saturated fatty acids.
Beta-D-galactopyranosidase that specifically recognizes the beta-glycosidic bonds formed with beta-D-galactopyranose (beta-D-Gal) or N-acetylgalactosamine (beta-D-GalNAc) (PubMed:33584576). May target the galactoside linkages in the exopolysaccharide component of the mycobacterial extracellular polymeric substance (EPS) and help dispersal of Mtb bacteria from a deteriorating biofilm (PubMed:33584576).
Beta-galactosidase activity is activated by Mg(2+) and significantly inhibited by Ca(2+), Cd(2+), Fe(2+), Ni(2+), Cu(2+) and Zn(2+) (PubMed:33584576). Inhibited by EDTA (PubMed:33584576).
Expression in M.smegmatis, which lacks an ortholog of the protein, changes its colony morphology, cell wall permeability and sensitivity to the cell wall perturbing agent SDS (PubMed:33584576). It also reduces the ability to form biofilms and pellicles, and to autoagglutinate (PubMed:33584576).
Expression is probably maintained throughout planktonic growth at a certain basal level, down-regulated during biofilm growth and promptly up-regulated when dispersal from the biofilm is imminent.
The knock-down strain shows significantly lower biofilm dispersion compared to the wild type.
It is uncertain whether Met-1 or another residue is the initiator.
Antitoxin component of a type II toxin-antitoxin (TA) system. Upon expression in M.smegmatis neutralizes the effect of cognate toxin MazF5.
Forms a complex with cognate toxin MazF5.
Belongs to the acyltransferase PapA5 family.
Catalyzes diesterification of phthiocerol, phthiodiolone, and phenolphthiocerol with mycocerosic acids, the final step in the phthiocerol, phthiodiolone and phenolphthiocerol dimycocerosate esters (PDIM) synthesis. Can directly transfer the mycocerosate bound to the mycocerosic acid synthase (mas) onto the substrate alcohols. Is also able to catalyze acyl transfer using various nucleophiles as acceptors and several acyl-CoA thioesters as donors in vitro; preference is observed for saturated medium chain alcohols and long chain acyl-CoA thioesters.
Consists of two structural domains that are related to each other.
Monomer. Interacts directly with the acyl carrier protein (ACP) domain of the mycocerosic acid synthase (mas) protein. Interacts with FhaB.
Phosphorylated by PknB at Thr-198 (PubMed:19826007, PubMed:26271001). Dephosphorylated by PstP (PubMed:19826007).
Forms a tight 1:1 complex with EsxT (PubMed:20085764, PubMed:29559126). Complex formation results in induction of alpha-helical conformation and stability against chemical denaturation (PubMed:29559126).
Belongs to the class-III pyridoxal-phosphate-dependent aminotransferase family. BioA subfamily.
Catalysis proceeds by a classical ping-pong bi-bi reaction mechanism.
Catalyzes the reversible transfer of the alpha-amino group from S-adenosyl-L-methionine (SAM) to 7-keto-8-aminopelargonic acid (KAPA) to form 7,8-diaminopelargonic acid (DAPA). It is the only aminotransferase known to utilize SAM as an amino donor (PubMed:20565114, PubMed:16984394). Can also use sinefungin but not S-adenosylhomocysteine as substrate (PubMed:20565114).
Competitively inhibited by KAPA at concentrations above 10 uM and by amiclenomycin.
Homotetramer (PubMed:16984394). Homodimer (PubMed:20565114).
Belongs to the SOS response-associated peptidase family.
Toxic component of a type II toxin-antitoxin (TA) system. An RNase. Its cognate antitoxin is VapB48.
To M.paratuberculosis 34 kDa antigenic protein.
Belongs to the rhamnosyl O-methyltransferase family.
Catalyzes the O-methylation of the hydroxyl group located on C-2 of the first rhamnosyl residue linked to the phenolic group of glycosylated phenolphthiocerol dimycocerosates (PGL) and p-hydroxybenzoic acid derivatives (p-HBAD).
Catalyzes the formation of trans cyclopropanated ketomycolate or methoxymycolate through the conversion of a double bond to a cyclopropane ring at the proximal position of an oxygenated mycolic acid via the transfer of a methylene group from S-adenosyl-L-methionine. In the absence of MmaA2, CmaA2 has a non-specific cis-cyclopropanating activity and is able to catalyze the conversion of a double bond to a cis cyclopropane ring at the distal position of an alpha mycolic acid. Cyclopropanated mycolic acids are key factors participating in cell envelope permeability, host immunomodulation and persistence.
Inactivation of cmaA2 causes accumulation of unsaturated derivatives of both the methoxy- and ketomycolates. The mycolic acids of the cmaA2 mutant lack trans-cyclopropane rings but are otherwise intact with respect to cyclopropane and methyl branch content. Deletion of cmaA2 has no effect on bacterial loads during mouse infection but causes hypervirulence due to an excessive immune activation which produces more-severe granulomatous pathology than wild-type, and increases both the macrophage activation and the macrophage inflammatory response.
Expressed in both low and standard phosphate concentrations.
Essential protein that may act as a regulatory protease that is conditionally activated upon appropriate environmental triggers.
The C-terminal region exhibits both monomeric and trimeric forms in solution.
The periplasmic region consists of a protease domain (PD) and a PDZ domain, connected by a ten-residue linker (PubMed:30198900). Interactions between the PDZ domain and the catalytic domain lead to an inactive conformation (PubMed:30511675).
Participates actively in the response to hyperosmotic and heat shock by preventing the aggregation of stress-denatured proteins and by disaggregating proteins, also in an autonomous, DnaK-independent fashion. Unfolded proteins bind initially to DnaJ; upon interaction with the DnaJ-bound protein, DnaK hydrolyzes its bound ATP, resulting in the formation of a stable complex. GrpE releases ADP from DnaK; ATP binding to DnaK triggers the release of the substrate protein, thus completing the reaction cycle. Several rounds of ATP-dependent interactions between DnaJ, DnaK and GrpE are required for fully efficient folding. Also involved, together with DnaK and GrpE, in the DNA replication of plasmids through activation of initiation proteins.
Forms a complex with cognate antitoxin Rv3098B/RVBD_3098B.
Putative toxic component of a possible type II toxin-antitoxin (TA) system. Its toxic effect may be neutralized by cognate antitoxin Rv3098B/RVBD_3098B.
Belongs to the endoribonuclease YbeY family.
Single strand-specific metallo-endoribonuclease involved in late-stage 70S ribosome quality control and in maturation of the 3' terminus of the 16S rRNA.
Belongs to the histidinol dehydrogenase family.
Catalyzes the sequential NAD-dependent oxidations of L-histidinol to L-histidinaldehyde and then to L-histidine.
Slightly induced towards stationary phase. Induced by heat and oxidative stresses.
Peptidoglycan endopeptidase that cleaves the bond between D-glutamate and meso-diaminopimelate. Binds high-molecular weight peptidoglycan, but does not degrade it. Required for normal separation of daughter cells after cell division and cell wall integrity. Required for host cell invasion.
Catalyzes the dismutation of two molecules of 6,7-dimethyl-8-ribityllumazine, resulting in the formation of riboflavin and 5-amino-6-(D-ribitylamino)uracil.
AccD6 is dispensable in nonpathogenic strains.
Activity of the AccA3/AccD6 complex is inhibited by interaction with the epsilon subunit AccE5 (PubMed:17114269). Inhibited by dimethyl itaconate, C75, the herbicide haloxyfop, cerulenin, and 1,2-cyclohexanedione (PubMed:17114269, PubMed:25092705).
Component of a biotin-dependent acyl-CoA carboxylase complex. This subunit transfers the CO2 from carboxybiotin to the CoA ester substrate (PubMed:17114269). When associated with the alpha3 subunit AccA3, is involved in the carboxylation of acetyl-CoA and propionyl-CoA, with a preference for acetyl-CoA (PubMed:17114269).
Essential. Cannot be deleted. Limited expression level affects growth, mycolic acid content and cell morphology.
Homodimer (PubMed:25092705). The biotin-dependent acyl-CoA carboxylase complex is composed of AccA3, which contains the biotin carboxylase (BC) and biotin carboxyl carrier protein (BCCP) domains, and AccD6, which contains the carboxyl transferase (CT) domain (PubMed:17114269). The AccA3/AccD6 complex forms a dodecamer (PubMed:17114269).
Belongs to the methyltransferase superfamily. Phthiotriol/phenolphthiotriol dimycocerosates methyltransferase family.
Catalyzes the methylation of the lipid moiety of the intermediate compounds phthiotriol and glycosylated phenolphthiotriol dimycoserosates to form phthiocerol dimycocerosates (DIM A) and glycosylated phenolphthiocerol dimycocerosates (PGL).
Belongs to the helicase family. RecG subfamily.
Critical role in recombination and DNA repair. Helps process Holliday junction intermediates to mature products by catalyzing branch migration. Has a DNA unwinding activity characteristic of a DNA helicase with a 3'- to 5'- polarity. Unwinds branched duplex DNA (Y-DNA) (By similarity).
Belongs to the bacterial ribosomal protein bL35 family.
Binds 1 heme b group per subunit, that coordinates a highly solvent-exposed Fe(III) atom.
Forms a 10-stranded antiparallel beta-barrel structure able to accommodate a hydrophobic ligand in its interior (Ref.4). In fact, this fold hosts the heme group, which is located in a wide surface cleft (PubMed:32295384).
Heme-binding protein able to scavenge peroxynitrite and to protect free L-tyrosine against peroxynitrite-mediated nitration, by acting as a peroxynitrite isomerase that converts peroxynitrite to nitrate. Therefore, this protein likely plays a role in peroxynitrite sensing and in the detoxification of reactive nitrogen and oxygen species (RNS and ROS, respectively). In M.tuberculosis, could be part of the pool of proteins required to scavenge RNS and ROS produced by the host during the immunity response. Is able to bind nitric oxide (NO) in vitro, but may act as a sensor of peroxynitrite levels in vivo.
Toxic component of a type II toxin-antitoxin (TA) system. An RNase (By similarity). Upon expression in M.smegmatis inhibits colony formation. Its toxic effect is neutralized by coexpression with cognate antitoxin VapB21.
Belongs to the ABC transporter superfamily. Drug exporter-1 (DrugE1) (TC 3.A.1.105) family.
Part of the ABC transporter complex DrrABC involved in doxorubicin resistance. Responsible for energy coupling to the transport system. Binds ATP.
Forms a tight complex with EsxS (PubMed:15336430). Exists in heterodimeric and heterotetrameric forms (PubMed:20629176).
Cells lacking TcrX and TcrY show an increase in virulence in mouse model of infection, with significantly shorter survival times.
Member of the two-component regulatory system TcrY/TcrX.
Belongs to the 'phage' integrase family. XerC subfamily.
Forms a cyclic heterotetrameric complex composed of two molecules of XerC and two molecules of XerD.
Site-specific tyrosine recombinase, which acts by catalyzing the cutting and rejoining of the recombining DNA molecules. The XerC-XerD complex is essential to convert dimers of the bacterial chromosome into monomers to permit their segregation at cell division. It also contributes to the segregational stability of plasmids (By similarity).
Belongs to the methylmalonyl-CoA epimerase family.
IGPS catalyzes the conversion of PRFAR and glutamine to IGP, AICAR and glutamate. The HisH subunit catalyzes the hydrolysis of glutamine to glutamate and ammonia as part of the synthesis of IGP and AICAR. The resulting ammonia molecule is channeled to the active site of HisF (By similarity).
Converts 2C-methyl-D-erythritol 2,4-cyclodiphosphate (ME-2,4cPP) into 1-hydroxy-2-methyl-2-(E)-butenyl 4-diphosphate.
Phosphorylated by the PknB kinase at three threonine residues (Thr-84, Thr-202, and Thr-178) in a sequential manner. Phosphorylation enhances proteolytic activity of the proteasome.
The 20S proteasome core is composed of 14 alpha and 14 beta subunits that assemble into four stacked heptameric rings, resulting in a barrel-shaped structure. The two inner rings, each composed of seven catalytic beta subunits, are sandwiched by two outer rings, each composed of seven alpha subunits. The catalytic chamber with the active sites is on the inside of the barrel. Has a gated structure, the ends of the cylinder being occluded by the N-termini of the alpha-subunits. Is capped by the proteasome-associated ATPase, ARC (Mpa). Can also interact with the bacterial proteasome activator Bpa through the C-terminal hydrophobic-tyrosine-X motif (HbYX motif) of Bpa; Bpa forms a homooligomeric ring-like structure which stacks co-axially with the proteasomal alpha-rings (PubMed:25469515).
Belongs to the lyase 1 family. Argininosuccinate lyase subfamily.
Catalyzes the conversion of 1-hydroxy-2-methyl-2-(E)-butenyl 4-diphosphate (HMBPP) into a mixture of isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP) (PubMed:23091471). Acts in the terminal step of the DOXP/MEP pathway for isoprenoid precursor biosynthesis. Has a higher activity compared with LytB2 (PubMed:23091471). Is essential for M.tuberculosis growth in vitro (PubMed:26309039).
The lytB2 gene cannot be deleted, unless an additional copy is provided elsewhere, demonstrating that this is the essential homolog. lytB1 cannot complement for loss of function of lytB2, but the sole LytB homolog of M.smegmatis is able to compensate for loss of LytB2 in M.tuberculosis.
Belongs to the type-I restriction system S methylase family.
Antitoxin component of a type II toxin-antitoxin (TA) system. Upon expression in M.smegmatis neutralizes the effect of cognate toxin Rv0910.
Belongs to the ABC transporter superfamily. Ycf16 family.
Belongs to the truncated hemoglobin family. Group II subfamily.
Contains L-DOPA (3',4'-dihydroxyphenylalanine).
When expressed in E.coli and M.smegmatis, HbO increases oxygen uptake. Membrane vesicles of E.coli carrying HbO show a respiration activity about twice that of membranes without HbO. HbO seems to interact with a terminal oxidase. Therefore, HbO could participate in oxygen/electron-transfer process, suggesting a function related to the facilitation of oxygen transfer during aerobic metabolism of M.tuberculosis.
Forms homooligomers. Interacts with PbpB and CwsA.
Important for maintaining cell shape and cell wall integrity by localizing peptidoglycan synthesis to the cell poles. Protects PbpB (PBP3, FtsI) from oxidative stress-induced cleavage.
Phosphorylated by PknA. Phosphorylation enhances polar localization, which in turn heightens polar peptidoglycan biosynthesis.
Positively regulated by the stringent response.
Proteolysis of PbpB (PBP3, FtsI) upon oxidative stress in depletion experiments; degradation is prevented by overexpression of Wag31 but not the 46-Asn--Asp-48 deletion.
Constitutively expressed at a low level under all conditions tested, including stationary phase and several stresses. 3-fold induced during starvation (PubMed:11929527). Positively controls expression of its own operon (rsbW-sigF).
Infected guinea pigs mutant and wild-type bacteria grow comparably (PubMed:16735723). A double rsbW-sigF disruption shows no effect in the presence or absence of rifampicin (PubMed:20729364).
Monomer. Interacts transiently with the RNA polymerase catalytic core formed by RpoA, RpoB, RpoC and RpoZ (2 alpha, 1 beta, 1 beta' and 1 omega subunit) to form the RNA polymerase holoenzyme that can initiate transcription. Interacts (via sigma-70 factor domain 4) with anti-sigma-F factor RsbW (UsfX) with a possible 2:1 RbsW:SigF stoichiometry, which inhibits SigF activity.
Sigma factors are initiation factors that promote the attachment of RNA polymerase to specific initiation sites and are then released. Held in an inactive form by a cognate anti-sigma factor RsbW (UsfX) until released. Increased expression decreases growth rate, and after 3 days increases the expression of 51 loci encoding 33 protein-coding genes as well as some non-coding RNA (PubMed:22307756).
Belongs to the glycosyl hydrolase 92 family.
Belongs to the glycosyltransferase 4 family. WecA subfamily.
Involved in the biosynthesis of the disaccharide D-N-acetylglucosamine-L-rhamnose which plays an important role in the mycobacterial cell wall as a linker connecting arabinogalactan and peptidoglycan via a phosphodiester linkage. Catalyzes the transfer of the N-acetylglucosamine-1-phosphate (GlcNAc-1P) moiety from UDP-GlcNAc onto the carrier lipid decaprenyl phosphate (C50-P), yielding GlcNAc-pyrophosphoryl-decaprenyl (GlcNAc-PP-C50).
Mycobacteria use decaprenyl phosphate (C50-P) as a lipid carrier in all known cell wall biosynthetic pathways, rather than the usual undecaprenyl phosphate (C55-P) usually used in Gram-negative bacteria.
Belongs to the universal ribosomal protein uL5 family.
Part of the 50S ribosomal subunit; part of the 5S rRNA/L5/L18/L25 subcomplex. Contacts the 5S rRNA and the P site tRNA. Forms a bridge to the 30S subunit in the 70S ribosome.
This is one of the proteins that bind and probably mediate the attachment of the 5S RNA into the large ribosomal subunit, where it forms part of the central protuberance. In the 70S ribosome it contacts protein S13 of the 30S subunit (bridge B1b), connecting the 2 subunits; this bridge is implicated in subunit movement. Contacts the P site tRNA; the 5S rRNA and some of its associated proteins might help stabilize positioning of ribosome-bound tRNAs.
Acts as a transcriptional regulator. Probably redox-responsive. The apo- but not holo-form probably binds DNA (By similarity). The apo-form has been shown to act as a protein disulfide reductase.
Weakly expressed in exponential phase, more induced upon entry into stationary phase. 3-fold induced by streptomycin and pH 4.5, 4-fold by ethanol. Slightly induced during entry into hypoxia, by cAMP, in macrophage infection and 5-fold induced by NO. Repressed by WhiB4.
A fairly frequent variant (Ala-64) was originally (PubMed:17970586) suggested to be responsible for some cases of rifampicin resistance. This has since been shown not to be true (PubMed:18550732), although it is a good marker for the Beijing-W clade/SCG-2 phylogenetic group.
Induced by anaerobisis (at protein level). A member of the dormancy regulon. Induced in response to reduced oxygen tension (hypoxia), low levels of nitric oxide (NO) and carbon monoxide (CO). It is hoped that this regulon will give insight into the latent, or dormant phase of infection.
Member of the two-component regulatory system TcrY/TcrX. Activates TcrX by phosphorylation.
Toxic component of a type II type II toxin-antitoxin (TA) system. An RNase. The cognate antitoxin is VapB6 (By similarity).
Belongs to the ABC transporter superfamily. Sulfate/tungstate importer (TC 3.A.1.6) family.
Part of the ABC transporter complex CysAWTP involved in sulfate/thiosulfate import. Responsible for energy coupling to the transport system.
Catalyzes the formation of phosphoribosylamine from phosphoribosylpyrophosphate (PRPP) and glutamine.
In the C-terminal section; belongs to the purine/pyrimidine phosphoribosyltransferase family.
Antitoxin component of a type II toxin-antitoxin (TA) system. Upon expression in M.smegmatis neutralizes the effect of cognate toxin Rv2653c.
Belongs to the NAD-dependent glycerol-3-phosphate dehydrogenase family.
Expression is early up-regulated during acidic stress as compared to normal whereas no expression is observed under nutrient and oxidative stress conditions.
Is inbibited by tetrahydrolipstatin, a specific lipase inhibitor and RHC 80267, a diacylglycerol lipase inhibitor, but not by phenylglyoxal and iodoacetate.
Lipase that displays broad substrate specificity and preferentially hydrolyzes p-nitrophenyl myristate in vitro. Also shows significant activity with pNP-butyrate (68%), pNP-octanoate (82%), pNP-decanoate (90%), and pNP-laurate (74%). Is probably involved in lipid catabolism. Is active at low pH, and might play some important role in mycobacterial biology in macrophages where the bacteria encounters acidic stress.
Belongs to the universal ribosomal protein uL6 family.
This protein binds to the 23S rRNA, and is important in its secondary structure. It is located near the subunit interface in the base of the L7/L12 stalk, and near the tRNA binding site of the peptidyltransferase center.
Belongs to the CRISPR-associated Cas10/Csm1 family.
Part of the Csm effector complex, that includes Cas10, Csm2, Csm3, Csm4, Csm5 and mature crRNA.
The N-terminal HD domain has ssDNase activity. The C-terminal GGDEF domain has the cOA synthesis activity.
This subunit is a single-strand-specific deoxyribonuclease (ssDNase) which digests both linear and circular ssDNA; it has both exo- and endonuclease activity.
When associated with the ternary Csm effector complex (the crRNA, Cas proteins and a cognate target ssRNA) synthesizes cyclic oligoadenylates (cOA) from ATP. cOAs are second messengers that stimulate the ssRNase activity of Csm6, inducing an antiviral state important for defense against invading nucleic acids.
ssDNase activity is stimulated in the ternary Csm effector complex; binding of cognate target RNA activates the ssDNase, as the target RNA is degraded ssDNA activity decreases.
Belongs to the complex I subunit 4L family.
Forms a complex with cognate toxin MazF2.
Putative antitoxin component of a possible type II toxin-antitoxin (TA) system. The cognate toxin is VapC12.
Fragments of the mature protein (residues 77-96, 97-116 and 117-136) prevent uptake of M.tuberculosis by a human macrophage-like cell line (PubMed:25041568).
Belongs to the class I-like SAM-binding methyltransferase superfamily. TrmB family.
Catalyzes the formation of N(7)-methylguanine at position 46 (m7G46) in tRNA.
Belongs to the gluconeogenesis factor family.
Required for morphogenesis under gluconeogenic growth conditions.
Belongs to the arsenical resistance-3 (ACR3) (TC 2.A.59) family.
Activated by dithiothreitol and inhibited by EDTA.
Binds 2 magnesium ions per subunit. Can also use manganese as divalent cation, however calcium and zinc ions are much less effective.
Catalyzes the sequential condensation of isopentenyl diphosphate (IPP) in the cis configuration with (2Z,6E)-farnesyl diphosphate (Z-FPP or EZ-FPP) generating the 50 carbon product trans,polycis-decaprenyl diphosphate. When (2E,6E)-farnesyl diphosphate (E-FPP or EE-FPP) is used in vitro, both primary products decaprenyl diphosphate and (2E,6E,10E)-geranylgeranyl diphosphate (EEE-GGPP) are synthesized. M.tuberculosis does not synthesize (2E,6E,10Z)-geranylgeranyl diphosphate (EEZ-GGPP) and heptaprenyl diphosphate. Can also accept many different allylic substrates, including E-geranyl diphosphate (E-GPP), neryl diphosphate (NPP), and all-trans-geranyl-geranyl diphosphate.
Binding of Ca(2+) to PE_PGRS33 induces conformational changes and increases affinity for TLR2.
Constitutively expressed in vitro, suggesting that it could be an essential gene (PubMed:11967065, PubMed:16672626). Expression is regulated by SigA. Down-regulated during stationary phase, under nutrient starvation and oxygen depletion (PubMed:19068228).
Contains an N-terminal PE domain, followed by a conserved linker region and a C-terminal PGRS domain (PubMed:18028308, PubMed:21081760). The PE domain is responsible for the export and localization to the cell wall (PubMed:15101979, PubMed:18028308, PubMed:22110736). The PGRS domain is required for TNF-alpha secretion and is responsible for the main immunomodulatory properties of the protein (PubMed:17095513, PubMed:24106104). Variations within the PGRS domain alter the levels of TNF-alpha induction and are likely to have an impact on the innate immune response (PubMed:17095513). PGRS domain is also required to mediate cell entry into macrophages (PubMed:26978522). Colocalization to the mitochondria of host cells is dependent on the linker region and the PGRS domain, but not the PE domain (PubMed:21081760).
Deletion mutant is strongly impaired in its ability to enter macrophages. Deletion does not affect the intracellular growth in macrophages.
Expression of this gene in M.smegmatis leads to low levels of NO and IL-12, increased level of IL-10 and better survival of recombinant strains in macrophages.
Induces TNF-alpha release through human Toll-like receptor 2 (TLR2) signaling pathway, leading to macrophage apoptosis (PubMed:17095513, PubMed:17223373, PubMed:24106104). The signaling pathway involves TLR2-dependent activation of the mitogen-activated protein kinase kinase kinase 5 (ASK1), which activates the p38 and JNK MAPKs, leading to enhanced expression of TNF-alpha and tumor necrosis factor receptor superfamily member 1A (TNFRI) genes. Signals are amplified through classical caspase 8-dependent mitochondrial release of cytochrome c, leading to the activation of caspases 9 and 3 (PubMed:17095513). Mediates Ca(2+)-dependent up-regulation of the anti-inflammatory cytokine IL-10 (PubMed:27483162). Mediates entry into macrophages in a TLR2-dependent mechanism and activates the TLR2-dependent pro-adhesive pathway (PubMed:26978522).
PE domain induces protective cellular immune response and PGRS domain induces humoral immune response during infection in mice, suggesting that this protein is a promising candidate for the development of M.tuberculosis vaccines (PubMed:11500435). Immunization of mice with the PE_PGRS33 protein stimulated CD4(+) and CD8(+) T-cell proliferation as well as IFN-gamma secretion, supporting the potential use of PE_PGRS33 as a vaccine candidate for tuberculosis (PubMed:24904584). Elicits a strong B-cell humoral response among different clinical categories of both adult and child tuberculosis patients, indicating that it could be used in the serodiagnosis of tuberculosis (PubMed:17687113).
Also displays a weak uracil phosphoribosyltransferase activity which is not physiologically significant.
Belongs to the purine/pyrimidine phosphoribosyltransferase family. PyrR subfamily.
Regulates the transcription of the pyrimidine nucleotide (pyr) operon in response to exogenous pyrimidines.
DNA polymerase III is a complex, multichain enzyme responsible for most of the replicative synthesis in bacteria. This DNA polymerase also exhibits 3' to 5' exonuclease activity.
Interacts with the beta sliding-clamp (dnaN) (PubMed:22545130). DNA polymerase III contains a core (composed of alpha, epsilon and theta chains) that associates with a tau subunit. This core dimerizes and associates with the clamp-loading (or gamma) complex (composed of gamma/tau, delta, delta', psi and chi subunits) and with the beta sliding clamp dimer to form the complete DNA polymerase III complex (By similarity).
Despite significant sequence similarity to lipoamide dehydrogenases this protein cannot catalyze the reduction of lipoyl substrates. It lacks one of two cysteine residues involved in dithiol-disulfide interchange with lipoyl substrates and a His-Glu pair involved in general acid catalysis.
May contribute to virulence by increasing resistance to reactive oxygen intermediates. It can reduce 2,6-dimethyl-1,4-benzoquinone (DMBQ), 5-hydroxy-1,4-naphthaquinone (5-HNQ) and menadione. NADPH is the physiological reductant rather than NADH.
Antitoxin component of a type II toxin-antitoxin (TA) system. Upon expression in M.smegmatis neutralizes the effect of toxin RelE.
Expressed in log phase cells. A member of the relBE operon.
Induces its own promoter, in combination with RelE represses its own promoter. Binds DNA in complex with toxin RelE but not alone.
Interacts with toxin RelE, which neutralizes its toxicity. Also interacts with toxins RelG and RelK in vitro, in M.smegmatis coexpression with non-cognate toxins neutralizes the toxicity of RelG while increasing the toxicity of RelK.
Asparagine transport is partially impaired in the mutant. Knockout mutant is impaired in nitrogen incorporation from asparagine into other amino acids, such as glutamate and glutamine. Growth of the knockout strain is greatly reduced at pH 5.5 in the presence of asparagine as sole nitrogen source. Mutant is not attenuated in immune-competent mice.
Dual function in both nitrogen assimilation and in protection against acid stress during infection (PubMed:24586151). Involved in asparagine uptake (PubMed:24586151).
Toxic component of a type II toxin-antitoxin (TA) system. An RNase (By similarity). Upon expression in M.smegmatis inhibits colony formation. Its toxic effect is neutralized by coexpression with cognate antitoxin VapB35.
Belongs to the chorismate pyruvate-lyase type 2 family.
Inhibited by 4-hydroxybenzoate, but not by pyruvate.
Removes the pyruvyl group from chorismate to provide 4-hydroxybenzoate (4HB). Involved in the synthesis of glycosylated p-hydroxybenzoic acid methyl esters (p-HBADs) and phenolic glycolipids (PGL) that play important roles in the pathogenesis of mycobacterial infections.
Surface-exposed protein required for multiplication and intracellular growth.
A member of the dormancy regulon. Induced in response to reduced oxygen tension (hypoxia), low levels of nitric oxide (NO) and carbon monoxide (CO). It is hoped that this regulon will give insight into the latent, or dormant phase of infection. Member of the Rv3134c-devR-devS operon.
A strain lacking this gene does not induce most genes of the dormancy regulon, due to polar effects on the downstream devR (dosR) gene (PubMed:11416222). Restoration of induction only occurs when both this gene and devR (dosR) are transformed into the deleted strain.
Belongs to the phosphatidylserine decarboxylase family. PSD-A subfamily.
Catalyzes the formation of phosphatidylethanolamine (PtdEtn) from phosphatidylserine (PtdSer).
Heterodimer of a large membrane-associated beta subunit and a small pyruvoyl-containing alpha subunit.
Is synthesized initially as an inactive proenzyme. Formation of the active enzyme involves a self-maturation process in which the active site pyruvoyl group is generated from an internal serine residue via an autocatalytic post-translational modification. Two non-identical subunits are generated from the proenzyme in this reaction, and the pyruvate is formed at the N-terminus of the alpha chain, which is derived from the carboxyl end of the proenzyme. The post-translation cleavage follows an unusual pathway, termed non-hydrolytic serinolysis, in which the side chain hydroxyl group of the serine supplies its oxygen atom to form the C-terminus of the beta chain, while the remainder of the serine residue undergoes an oxidative deamination to produce ammonia and the pyruvoyl prosthetic group on the alpha chain.
Catalyzes the formation of GDP-mannose from D-mannose-1-phosphate and GTP (PubMed:11302803, PubMed:34644596). Plays an important role in the synthesis of different glycoconjugates which are responsible for cell wall structure, virulence and immunomodulatory activity of M.tuberculosis (PubMed:34644596).
Could be the potential target for novel anti-tuberculosis drug.
Essential for in vitro growth (PubMed:34644596). Knockdown of the gene decreases the cell growth and alters the integrity of cell wall and cell membrane (PubMed:34644596).
Positively regulated by LysG in the presence of lysine or histidine.
Deletion reduces growth on glycerol and glucose as sole carbon sources. Deletion mutant does not replicate in differentiated THP-1 macrophages and lacks cytotoxicity (PubMed:24753609). Lack of cpnT does not increase drug resistance in vitro (PubMed:25645841). Deletion mutant does not decrease NAD(+) levels in infected macrophages (PubMed:26237511).
Glycohydrolase activity is completely inhibited by interaction with the immunity factor for TNT (IFT). This inhibition protects M.tuberculosis from self-poisoning.
Has a dual function in uptake of nutrients and induction of host cell death. The N-terminal domain (NTD) forms an outer membrane channel and is used for uptake of nutrients across the outer membrane. The secreted C-terminal toxic domain (TNT) acts as a glycohydrolase, which hydrolyzes the essential cellular coenzyme NAD(+) in the cytosol of infected macrophages, leading to necrotic host cell death. Both functions are required for survival, replication and cytotoxicity of M.tuberculosis in macrophages.
Interacts with the immunity factor for TNT (IFT) (PubMed:26237511). Oligomer formation is required for channel activity (PubMed:24753609).
The C-terminal toxic domain is cleaved, probably after integration of CpnT into the outer membrane.
Belongs to the peptide transporter carbon starvation (CstA) (TC 2.A.114) family.
Interacts with the AccA3/AccD5 biotin-dependent acyl-CoA carboxylase complex (PubMed:16354663, PubMed:16385038). Interacts with the AccA3/AccD6 complex (PubMed:17114269). Is also part of the long-chain acyl-CoA carboxylase (LCC) complex, which is composed of AccA3, AccD4, AccD5 and AccE5. The four subunits are essential for activity, but AccD5, together with AccE5, probably plays a structural role rather than a catalytic one (PubMed:28222482).
It is uncertain whether the five sets of tandem repeats at the N terminus are required, or not, for maximal enhancement of carboxylase activity.
Protein level is maximal in exponential growth phase and declines during late log and stationary phase.
Stimulates activity of the AccA3/AccD5 biotin-dependent acyl-CoA carboxylase complex (PubMed:16354663, PubMed:16385038). Interacts with AccD5 and modulates its carboxylase activity for acetyl-CoA and propionyl-CoA (PubMed:16354663, PubMed:16385038). Inhibits activity of the AccA3/AccD6 complex (PubMed:17114269). Is also required for the activity of the long-chain acyl-CoA carboxylase (LCC) complex (PubMed:28222482).
Cleaved by Rip1 in response to oxidative stress (H(2)O(2)), prevented by Wag31. Cleavage probably occurs near residues 102-103.
Synthesis of cross-linked peptidoglycan from the lipid intermediates.
The enzyme has an N-terminal penicillin insensitive transglycosylase domain (formation of linear glycan strands) and a C-terminal penicillin-sensitive transpeptidase domain (cross-linking of the peptide subunits).
No effect on growth in culture, or in isolated macrophages; infected guinea pigs have a highly attenuated infection with few granulomas and no necrotic centers.
Sigma factors are initiation factors that promote the attachment of RNA polymerase to specific initiation sites and are then released. Extracytoplasmic function (ECF) sigma factors are usually held in an inactive form by an anti-sigma factor until released by regulated intramembrane proteolysis; this sigma factor does not seem to have a cognate anti-sigma factor however. It has been suggested that the sigma domains 2 and 4 may interact via polar residues in this protein to autoregulate. Positively regulates expression of a small regulon of genes.
The most abundant of the sigma factor transcripts, it is expressed in exponential phase; repressed by detergent (7-fold), heat shock (9-fold, 45 degrees Celsius) and in stationary phase. Not autoregulated (PubMed:22015173).
The protein has been shown to be 126 residues longer (PubMed:17145760), but in (PubMed:19118359) no evidence of this longer protein was seen.
Belongs to the class-A beta-lactamase family.
Can be used as a biomarker, which together with BlaC-specific fluorogenic substrates, allows a rapid and accurate detection of very low numbers of M.tuberculosis for the clinical diagnosis of tuberculosis in sputum and other specimens.
Cells lacking this gene become significantly more susceptible (16- to 32-fold) to penicillins as well as third-generation cephalosporins and carbapenems. They have no detectable beta-lactamase activity.
Exported by the Tat system. The position of the signal peptide cleavage has not been experimentally proven.
Extended spectrum beta-lactamase (ESBL) that inactivates beta-lactam antibiotics by hydrolyzing the amide group of the beta-lactam ring. Displays high levels of penicillinase and cephalosporinase activity as well as measurable activity with carbapenems, including imipenem and meropenem. Plays a primary role in the intrinsic resistance of M.tuberculosis to beta-lactam antibiotics.
Is inhibited by sulbactam, tazobactam, and clavulanate. Sulbactam inhibits the enzyme competitively and reversibly with respect to nitrocefin. Tazobactam inhibits the enzyme in a time-dependent manner, but the activity of the enzyme reappears due to the slow hydrolysis of the covalently acylated enzyme. In contrast, clavulanate reacts with the enzyme quickly to form hydrolytically stable, inactive forms of the enzyme, via irreversible acylation of the catalytic serine residue. Clavulanate has potential to be used in combination with approved beta-lactam antibiotics to treat multi-drug resistant (MDR) and extremely drug resistant (XDR) strains of M.tuberculosis. Is also irreversibly inhibited by NXL104, which forms an extremely stable carbamoyl adduct with the enzyme but shows an inhibition efficiency more than 100-fold lower than that of clavulanate. Is inhibited by carbapenems, that are very poor substrates for the enzyme.
A member of the dormancy regulon. Induced in response to reduced oxygen tension (hypoxia), low levels of nitric oxide (NO) and carbon monoxide (CO). It is hoped that this regulon will give insight into the latent, or dormant phase of infection. Following a shift from stationary to anaerobic growth this protein is not seen to not be further induced (at protein level). Induced in mouse lungs at the same time that adaptive host immunity induces bacterial growth arrest; induction is dependent on interferon gamma.
Has been detected extracellularly but no signal sequence is predicted by bioinformatic programs.
Homodimer. Forms an SDS-resistant dimer that requires Cys-136 for SDS-resistance.
Unlike some other CBS-domain containing proteins does not seem to bind AMP.
Expressed in exponential phase, peaks at 10 days and decreases after up to 50 days in culture; induced by detergent (11-fold), heat shock (23-fold, 45 degrees Celsius), low aeration (2.5-fold) and oxidative stress (2.7-fold, SigE and SigH responsive). Seen to be induced (PubMed:9882660) and slightly repressed (PubMed:10027986) by 10 mM H(2)O(2). 2- to 6-fold induced by starvation. Its basal expression is largely under control of SigE, probably via MrpAB, although other factors including SigH also play a role. Half-life of about 2 minutes.
Monomer (Probable). Interacts transiently with the RNA polymerase catalytic core formed by RpoA, RpoB, RpoC and RpoZ (2 alpha, 1 beta, 1 beta' and 1 omega subunit) to form the RNA polymerase holoenzyme that can initiate transcription (By similarity). Interacts with RbpA, probably 1:1.
More sensitive to SDS (cell envelope stress) and hypoxic treatment in vitro. No effect in human THP-1 macrophage-like cells, intravenously inoculated BALB/c mice or aerosol-infected Hartley strain guinea pigs.
Sigma factors are initiation factors that promote the attachment of RNA polymerase to specific initiation sites and are then released. A non-essential principal sigma factor that responds to cell envelope stress and hypoxia. Controls a regulon of about 40 genes, with another 100 genes expression being altered during SDS stress and about 50 gene being altered during diamide (oxidative) stress.
Belongs to the low molecular weight phosphotyrosine protein phosphatase family.
Deletion mutant is attenuated in human macrophages (PubMed:18474358). The mutant is not defective when grown in vitro and also shows no growth defect in a mouse infection model (PubMed:18752626).
Interacts with the host VPS33B protein in macrophages (PubMed:18474358). Interacts with subunit H of host V-ATPase (PubMed:22087003). Interacts with host GSK-3 alpha (PubMed:25187516). Interacts (via UIM-like region) with host ubiquitin (PubMed:25642820, PubMed:36227980). Interacts with host adapter TAB3 (PubMed:25642820). Interacts with host TRIM27 (PubMed:27698396).
Key virulence factor required for mycobacterial survival within host macrophages (PubMed:16085396, PubMed:18474358, PubMed:22087003, PubMed:25187516, PubMed:25642820, PubMed:27698396). Exhibits protein tyrosine phosphatase activity (PubMed:10986245, PubMed:12066895, PubMed:17975835, PubMed:23102706, PubMed:25187516, PubMed:32142609). Shows no detectable activity towards substrates containing phosphoserine/threonine residues (PubMed:10986245, PubMed:12066895).
Phosphatase activity is stimulated by phosphorylation (PubMed:25535696). Inhibited by sodium molybdate, sodium orthovanadate and sodium tungstate (PubMed:10986245, PubMed:17975835). Inhibited by S-nitrosylation (PubMed:20830431, PubMed:23102706). Subjected to substrate activation, triggered by pNPP or by phosphotyrosine. Is also activated by phosphoserine, with serine being ineffective in enhancing PtpA activity (PubMed:32142609).
Phosphorylated on tyrosines 128 and 129 by PtkA (PubMed:19366344, PubMed:22888002, PubMed:25535696). Both Tyr-128 and Tyr-129 together are essential for PtpA phosphatase activity (PubMed:25535696). In vitro, can be phosphorylated by several eukaryotic-like Ser/Thr protein kinases, such as protein kinase A (PknA), which phosphorylates PtpA at Thr-45 and increases its activity (PubMed:25535696).
S-nitrosylation at Cys-53 decreases activity (PubMed:20830431). Modification does not affect substrate affinity, but decreases protein thermal stability and promotes a local effect in the surroundings of the Cys-53 residue, which interferes in both protein stability and function (PubMed:23102706).
Supports mycobacteria survival during infection by modulation of the phagosome maturation and modulation of the normal host signaling pathways, including host innate immune responses and cell apoptosis (PubMed:18474358, PubMed:22087003, PubMed:25187516, PubMed:25642820, PubMed:27698396). Affects the phagocytosis process by preventing phagosome acidification and maturation in the macrophage (PubMed:22087003, PubMed:16085396, PubMed:18474358). This inhibition depends on both PtpA phosphatase activity and its ability to bind to host vacuolar-H(+)-ATPase (V-ATPase) machinery (PubMed:22087003). Enters into the host cytosol and binds to subunit H of the human V-ATPase machinery to block V-ATPase trafficking and phagosome acidification (PubMed:22087003). Dephosphorylates and inactivates host VPS33B protein, which inhibits phagosome maturation, fusion with the lysosome and promotes bacteria survival (PubMed:18474358, PubMed:22087003). Dephosphorylation of VPS33B requires interaction of PtpA with host V-ATPase and ubiquitin (PubMed:22087003, PubMed:25642820). Binding to host ubiquitin also leads to the dephosphorylation of phosphorylated Jnk and MAPK p38, leading to suppression of innate immunity (PubMed:25642820). Dephosphorylates host GSK-3 alpha on Tyr-279, which leads to modulation of GSK-3 alpha anti-apoptotic activity, promoting pathogen survival early during infection (PubMed:25187516). In vitro, dephosphorylates two subunits of the trifunctional enzyme TFP (ECHA/ ECHB), which means that it may also affect pathways involved in cell energy metabolism (PubMed:25743628). Furthermore, blocks innate immune system responses mediated by the host adapter TAB3 and dependent on NF-kappa-B by competitively binding the ubiquitin-interacting domain of TAB3, in a phosphatase activity-independent manner (PubMed:25642820). Antagonizes TRIM27-promoted JNK/p38 MAPK pathway activation and cell apoptosis through competitively binding to the RING domain of TRIM27 (PubMed:27698396). In addition, PtpA enters the nucleus of host cells and regulates the expression of several host genes, some of which are known to be involved in host innate immunity or in cell proliferation and migration, either by directly binding to the promoters of its target genes, or in an indirect manner (PubMed:28811474). In vitro, can bind directly to the promoter region of GADD45A, a gene encoding a protein involved in cell division, cell death and senescence, and DNA-damage repair (PubMed:28811474).
The activation most likely occurs via a reversible conformational rearrangement of the enzyme, leading to a catalytically competent form (PubMed:32142609). Both the P- and D-loop form part of the binding interface (PubMed:22888002).
The important role played by PtpA in virulence makes it a highly promising target for the treatment of tuberculosis infections. Several classes of potent inhibitors have been developed and studied to date. Drug candidates include, among others, stevastelins, roseophilins, prodigiosins, hydroxypyrrole benzoic acids, difluoromethylphosphonic acid (DFMP) and chalcone derivatives.
Up-regulated upon infection of human monocytes.
Part of the high-affinity ATP-driven potassium transport (or Kdp) system, which catalyzes the hydrolysis of ATP coupled with the electrogenic transport of potassium into the cytoplasm. This subunit acts as a catalytic chaperone that increases the ATP-binding affinity of the ATP-hydrolyzing subunit KdpB by the formation of a transient KdpB/KdpC/ATP ternary complex.
Belongs to the dTDP-4-dehydrorhamnose reductase family.
Involved in the biosynthesis of the dTDP-L-rhamnose which is a component of the critical linker, D-N-acetylglucosamine-L-rhamnose disaccharide, which connects the galactan region of arabinogalactan to peptidoglycan via a phosphodiester linkage (PubMed:12029057). Catalyzes the reduction of dTDP-6-deoxy-L-lyxo-4-hexulose to yield dTDP-L-rhamnose (By similarity).
Catalyzes the phospholipid dependent N-acylation of the N-terminal cysteine of apolipoprotein, the last step in lipoprotein maturation.
Consists of 2 domains; the N-terminus (residues 1-593) probably has the N-acyltransferase activity while the C-terminus (residues 594-874) has polyprenol monophosphomannose (PPM) synthase activity. The whole protein has higher PPM synthase than the second domain alone when expressed in M.smegmatis, suggesting the N-acyltransferase domain plays a stimulating role in PPM synthesis.
In a number of other Mycobacteria, including M.avis, M.leprae and M.smegmatis, these domains are encoded by 2 separate adjacent genes.
In the C-terminal section; belongs to the glycosyltransferase 2 family.
In the N-terminal section; belongs to the CN hydrolase family. Apolipoprotein N-acyltransferase subfamily.
Transfers mannose from GDP-mannose to lipid acceptors (works best on C20-C95 lipid monophosphate substrates in which the lipid can be modified, tested with the C-terminal domain expressed in M.smegmatis) to form polyprenol monophosphomannose (PPM). PMM is an alkai-stable sugar donor which adds mannose-phosphate residues to triacylated-phosphatidyl-myo-inositol mannosides (PIM2), eventually leading to generation of the cell wall glycolipid lipoglycan modulins lipoarabinomannan (LAM) and lipomannan (LM).
Belongs to the anthranilate phosphoribosyltransferase family.
Catalyzes the transfer of the phosphoribosyl group of 5-phosphorylribose-1-pyrophosphate (PRPP) to anthranilate to yield N-(5'-phosphoribosyl)-anthranilate (PRA).
Belongs to the pantothenate synthetase family.
Catalyzes the condensation of pantoate with beta-alanine in an ATP-dependent reaction via a pantoyl-adenylate intermediate.
Pantothenate exhibits uncompetitive inhibition toward both D-pantoate and ATP, and non-competitive inhibition toward beta-alanine. AMPCPP exhibits competitive inhibition toward ATP, uncompetitive inhibition toward beta-alanine, and non-competitive inhibition toward D-pantoate. The enzyme is most active in the presence of magnesium or manganese. Other divalent cations (cobalt, nickel, zinc) are less effective.
The reaction proceeds by a bi uni uni bi ping pong mechanism.
Responsible for the addition of alpha-(1-2) mannose branches to the linear mannan core on the biosynthetic pathway to mature lipoarabinomannan (LAM).
Can also use, to a lesser extent, Mg(2+) and Zn(2+).
Degradation of inorganic polyphosphates (polyP). Releases orthophosphate processively from the ends of the polyP chain. Prefers short-chain length polyphosphates as substrates. Can also hydrolyze ATP and ADP substrates, but lacks GTPase activity. Cannot hydrolyze pppGpp to ppGpp.
Exopolyphosphatase activity is inhibited by (p)ppGpp alarmones produced during the bacterial stringent response.
Autophosphorylated on serine and threonine residues. Dephosphorylated by PstP.
Important for survival of the bacterium in the host during infection. Promotes the survival of infected macrophages by activating multiple signaling responses and suppressing apoptosis of macrophages during nitrate stress. May contribute to the adaptation of M.tuberculosis during stress conditions by maintaining the cellular integrity. Can phosphorylate the FHA domain of Rv1747.
Induced by nitric oxide stress. Repressed under oxidative stress.
Mutants show increased resistance to nitric oxide donors, increased sensitivity to reducing agents, and growth reduction at pH 7.0 and in the presence of lysozyme. They increase macrophage apoptosis, and exhibit lower rates of survival and multiplication in an in vitro macrophage model of infection.
Involved in the final steps of cholesterol and steroid degradation (PubMed:28377529). Probably catalyzes the oxidation of the 5-OH group of (5R,7aS)-5-hydroxy-7a-methyl-1-oxo-2,3,5,6,7,7a-hexahydro-1H-indene-carboxyl-CoA, leading to the formation of HIEC-CoA (Probable).
ATP-dependent 3'-5' DNA helicase, unwinds 3'-overhangs, 3'- flaps, and splayed-arm DNA substrates but not 5'-overhangs, 5'-flap substrates, 3-way junctions or Holliday junctions. Not highly efficient in vitro (PubMed:19199647, PubMed:22615856). Requires ATP hydrolysis for helicase activity; the ATPase activity is DNA-dependent and requires a minimum of 4 single-stranded nucleotides (nt) with 6-10 nt providing all necessary interactions for full processive unwinding. The ATPase prefers ATP over CTP or GTP, is almost inactive with TTP (PubMed:19199647). DNA helicase activity requires ATP or dATP and only acts when the 3'-overhang is >20 nt. Capable of unwinding a DNA:RNA hybrid if the 3'-overhang is DNA. Also catalyzes ATP-independent annealing of complementary DNA strands; annealing requires Mg(2+) (PubMed:22615856).
ATPase activity has a small preference for Mn(2+) over Mg(2+), Ca(2+) supports ATPase activity less well. Co(2+) and Zn(2+) are inactive (PubMed:19199647). Another study shows equal activity with Mg(2+) and Mn(2+), none with Ca(2+) (PubMed:22615856).
Belongs to the helicase family. RAD25/XPB subfamily.
Removal of the N-terminus decreases solubility and/or structural integrity of the protein.
Catalyzes the ATP-dependent conversion of 5-aminoimidazole ribonucleotide (AIR) and HCO(3)(-) to N5-carboxyaminoimidazole ribonucleotide (N5-CAIR).
Belongs to the KhpA RNA-binding protein family.
Cells lacking this gene exhibit reduced survival both in macrophages and in a mouse infection model.
Controls the expression of genes important for virulence.
Belongs to the universal ribosomal protein uS2 family.
Catalyzes the methylation of both C-5 and C-15 in precorrin-6Y to form precorrin-8X.
Deletion mutant accumulates important amounts of DAT and is devoid of PAT. DAT only accumulates inside the cells and is not exported to the cell surface.
Required for the biosynthesis of polyacyltrehalose (PAT) and the transport of diacyltrehalose (DAT) and possibly PAT to the cell surface.
Composed of an N-terminal alpha/beta-hydrolase domain and a C-terminal cyclase homology domain (CHD).
Expression in M.smegmatis leads to altered colony morphology, growth, cell surface properties and cell wall permeability (PubMed:33960821, PubMed:34019937). M.smegmatis shows enhanced biofilm formation and survival under lysozyme, acidic, nutritive and antibiotic stress conditions (PubMed:33960821, PubMed:34019937). It also enhances the infection capability and the intracellular survival of mycobacteria (PubMed:34019937).
Expression is up-regulated in acidic, nutritive and iron stress in M.tuberculosis H37Ra.
In the C-terminal section; belongs to the adenylyl cyclase class-4/guanylyl cyclase family.
In the N-terminal section; belongs to the AB hydrolase superfamily.
May play a role in cell wall modulation (PubMed:33960821, PubMed:34019937). The N-terminal domain exhibits lipolytic activity (PubMed:33960821). In vitro, hydrolyzes various p-nitrophenyl (pNP) esters (PubMed:33960821). pNP-decanoate (C10) is the best substrate, followed by pNP-octonate (C8), pNP-laurate (C12) and pNP-butyrate (C4) (PubMed:33960821). Exhibits lower activity with pNP-acetate (C2), pNP-myristate (C14) and pNP-palmitate (C16) (PubMed:33960821). Can also use tributyrin (PubMed:33960821). The C-terminal domain catalyzes the biosynthesis of cyclic AMP (cAMP) from ATP (PubMed:15678099). It has a guanylyl cyclase side-activity, corresponding to 7% of the adenylate cyclase activity (PubMed:15678099).
The C-terminal adenylyl cyclase domain forms homodimers (PubMed:15678099). Homodimers are asymmetric in both unliganded and ligand-bound states (PubMed:15678099).
The lipolytic activity of the full-length protein is regulated/inhibited by the presence of the C-terminal adenylate cyclase domain (PubMed:33960821). Lipolytic activity of the full-length protein decreases in the presence of ATP, but ATP does not affect activity of the N-terminal domain in the absence of the C-terminal cyclase domain (PubMed:33960821). Lipolytic activity is inhibited by the serine modifier phenylmethylsulfonyl fluoride (PMSF) (PubMed:33960821).
Belongs to the limonene-1,2-epoxide hydrolase family.
Epoxide hydrolase capable of hydrolyzing long or bulky lipophilic epoxides such as 9,10-epoxystearic acid and cholesterol 5,6-oxide in vitro. The physiological substrates have yet to be identified, but could be fatty acid or steroid derivatives.
Homodimer. Is also present as monomer in solution.
Is inhibited by the anti-epileptic drug valpromide (Ki value of about 100 uM).
Probably involved in ribonucleotide reductase function.
Belongs to the glucosamine/galactosamine-6-phosphate isomerase family. 6-phosphogluconolactonase subfamily.
Hydrolysis of 6-phosphogluconolactone to 6-phosphogluconate.
Shows lipase activity (PubMed:26398213). Is highly immunogenic and may play an important role in the virulence and pathogenesis of M.tuberculosis infection, by altering the balance of cytokines. Significantly down-regulates the expression level of pro-inflammatory cytokines (TNF-alpha and IFN-gamma) and up-regulates the level of anti-inflammatory cytokines such as IL-4 and IL-10 as compared to LPS stimulated macrophages. Also inhibits the expression of iNOS, TLR2 and transcription factor NF-kappa-B in LPS stimulated macrophages whereas the expression of TLR-4 remains unchanged (PubMed:28412202).
Not known, could be involved in the transport of ribonucleotides.
Controls the expression of genes used for utilizing diverse lipids as energy sources.
Belongs to the complex I 51 kDa subunit family.
Homodimer. Forms a membrane-associated complex with FtsX.
Part of the ABC transporter FtsEX involved in cellular division. Has ATPase activity.
Belongs to the Stf0 sulfotransferase family.
Catalyzes the sulfuryl group transfer from 3'-phosphoadenosine-5'-phosphosulfate (PAPS) to trehalose, leading to trehalose-2-sulfate (T2S). The sulfation of trehalose is the first step in the biosynthesis of sulfolipid-1 (SL-1), a major cell wall glycolipid and the most abundant sulfated metabolite found in Mycobacterium tuberculosis, that is a potential virulence factor thought to mediate host-pathogen interactions.
Loss of T2S and SL-1 formation. Unsulfated acylated precursors of SL-1 are not detected, which indicates that Stf0 acts before lipid addition to trehalose.
Probable toxic component of a type II toxin-antitoxin (TA) system. The cognate antitoxin is VapB5. Has limited RNase activity on substrates; activity is seen with a VapC5-VapB5 complex.
Expressed following heat shock under control of SigH. There is another promoter.
Homohexamer. The oligomerization is ATP-dependent (By similarity).
Part of a stress-induced multi-chaperone system, it is involved in the recovery of the cell from heat-induced damage, in cooperation with DnaK, DnaJ and GrpE. Acts before DnaK, in the processing of protein aggregates. Protein binding stimulates the ATPase activity; ATP hydrolysis unfolds the denatured protein aggregates, which probably helps expose new hydrophobic binding sites on the surface of ClpB-bound aggregates, contributing to the solubilization and refolding of denatured protein aggregates by DnaK (By similarity).
The Clp repeat (R) domain probably functions as a substrate-discriminating domain, recruiting aggregated proteins to the ClpB hexamer and/or stabilizing bound proteins. The NBD2 domain is responsible for oligomerization, whereas the NBD1 domain stabilizes the hexamer probably in an ATP-dependent manner. The movement of the coiled-coil domain is essential for ClpB ability to rescue proteins from an aggregated state, probably by pulling apart large aggregated proteins, which are bound between the coiled-coils motifs of adjacent ClpB subunits in the functional hexamer (By similarity).
A helicase/nuclease that prepares dsDNA breaks (DSB) for recombinational DNA repair. Binds to DSBs and unwinds DNA via a highly rapid and processive ATP-dependent bidirectional helicase activity. Unwinds dsDNA until it encounters a Chi (crossover hotspot instigator) sequence from the 3' direction. Cuts ssDNA a few nucleotides 3' to the Chi site. The properties and activities of the enzyme are changed at Chi. The Chi-altered holoenzyme produces a long 3'-ssDNA overhang and facilitates RecA-binding to the ssDNA for homologous DNA recombination and repair. Holoenzyme degrades any linearized DNA that is unable to undergo homologous recombination. In the holoenzyme this subunit has ssDNA-dependent ATPase and 5'-3' helicase activity. When added to pre-assembled RecBC greatly stimulates nuclease activity and augments holoenzyme processivity. Negatively regulates the RecA-loading ability of RecBCD.
Cloning (to improve crystallization) removed residues 121-133 which corresponds to the target-loading peptide for the encapsulin nanocompartment. Target peptide removal does not change enzyme activity.
Homotetramer in the absence of substrate. Homooctamer in the presence of substrate.
Possible cargo protein of a type 1 encapsulin nanocompartment involved in protection against oxidative stress (Probable). Catalyzes the conversion of 7,8-dihydroneopterin to 6-hydroxymethyl-7,8-dihydropterin, 7,8-dihydromonapterin and 7,8-dihydroxanthopterin, respectively, in equal quantities. After longer incubation times the only product is 6-hydroxymethyl-7,8-dihydropterin (PubMed:23150985, PubMed:24855650). Retains aldolase activity when encapsulated with a slight decrease in rate. It is not known if this protein is normally found in the encapsulin nanocompartment (PubMed:24855650).
The C-terminus (residues 119-133) targets the protein to the encapsulin nanocompartment.
Gene Rv1954A is encoded entirely within Rv1954c (this gene), on the opposite strand.
It is uncertain whether Met-1 or Met-38 is the initiator. PCR experiments indicate the protein is probably shorter than indicated here, but the transcription start site was not precisely identified.
Catalyzes the meta-cleavage of 3,4-dihydroxy-9,10-seconandrost-1,3,5(10)-triene-9,17-dione (3,4-DHSA) to produce 4,5-9,10-diseco-3-hydroxy-5,9,17-trioxoandrosta-1(10),2-diene-4-oic acid (4,9-DSHA).
Cells lacking this gene completely fail to grow on cholesterol due the blockage of the catabolic pathway and develop a pink color consistent with the accumulation of toxic catechols. Mice intravenously infected with the mutant survive substantially longer than those infected with the wild-type.
A Gly-cisPro motif from one monomer fits into the active site of the other monomer to allow specific chiral rejection of L-amino acids.
An aminoacyl-tRNA editing enzyme that deacylates mischarged D-aminoacyl-tRNAs. Also deacylates mischarged glycyl-tRNA(Ala), protecting cells against glycine mischarging by AlaRS. Acts via tRNA-based rather than protein-based catalysis; rejects L-amino acids rather than detecting D-amino acids in the active site. By recycling D-aminoacyl-tRNA to D-amino acids and free tRNA molecules, this enzyme counteracts the toxicity associated with the formation of D-aminoacyl-tRNA entities in vivo and helps enforce protein L-homochirality.
Heterotetramer composed of FadE28 and FadE29.
Induced by cholesterol and repressed by KtsR.
Involved in the third cycle of side chain dehydrogenation in the beta-oxidation of cholesterol catabolism (PubMed:26161441). Contributes partly to the virulence by increasing the efficiency of beta-oxidation (PubMed:22045806, PubMed:23560677). Catalyzes the dehydrogenation of 2'-propanoyl-CoA ester side chains of 3-oxo-4-pregnene-20-carboxyl-CoA (3-OPC-CoA) to yield 3-oxo-4,17-pregnadiene-20-carboxyl-CoA (3-OPDC-CoA). Also able to dehydrogenate steroyl-CoA such as 3-oxo-chol-4-en-24-oyl-CoA (3-OCO-CoA), 1beta-(2'-propanoyl-CoA)-3a-alpha-H- 7a-beta-methylhexahydro-4-indanone (indanone-CoA ester), hexahydroindanone and pregenenone (PubMed:22045806, PubMed:23560677).
Belongs to the ribulose-phosphate 3-epimerase family.
Catalyzes the reversible epimerization of D-ribulose 5-phosphate to D-xylulose 5-phosphate.
2 inhibitors of ESX-1 secretion decrease secretion of this protein, without being bacteriocidal. BTP15 inhibits autophosphorylation of MprB with subsequent up-regulation of espA and decreased secretion of EspB and EsxA. BBH7 also inhibits TAT-dependent secretion of (at least) Ag85C (fbpC) and up-regulates members of the ESX-5 locus as well as other genes that are involved in cell wall biogenesis and metal ion homeostasis (PubMed:25299337).
A good candiate for vaccine development (PubMed:7897219). It has been tested in a number of experimental situations.
A secreted protein that plays a number of roles in modulating the host's immune response to infection as well as being responsible for bacterial escape into the host cytoplasm. Acts as a strong host (human) T-cell antigen (PubMed:7729876, PubMed:11940590). Inhibits IL-12 p40 (IL12B) and TNF-alpha expression by infected host (mouse) macrophages, reduces the nitric oxide response by about 75% (PubMed:14557536). In mice previously exposed to the bacterium, elicits high level of IFN-gamma production by T-cells upon subsequent challenge by M.tuberculosis, in the first phase of a protective immune response (PubMed:7897219, PubMed:7729876). Higher levels (1.6-3.3 uM) of recombinant protein inhibit IFN-gamma production by host (human) T-cells and also IL-17 and TNF-alpha production but not IL-2; decreases expression of host ATF-2 and JUN transcription factors by affecting T-cell receptors signaling downstream of ZAP70, without cytotoxicity or apoptosis (PubMed:19265145). EsxA inhibits IFN-gamma production in human T-cells by activating p38 MAPK (MAPK14), p38 MAPK is not responsible for IL-17 decrease (PubMed:21586573). Binds host (mouse) Toll-like receptor 2 (TLR2) and decreases host MYD88-dependent signaling; binding to TLR2 activates host kinase AKT and subsequently inhibits downstream activation of NF-kappa-B; the C-terminal 20 residues (76-95) are necessary and sufficient for the TLR2 inhibitory effect (PubMed:17486091). Required for induction of host (human) IL-1B maturation and release by activating the host NLRP3/ASC inflammasome; may also promote access of other tuberculosis proteins to the host cells cytoplasm (PubMed:20148899). Induces IL-8 (CXCL8) expression in host (human) lung epithelial cells (PubMed:23867456). Exogenously applied protein, or protein expressed in host (human and mouse), binds beta-2-microglobulin (B2M) and decreases its export to the cell surface, probably leading to defects in class I antigen presentation by the host cell (PubMed:25356553). Responsible for mitochondrial fragmention, redistribution around the cell nucleus and decreased mitochondrial mass; this effect is not seen until 48 hours post-infection (PubMed:26092385). Able to disrupt artificial planar bilayers in the absence of EsxB (CFP-10) (PubMed:14557547). Native protein binds artificial liposomes in the absence but not presence of EsxB and is able to rigidify and lyse them; the EsxA-EsxB complex dissociates at acidic pH, EsxB might serve as a chaperone to prevent membrane lysis (PubMed:17557817). Recombinant protein induces leakage of phosphocholine liposomes at acidic pH in the absence of ExsB, undergoes conformational change, becoming more alpha-helical at acidic pH (PubMed:23150662, PubMed:25645924). The study using recombinant protein did not find dissociation of EsxA-EsxB complex at acidic pH (PubMed:23150662). Involved in translocation of bacteria from the host (human) phagolysosome to the host cytoplasm (PubMed:17604718, PubMed:22319448). Translocation into host cytoplasm is visible 3 days post-infection using cultured human cells and precedes host cell death (PubMed:22319448). Recombinant protein induces apoptosis in host (human) differentiated cell lines, which is cell-line dependent; bacteria missing the ESX-1 locus do not induce apoptosis (PubMed:17298391). Host (human) cells treated with EsxA become permeable to extracellular dye (PubMed:17298391). EsxA and EsxA-EsxB are cytotoxic to pneumocytes (PubMed:19906174). ESX-1 secretion system-induced host (mouse) cell apoptosis, which is probably responsible for infection of new host cells, might be due to EsxA (PubMed:23848406). EsxA induces necrosis in aged neutrophils (PubMed:25321481). May help regulate assembly and function of the type VII secretion system (T7SS) (By similarity). EsxA disassembles pre-formed EccC-EsxB multimers, possibly by making EccC-EsxA-EsxB trimers instead of EccC-EsxB-EsxB-EccC tetramers (By similarity).
Bacteria no longer translocate from the phagolysosome to the cytosol of host (human) cells; bacteria replicate only in host phagolysosome rather than cytoplasm, decreased apoptosis of infected host (human) dendritic cells (PubMed:17604718). Bacteria missing the RD1 locus do not gain access to host (human) cytoplasm; complementation with the RD1 locus restores access, but if EsxA is missing the last 12 residues cytoplasmic access is not restored although truncated EsxA is secreted by bacteria (PubMed:22319448). Loss of ability to lyse host (human) lung epithelial cells, possibly due to polar effects from the upstream esxB gene; in BALB/c-infected mice bacteria are not as invasive and cause decreased lung disease (PubMed:14557547). No growth in the human macrophage-like cell line THP-1, no cytotoxicity (PubMed:14756778). Severely attenutated infection in mice, nearly 1000-fold less bacteria in lung and spleen of C57BL/6 (PubMed:14557536, PubMed:14756778). Inactivation leads to absence of EsxA and EsxB from cell lysates (PubMed:14756778, PubMed:16368961). No secretion of EspA (PubMed:16030141). No longer decreases expression of IL-12 p40 and TNF-alpha by infected murine macrophages, while the nitric oxide response is only partially reduced (PubMed:14557536). Significantly decreased production of IL-1 beta (IL1B), decreased activation of host (human) CASP-1 in response to bacterial infection (PubMed:20148899). Mitochondrial morphology is no longer perturbed in human alveolar epithelial cell line A549 (PubMed:26092385).
Constitutively expressed in culture (at protein level) (PubMed:9846755, PubMed:23848406). Up-regulated in infected human pneumonocytes (PubMed:19906174). Zinc increases secreted levels of this protein; 0.5 mM Zn(2+), the physiological concentration in macrophages, induces 6-fold more secreted protein (PubMed:25299337). Part of the esxB-esxA operon (PubMed:9846755).
Forms a tight 1:1 complex with EsxB (CFP-10) (PubMed:11940590, PubMed:14557536, PubMed:16048998, PubMed:16973880, PubMed:19854905, PubMed:19906174, PubMed:23150662, PubMed:26260636, PubMed:20085764, PubMed:15973432, PubMed:24586681). The complex persists even after secretion (PubMed:16048998). Recombinant His-tagged protein forms dimers and higher order multimers; how the protein is prepared influences its multimerization and its subsequent properties in vitro (PubMed:26260636). In vitro EsxB only interacts with non-acetylated EsxA; it also interacts with C-terminally truncated EsxA (missing the last 10 residues) (PubMed:15378760). The native EsxA-EsxB complex dissociates at pH 4.0, and EsxA may then be freed to lyse (host) membranes (PubMed:17557817). Another study using recombinant protein did not find dissociation at acidic pH (PubMed:23150662). Recombinant heterodimer (with a His tag on EsxB) can be dissociated by the detergents amidosulfobetaine-14 and lauryldimethylamine N-oxide (PubMed:26260636). Interacts with EspF (PubMed:19682254). An artificial EsxB-EsxA heterodimer interacts with EspA, EccB1, EccCa1, EccCb1, EspI, EspJ, EccA2 and EccE2; the latter 2 are from the adjacent ESX-2 locus (PubMed:19854905). Contributes to the heterodimer's interaction with EccCb1 (PubMed:19854905). Interacts with host (mouse and human) TLR2 (PubMed:17486091, PubMed:20800577). Interacts with host (human) beta-2-microglobulin (B2M) alone and in complex with EsxB; only binds free B2M and not B2M in complex with HLA-I (PubMed:25356553). The EsxA-EsxB-B2M complex can be detected in the host endoplasmic reticulum (PubMed:25356553). The B2M-EsxA complex can be detected in patients with pleural tuberculosis and is stable from pH 4.0 to 8.0 and in the presence of 2M NaCl (PubMed:25356553).
Genes esxA and esxB are part of RD1 (part of a 15-gene locus known as ESX-1), a section of DNA deleted in the M.bovis BCG strain used for vaccination. Deletion of this region is thought to be largely responsible for the attenuation of BCG, and esxA and esxB in particular are very important in this effect (PubMed:14557547, PubMed:14756778, PubMed:16368961, PubMed:17298391, PubMed:22319448, PubMed:22524898).
May be critical in pro-bacteria versus pro-host interactions; ESX-1 mediates DNA mediated export (maybe via EsxA). The DNA interacts with host (human) cGAS, leading to cGAMP production and activation of the host STING-TBK-1-IRF-3 signaling pathway that leads to IFN-beta which is thought to be 'pro-bacteria'. Mycobacterial dsDNA also interacts with AIM2-NLRP3-ASC to activate an inflammasome, leading to the 'pro-host' IL-1-beta (PubMed:26048138, PubMed:26048136).
May be secreted as a 4 coiled-coil complex with EsxB (PubMed:16048998).
Secretion of EspA, EsxA and EsxB is mutually dependent (PubMed:16030141).
To improve expression in E.coli the proteins were cloned as a single protein in the order esxB-esxA with a cleavable thrombin tag (PubMed:19854905).
Upon purification from strain ATCC 27294 a C-terminally truncated peptide (missing residues 85-95) has been found; it is not clear if this is physiologically relevant (PubMed:15378760). An additional unknown modification on peptide Thr-86-Ala-95 has also been seen (PubMed:15378760).
Belongs to the cation transport ATPase (P-type) (TC 3.A.3) family. Type IIA subfamily.
Catalyzes the NADH-dependent reduction of beta-ketoacyl derivatives (PubMed:19685079, PubMed:21081168, PubMed:23163771). Can accept the beta-oxo fatty acyl group covalently linked with CoA or ACP for catalysis (PubMed:23163771). Highly specific for NADH (PubMed:19685079, PubMed:21081168). Could be involved in fatty acid biosynthesis (Probable).
Contains an N-terminal flavodoxin-type domain and a C-terminal ketoreductase domain (PubMed:21081168). The C-terminal residues participate in intercatalytic domain interaction and play a pivotal role in stabilization of loop I, which is responsible for interaction with phosphopentethine moiety-linked fatty acyl substrates of CoA or ACP (PubMed:23163771).
Was identified as a putative drug target. Inhibited by triazole linked polyphenol-gallol hybrids and triazole linked polyphenol-aminobenzene hybrids. These compounds may be possible candidates for alternate anti-tubercular drugs.
Belongs to the class-V pyridoxal-phosphate-dependent aminotransferase family. EgtE subfamily.
Probably catalyzes the conversion of hercynylcysteine sulfoxide to ergothioneine. Ergothioneine is an antioxidant that protects mycobacteria from oxidative stress.
Belongs to the CocE/NonD hydrolase family.
Aspartyl-tRNA synthetase with relaxed tRNA specificity since it is able to aspartylate not only its cognate tRNA(Asp) but also tRNA(Asn). Reaction proceeds in two steps: L-aspartate is first activated by ATP to form Asp-AMP and then transferred to the acceptor end of tRNA(Asp/Asn).
Belongs to the class-II aminoacyl-tRNA synthetase family. Type 1 subfamily.
Aspartic protease that processes the lipase LipY and other PE_PGRS proteins. Can also cleave itself.
Belongs to the bacterial ribosomal protein bL34 family.
Carboxypeptidase that cleaves terminal D-alanine from peptidoglycan in the mycobacterial cell wall. May cleave L-Lys-D-Ala and/or D-Ala-D-Ala peptide bonds. Exerts important effects on mycobacterial cell morphology and cell division.
Overexpression in M. smegmatis leads to elongated cells and promotes the formation of increased numbers of Z-rings.
Belongs to the bacterial ribosomal protein bL21 family.
Part of the 50S ribosomal subunit. Contacts protein L20.
This protein binds to 23S rRNA in the presence of protein L20.
Binds heme and acts as a three-way sensor with three levels of activity (PubMed:25333974). The oxidation of the heme by oxygen leads to the activation of the autokinase activity, whereas the deoxy-ferrous state confers a moderate kinase activity (PubMed:25333974). Kinase activity is strongly inhibited by binding of NO and CO, which lock SenX3 in an inactive state (PubMed:25333974). Activation of the SenX3-RegX3 two-component system is inhibited by PhoY1 and PhoY2 when phosphate is readily available (PubMed:28698272).
Member of the two-component regulatory system SenX3/RegX3 involved in stress response (PubMed:12777483, PubMed:21698211, PubMed:35980355). Autophosphorylates, and then transfers the phosphate group to RegX3 (By similarity). The system is involved in phosphate starvation response (PubMed:28698272). Plays a role in modulating expression of aerobic response and in the regulation of response to hypoxia (PubMed:21698211, PubMed:35980355). Involved in virulence (PubMed:12777483, PubMed:25333974). SenX3 is a key regulator of mycobacterial replication in response to oxygen, nitric oxide (NO) and carbon monoxide (CO), and acts as an O(2) sensor that plays an important role in the reactivation of growth in response to the restoration of aerobic conditions (PubMed:25333974).
The senX3-regX3 deletion mutant shows a growth defect after infection of macrophages and is attenuated in both immunodeficient and immunocompetent mice.
Toxic component of a type II toxin-antitoxin (TA) system. An RNase (By similarity). Upon expression in M.smegmatis inhibits translation and colony formation. Its toxic effect on colony formation is neutralized by coexpression with cognate antitoxin VapB22; the effect on translation has not been tested but is probably neutralized also.
Belongs to the NucS endonuclease family.
Cleaves both 3' and 5' ssDNA extremities of branched DNA structures.
Belongs to the universal ribosomal protein uS11 family.
Located on the platform of the 30S subunit, it bridges several disparate RNA helices of the 16S rRNA. Forms part of the Shine-Dalgarno cleft in the 70S ribosome.
Part of the 30S ribosomal subunit. Interacts with proteins S7 and S18. Binds to IF-3.
Belongs to the F420-dependent glucose-6-phosphate dehydrogenase family.
Catalyzes the coenzyme F420-dependent oxidation of glucose 6-phosphate to 6-phosphogluconolactone (PubMed:18434308). Appears to have a role in resistance to oxidative stress, via its consumption of G6P that serves as a source of reducing power to combat oxidative stress in mycobacteria. More precisely, is likely involved in a F420-dependent anti-oxidant mechanism that protects M.tuberculosis against oxidative stress and bactericidal agents (PubMed:23240649).
Cells lacking this gene display a strong resistance to PA-824 and CGI-17341 (a nitroimidazo-oxazole).
Is essential for the bioreductive activation of the bicyclic 4-nitroimidazole prodrug PA-824 (a nitroimidazo-oxazine) developed for anti-tuberculosis therapy against both replicating and persistent bacteria. It does not interact directly with PA-824 but, rather, provides reduced F420 to the deazaflavin-dependent nitroreductase Ddn, which in turn activates PA-824.
Component of the DprE1-DprE2 complex that catalyzes the 2-step epimerization of decaprenyl-phospho-ribose (DPR) to decaprenyl-phospho-arabinose (DPA), a key precursor that serves as the arabinose donor required for the synthesis of cell-wall arabinans (PubMed:16291675, PubMed:19299584). DprE1 catalyzes the first step of epimerization, namely FAD-dependent oxidation of the C2' hydroxyl of DPR to yield the keto intermediate decaprenyl-phospho-2'-keto-D-arabinose (DPX) (PubMed:22733761). The intermediate DPX is then transferred to DprE2 subunit of the epimerase complex, most probably through a 'substrate channel' at the interface of DprE1-DprE2 complex (PubMed:25789990). Can also use farnesyl-phosphoryl-beta-D-ribofuranose (FPR) as substrate in vitro (PubMed:25427196). Appears to be essential for the growth and survival of M.tuberculosis (PubMed:12657046, PubMed:24517327).
DprE1 is a highly vulnerable and fully validated tuberculosis drug target.
Is inhibited by 8-nitro-benzothiazinones (BTZs) such as BTZ043 and PBTZ169; BTZs are a new class of antimycobacterial agents that kill M.tuberculosis in vitro, ex vivo, and in mouse models of tuberculosis (PubMed:20828197, PubMed:19299584, PubMed:22733761, PubMed:24500695). Is also inhibited by dinitrobenzamide derivatives (DNBs), which thus block formation of both cell-wall lipoarabinomannan and arabinogalactan via inhibition of decaprenyl-phospho-arabinose (DPA) synthesis; DNBs show high activity against intracellular growth of M.tuberculosis inside macrophages, including extensively drug resistant (XDR) strains (PubMed:19876393). BTZs and DNBs are suicide inhibitors that act via covalent modification of DprE1; the essential nitro group of these compounds is reduced by DprE1 to a nitroso group, which then specifically reacts with Cys-387 of DprE1 to form an irreversible semimercaptal adduct (PubMed:20828197, PubMed:22733761, PubMed:24500695). Many other compounds with diverse scaffolds were found to act as either covalent (e.g. nitroquinoxalines, nitroimidazoles) or non-covalent (e.g. the benzothiazole derivative TCA1, the 2-carboxyquinoxaline Ty38C, 8-pyrrole-benzothiazinones, 1,4-azaindoles, pyrazolopyridones, 4-aminoquinolone piperidine amides) DprE1 inhibitors (PubMed:23776209, PubMed:25427196, PubMed:25987616, PubMed:24215368, PubMed:24818517, PubMed:27666194).
Monomer. Although forming apparent dimer in crystals, DprE1 does not dimerize appreciably in solution (PubMed:22733761). Interacts with DprE2 to form an epimerase complex (PubMed:25789990).
Traditional knockout mutant with dprE1 disruption could not be achieved, suggesting this gene is essential (PubMed:24517327). Conditional knock-down mutant of dprE1 show that down-regulation of DprE1 results in rapid in vitro growth arrest, swelling of the bacteria, cell wall damage, stop of cell division or lysis, decreased survival in macrophages and virulence attenuation (PubMed:24517327). Cells lacking this gene display impaired growth (PubMed:12657046).
Belongs to the heat shock protein 70 family.
By stress conditions e.g. heat shock and oxidative stress under control of SigH. There is another promoter.
Recombinant extracellular protein activates expression of NF-kappa-B in immortalized human dermal endothelial cells in a TLR2- and TLR4-dependent manner. Activation occurs via MYD88-dependent and -independent pathways and requires TIRAP, TRIF and TRAM (some experiments done in mouse cells, mice do not usually catch tuberculosis) (PubMed:15809303).
Forms a 10-stranded antiparallel beta-barrel structure able to accommodate a hydrophobic ligand in its interior. In fact, this fold hosts the heme group, which is located in a wide surface cleft.
Heme-binding protein able to scavenge peroxynitrite and to protect free L-tyrosine against peroxynitrite-mediated nitration, by acting as a peroxynitrite isomerase that converts peroxynitrite to nitrate. Therefore, this protein likely plays a role in peroxynitrite sensing and in the detoxification of reactive nitrogen and oxygen species (RNS and ROS, respectively). Is able to bind nitric oxide (NO) in vitro, but may act as a sensor of peroxynitrite levels in vivo.
Activity is inhibited by unphosphorylated GarA.
Belongs to the Glu/Leu/Phe/Val dehydrogenases family.
Catalyzes the reversible conversion of L-glutamate to 2-oxoglutarate.
Negative regulator of class I heat shock genes (grpE-dnaK-dnaJ and groELS operons). Prevents heat-shock induction of these operons.
Deletion mutant shows increased production of SMK.
May play a regulatory role in sulfomenaquinone (SMK) biosynthesis (PubMed:27933784). Not essential for SMK biosynthesis (PubMed:27933784).
Part of an operon that includes stf3 and cyp128, which are required for the production of SMK.
Catalyzes the formation of pyridoxal 5'-phosphate from ribose 5-phosphate (RBP), glyceraldehyde 3-phosphate (G3P) and ammonia. The ammonia is provided by the PdxT subunit. Can also use ribulose 5-phosphate and dihydroxyacetone phosphate as substrates, resulting from enzyme-catalyzed isomerization of RBP and G3P, respectively.
In the presence of PdxT, forms a dodecamer of heterodimers.
Controls rRNA transcription by binding to the RNA polymerase (RNAP). Required for replication and persistence during infection of mice.
Interacts directly with the N-terminus of the RNA polymerase subunit beta (RpoB).
Belongs to the thiolase-like superfamily.
Homodimer (PubMed:29109182). Interacts with the ChsH1/ChsH2 hydratase via the DUF35 C-terminal region of ChsH2 (ChsH2-DUF35) (PubMed:29109182, PubMed:31568719). The ChsH1-ChsH2-Ltp2 protein complex is composed of two protomers that form a heterohexameric structure through the Ltp2 dimerization interface (PubMed:31568719).
Involved in cholesterol side chain degradation (PubMed:22045806, PubMed:29109182). When associated with the ChsH1/ChsH2 hydratase, catalyzes the retroaldol cleavage of 17-hydroxy-3-oxo-4-pregnene-20-carboxyl-CoA (17-HOPC-CoA) produced by the hydratase, forming androst-4-ene-3,17-dione and propionyl-CoA (PubMed:29109182, PubMed:31568719).
Inactivation of pcaA does not affect initial growth of the organism over the first 3 weeks, but after 6 weeks, when wild-type organisms persist at a constant level indefinitely, the pcaA mutant is progressively eliminated from the animal. Cells lacking this gene accumulates a hybrid mycolate with a cis double bond at the proximal position in place of the cis cyclopropane present in wild-type alpha mycolate.
Involved in the phagosome maturation block (PMB). Catalyzes the conversion of a double bond to a cyclopropane ring at the proximal position of an alpha mycolic acid via the transfer of a methylene group from S-adenosyl-L-methionine. It can use cis, cis 11,14-eicosadienoic acid and linoelaidic acid as substrate. Cyclopropanated mycolic acids are key factors participating in cell envelope permeability, host immunomodulation and persistence.
Phosphorylation by PknF at Thr-168 and Thr-183 regulates the mycolic acid profile which affects colonial cording, intramacrophage replication and abrogates the PMB.
Regulated by PknF. Inhibited by S-adenosyl-N-decyl-aminoethyl (SADAE), thiacetazone (TAC) and dioctylamine.
Catalyzes the synthesis of S-sulfocysteine, utilizing O-phosphoserine (OPS) and thiosulfate as substrates. To a lesser extent, can also use sulfide as donor substrate, producing L-cysteine. CysK2 thus provides a third metabolic route to cysteine, either directly using sulfide as donor or indirectly via S-sulfocysteine. S-sulfocysteine might also act as a signaling molecule triggering additional responses in redox defense in the pathogen upon exposure to reactive oxygen species during intracellular survival or dormancy. Cannot utilize thiocarboxylated CysO as a sulfur donor and O-acetylserine (OAS) as acceptor substrate.
The enzyme uses a mechanism via a central aminoacrylate intermediate that is similar to that of other members of this pyridoxal phosphate-dependent enzyme family.
Belongs to the Cu-Zn superoxide dismutase family.
Destroys radicals which are normally produced within the cells and which are toxic to biological systems. May play a role in favoring mycobacterial survival in phagocytes (By similarity).
Does not bind zinc ions. Has normal enzyme activity in the absence of zinc ions.
Inhibited by the copper chelator diethyl dithiocarbamate.
Lacks two conserved histidine residues that bind copper and zinc.
Involved in the biosynthesis of a unique class of isonitrile lipopeptides (INLPs) that seem to function as virulence factors in M.tuberculosis and to play a role in metal acquisition (PubMed:28634299). Catalyzes a Michael addition of glycine to the beta-position of an alpha,beta-unsaturated fatty acyl-[ACP], producing a (3R)-3-[(carboxymethyl)amino]fatty acid. Acts on the (2E)-decenoyl moiety loaded on the acyl-carrier protein (ACP) Rv0100, forming the product (3R)-3-[(carboxymethyl)amino]decanoate released from the ACP (By similarity). Displays thioesterase activity with a preference for long chain fatty acyl groups; in vitro, cleaves the thioester linkage of palmitoyl-CoA, stearoyl-CoA, lauroyl-CoA and hexanoyl-CoA (PubMed:17524985). Contains low levels of trans-enoyl hydratase activity (PubMed:19136596).
Autophosphorylated at His-115 and His-247 using polyP as a phosphate donor.
Belongs to the polyphosphate kinase 2 (PPK2) family. Class I subfamily.
Expression increases during the exponential phase of growth and remains at a steady level up to the stationary phase.
Uses inorganic polyphosphate (polyP) as a donor to convert GDP to GTP. In addition, modulates nucleotide triphosphate synthesis catalyzed by the nucleoside diphosphate kinase (Ndk) in favor of GTP production over CTP or UTP. Plays an important role in survival of M.tuberculosis in macrophages.
Belongs to the arylamine N-acetyltransferase family.
Catalyzes the transfer of the acetyl group from acetyl coenzyme A to the free amino group of arylamines and hydrazines (PubMed:18795795). Is able to utilize not only acetyl-CoA, but also n-propionyl-CoA and acetoacetyl-CoA as acyl donors, although at a lower rate (PubMed:19014350). As acetyl-CoA and propionyl-CoA are products of cholesterol catabolism and the nat gene is likely present in the same operon than genes involved in cholesterol degradation, this enzyme could have a role in the utilization and regulation of these CoA species (PubMed:19014350).
It has been reported that overexpression of this enzyme may be responsible for increased resistance to the front-line antitubercular drug isoniazid (INH), by acetylating and hence inactivating the prodrug (PubMed:9973365). However, isoniazid is an extremely poor substrate for the enzyme; therefore, the expression of TBNAT is unlikely to be a significant cause of isoniazid resistance in M.tuberculosis (PubMed:18795795).
Reactions proceed via a bi-bi ping-pong kinetic mechanism.
Resistance to the antitubercular drug isoniazid (INH) has been associated to mutations in this gene in some INH-resistant clinical isolates of M.tuberculosis.
Activity is decreased in the presence of the PGI inhibitor 6-phosphogluconate (PubMed:16212940, PubMed:17126561). Does not require mono- or divalent cations for activity (PubMed:16212940, PubMed:17126561).
Catalyzes the reversible isomerization of glucose-6-phosphate to fructose-6-phosphate.
Catalyzes the activation of long-chain fatty acids as acyl-adenylates (acyl-AMP), which are then transferred to a multifunctional polyketide synthase (PKS) for further chain extension.
Belongs to the disproportionating enzyme family.
Belongs to the DEAD box helicase family. DeaD/CsdA subfamily.
DEAD-box RNA helicase involved in various cellular processes at low temperature, including ribosome biogenesis, mRNA degradation and translation initiation.
Autocleaved. The autocleavage activity is significant only when no reducing agent is present in buffers.
Disruption leads to an increased sensitivity to acid and fails to maintain intrabacterial pH in acid in vitro and in activated macrophages. Growth is also severely attenuated in mice.
Disulfide bond increases the proteolytic activity by stabilizing the protease in the conformation in which the active site residues are properly positioned for substrate binding and catalysis.
Inhibited by reducing agents and activated during exposure to oxidative stress.
Required for M.tuberculosis resistance to oxidative stress in addition to its role in resistance to acid, which is essential for virulence. It protects M.tuberculosis against phagolysosomal concentrations of acid and maintains its intrabacterial pH when phagocytosed by IFN-gamma-activated macrophages.
A secreted protein. Acts as a strong host (human) T-cell antigen (PubMed:11940590). Involved in translocation of bacteria from the host (human) phagolysosome to the host cytoplasm (PubMed:17604718). Might serve as a chaperone to prevent uncontrolled membrane lysis by its partner EsxA; native protein binds poorly to artificial liposomes in the absence or presence of EsxA (PubMed:17557817, PubMed:26260636). EsxA and EsxA-EsxB are cytotoxic to pneumocytes (PubMed:19906174). EsxB (and EsxA-EsxB but not EsxA alone) activates human neutrophils; EsxB transiently induces host (human) intracellular Ca(2+) mobility in a dose-dependent manner, monocytes and lymphocytes do not respond (PubMed:25332123). Neutrophils respond to EsxB by chemotaxis and primed neutrophils treated with EsxB produce reactive oxygen species (ROS); Ca(2+) release and the ROS burst via are induced by an unidentified G-protein coupled receptor (PubMed:25332123). May help regulate assembly and function of the type VII secretion system (T7SS) (PubMed:25865481).
Able to form a homodimer (By similarity). Forms a tight 1:1 complex with EsxA (ESAT-6) (PubMed:11940590, PubMed:14557536, PubMed:16048998, PubMed:16973880, PubMed:19854905, PubMed:19906174, PubMed:23150662, PubMed:26260636, PubMed:20085764, PubMed:15973432, PubMed:24586681). The complex persists even after secretion (PubMed:16048998). In vitro EsxB only interacts with non-acetylated EsxA; it interacts with C-terminally truncated EsxA (missing the last 10 residues) (PubMed:15378760). The native EsxA-EsxB complex dissociates at pH 4.0, and EsxA may then be freed to then lyse membranes (PubMed:17557817). Another study using recombinant protein did not find dissociation at acidic pH (PubMed:23150662). Recombinant heterodimer (with a His tag on EsxB) can be dissociated by the detergents amidosulfobetaine-14 and lauryldimethylamine N-oxide (PubMed:26260636). Interacts with EccCb1 (PubMed:14557536, PubMed:16973880, PubMed:25865481). Interacts with PPE68 (PubMed:17433643). Interacts with EccCa1, EccCb1, EsxA, EspI and EspJ (PubMed:19854905). An artificial EsxB-EsxA heterodimer interacts with EspA, EccB1, EccCa1, EccCb1, EspI, EspJ, EccA2 and EccE2; the latter 2 are from the adjacent ESX-2 locus (PubMed:19854905). Interacts with host (human) beta-2-microglobulin (B2M) in complex with EsxA; only binds free B2M and not B2M in complex with HLA-I (PubMed:25356553).
Bacteria no longer translocate from the phagolysosome to the cytosol of host (human) cells probably due to polar effects on the downstream esxA gene; bacteria replicate in phagolysosome, decreased apoptosis of infected host (human) dendritic cells (PubMed:17604718). Loss of ability to lyse host (human) lung epithelial cells, possibly due to polar effects on the downstream esxA gene; in BALB/c-infected mice bacteria are not as invasive and cause decreased lung disease (PubMed:14557547). No growth in the human macrophage-like cell line THP-1, no cytotoxicity (PubMed:14756778). Inactivation leads to absence of EsxA and EsxB from cell lysates (PubMed:14756778, PubMed:16368961). No secretion of EspA (PubMed:16030141).
Constitutively expressed, part of the esxB-esxA operon (PubMed:9846755).
Genes esxA and esxB are part of RD1 (part of a 15-gene locus known as ESX-1), a section of DNA deleted in the M.bovis BCG strain used for vaccination. Deletion of this region is thought to be largely responsible for the attenuation of BCG, and esxA and EsxB in particular are quite important in this effect (PubMed:14557547, PubMed:14756778, PubMed:16368961).
May be secreted as a 4 coiled-coil complex with EsxA (PubMed:16048998). The C-terminal domain is required for interaction with both EsxA and EccCb1; the last 7 amino acids are necessary and sufficient for EccCb1 binding and secretion (PubMed:16973880).
Stimulates pro-inflammatory cytokine expression via TLR2 signaling pathway. Activation of TLR2 results in the phosphorylation and activation of NF-kappa-B. Also induces TLR2 expression. May influence the innate immune responses to facilitate the survival of M.tuberculosis in the granulomatous microenvironment.
This protein serves as an immunogenic antigen, inducing gamma-interferon responses in whole-blood cultures from M.tuberculosis-exposed adults in Uganda, and The Gambia but not from South Africa, indicating this might be a good vaccine candidate.
Produces ATP from ADP in the presence of a proton gradient across the membrane. The catalytic sites are hosted primarily by the beta subunits.
Belongs to the pyrroline-5-carboxylate reductase family.
Catalyzes the reduction of 1-pyrroline-5-carboxylate (PCA) to L-proline.
Antitoxin component of a type II toxin-antitoxin (TA) system. Its cognate toxin is MazF8.
Forms a complex with cognate toxin MazF8.
Belongs to the ATP-dependent AMP-binding enzyme family. Carboxylic acid reductase subfamily.
Catalyzes the ATP- and NADPH-dependent reduction of carboxylic acids to the corresponding aldehydes (By similarity). In vitro, also catalyzes the activation of medium/long-chain fatty acids as acyl-adenylates (acyl-AMP) (PubMed:19182784).
The N-terminal domain likely catalyzes substrate activation by formation of an initial acyl-AMP intermediate, the central region contains the phosphopantetheine attachment site, and the C-terminal domain catalyzes the reduction by NADPH of the intermediate thioester formed from the attack of the phosphopantetheine thiol at the carbonyl carbon of acyl-AMP.
Belongs to the NAGSA dehydrogenase family. Type 1 subfamily.
Catalyzes the NADPH-dependent reduction of N-acetyl-5-glutamyl phosphate to yield N-acetyl-L-glutamate 5-semialdehyde.
Belongs to the universal ribosomal protein uL16 family.
Binds 23S rRNA and is also seen to make contacts with the A and possibly P site tRNAs.
Deletion of the gene confers resistance to arylamide compounds.
May be involved in the import of arylamide compounds.
Overexpression is toxic in both wild-type and mutant backgrounds.
1-TbAd is highly prevalent among patient-derived M.tuberculosis strains, where it is among the most abundant lipids produced.
Belongs to the diterpene synthase family.
Deletion of the gene abolishes 1-TbAd biosynthesis and decreases the formation of swollen phagosomes.
Inhibited by the bisphosphonate inhibitor BPH-629.
Tuberculosinyl transferase that catalyzes the condensation of adenosine and tuberculosinyl diphosphate (TbPP) to generate 1-tuberculosinyladenosine (1-TbAd), which acts as an antiacid that directly protects M.tuberculosis from acid pH and physically remodels M.tuberculosis phagolysosomes (PubMed:24516143, PubMed:31427817). In addition, acts as a phosphatase that catalyzes the diphosphate-removal from TbPP to produce both tuberculosinol (TOH) and isotuberculosinol (iso-TOH) (PubMed:21228491, PubMed:24475925). Has broad substrate specificity, and can also use the 3 labdadienyl diphosphates, copalyl diphosphate (CDP), ent-CDP and syn-CDP in vitro (PubMed:21290071).
Contains multiple, broadly recognized T-cell epitopes and is a major target of cellular immunity in both active and latent tuberculosis infection, indicating this might be a good vaccine candidate (PubMed:21427227). A fusion protein (p846) of 3 well-defined antigens (EspC, EsxH and Rv2660c) induces robust specific T-cell immune response and could be an effective vaccine (PubMed:24280763).
Mutant exhibits pathogenesis defects, including reduced virulence in mice, attenuated growth in macrophages and an inability to suppress immunostimulatory cytokines such as IL-12 (PubMed:16135231). Host (human) cells no longer produce cytokine IP-10 (CXCL10) upon infection, but continue to produce IL-1 beta (IL1B) (PubMed:26048138).
Required for ESX-1 function. Required for either stability or expression of EspA.
The C-terminal region is required for secretion by the ESX-1 system.
In IrtB the ATP-binding domain (NBD) and the transmembrane domain (TMD) are fused.
Mutants show normal growth in iron-sufficient conditions, but show a growth defect under iron-deficient conditions.
Part of the ABC transporter complex IrtAB involved in the import of iron-bound mycobactin (Fe-MBT) and carboxymycobactin (Fe-cMBT) (PubMed:16385031, PubMed:19948799) (By similarity). Transmembrane domains (TMD) form a pore in the membrane and the ATP-binding domain (NBD) is responsible for energy generation (By similarity). Required for replication in human macrophages and in mouse lungs (PubMed:16385031).
PubMed:18461140 reports that IrtB forms a siderophore importer with Rv2895c, however this activity could be due to functional differences of IrtB in the molecular context of M.smegmatis and M.tuberculosis.
Associates with subunits I, II and III to form cytochrome c oxidase.
Belongs to the cytochrome c oxidase bacterial subunit CtaF family.
Part of cytochrome c oxidase, its function is unknown.
Antitoxin component of a type II toxin-antitoxin (TA) system. Upon expression in M.smegmatis neutralizes the effect of cognate toxin VapC21.
Monomer. Part of the FGAM synthase complex composed of 1 PurL, 1 PurQ and 2 PurS subunits.
Belongs to the glycosyl hydrolase 13 family. TreS subfamily.
Catalyzes the reversible interconversion of maltose and trehalose by transglucosylation (PubMed:18505459). Also displays amylase activity, catalyzing the endohydrolysis of (1->4)-alpha-D-glucosidic linkages in glycogen and maltooligosaccharides such as maltoheptaose, to produce maltose which then can be converted to trehalose (PubMed:18505459). TreS plays a key role in the utilization of trehalose for the production of glycogen and alpha-glucan via the TreS-Pep2 branch involved in the biosynthesis of maltose-1-phosphate (M1P) (PubMed:18505459, PubMed:27513637). Might also function as a sensor and/or regulator of trehalose levels within the cell (PubMed:18505459). Thus, when trehalose levels in the cell become dangerously low, TreS could expedite the conversion of glycogen to maltose via its amylase activity and then convert the maltose to trehalose; but this enzyme also could expedite or promote the conversion of trehalose to glycogen when cytoplasmic trehalose levels become too high (PubMed:18505459).
Cells lacking this gene are as virulent as wild-type in mice, however also show a profound impact on intracellular and capsular glucan (PubMed:20305657, PubMed:27513637). It is not possible to inactivate Rv3032 in a mutant lacking treS, suggesting the joint essentiality of the different alpha-(1->4)-glucans biosynthesis pathways involving these two genes (PubMed:20305657). Combined inactivation of glgM and treS results in absence of alpha-glucan (PubMed:27513637). Combined inactivation of treS and glgC results in absence of alpha-glucan content and is significantly attenuated for growth in the lung and spleen of BALB/C mice during both the acute and chronic phase of infection (PubMed:27513637).
Maltose-1-phosphate (M1P), the building block required for alpha-glucan production, is generated by two alternative routes: the TreS-Pep2 branch and the GlgC-GlgM branch, however it seems that TreS-Pep2 branch provides most of M1P for the GlgE pathway in M.tuberculosis.
Expression in M.smegmatis increases cell resistance to human beta-defensin 2 (hBD-2) and to sodium nitrite (PubMed:35365094). It also reduces the negative charge on the bacterial surface upon exposure to an acidic environment, enhances bacterial cell viability at lethal acidic pH and induces a slowdown in biofilm formation (PubMed:35365094).
Plays a role in mycobacterial fitness (PubMed:35365094). Likely enhances survival of pathogenic strains (PubMed:35365094). Considerably reduces the overall net negative charge on bacterial surface when bacteria are exposed to an acidic environment (PubMed:35365094).
Unlike homologous domains of MprF and LysX that are positioned in the cytoplasm, the MprF-like domain of LysX2 is in the extracytoplasmic region.
Putative antitoxin component of a type II toxin-antitoxin (TA) system. Its cognate toxin would be HigB2.
Belongs to the PEP-utilizing enzyme family.
Catalyzes the acetylation of serine by acetyl-CoA to produce O-acetylserine (OAS).
Antitoxin component of a type II toxin-antitoxin (TA) system. Upon expression in E.coli neutralizes the effect of cognate toxin ParE2.
Belongs to the polyribonucleotide nucleotidyltransferase family.
Involved in mRNA degradation. Catalyzes the phosphorolysis of single-stranded polyribonucleotides processively in the 3'- to 5'-direction.
Belongs to the glutamate--cysteine ligase type 2 family. EgtA subfamily.
Catalyzes the synthesis of gamma-glutamylcysteine (gamma-GC) (PubMed:16262797). This compound is used as substrate for the biosynthesis of the low-molecular thiol compound ergothioneine (By similarity).
Weakly inhibited by L-methionine-S,R-sulphoximine (MSO) and strongly inhibited by D,L-buthionine-S,R-sulphoximine (BSO) in vitro.
Acyl-CoA dehydrogenase that exhibits broad specificity for linear acyl-CoA substrates, with a preference for long-chain substrates.
A triple higB1-higA1-Rv1957 disruption mutant has no visible phenotype. A single deletion in this gene cannot be made, suggesting that it has antitoxin activity.
Antitoxin component of an atypical, type II toxin-antitoxin chaperone (TAC) system. Upon expression in M.smegmatis neutralizes the effect of cognate toxin HigB1. Neutralization of HigB1 toxin in E.coli or M.marinum also requires SecB-like chaperone Rv1957, making this the first toxin-antitoxin chaperone (TAC) system. Antitoxin aggregation and degradation are prevented by the chaperone.
In M.tuberculosis represses expression of the Rv1954A-higB1-higA1-Rv1957 operon promoter but not that of the higB1-higA1-Rv1957 operon.
Induced by hypoxia and probably by the DNA damaging agent mitomycin C. Part of the Rv1954A-higB1-higA1-Rv1957 operon, as well as the higB1 higA1-Rv1957 operon, which is probably the mitomycin-induced operon; the former but not latter operon is autorepressed by HigA1 (PubMed:20585061). Induced in persister cells in response to D-cycloserine (PubMed:21673191).
Interacts with SecB-like chaperone Rv1957.
Upon expression in E.coli, Rv1956 has been shown to function as a toxin inhibiting cell growth and colony formation that is neutralized by coexpression with Rv1955 (PubMed:19016878). It is not clear if these conflicting results are due to expression in a heterologous system. The gene names higA and higB have been assigned to both Rv1955 and Rv1956; we have chosen to call Rv1956 higA1 after consulting the authors.
Belongs to the thiamine-phosphate synthase family.
Condenses 4-methyl-5-(beta-hydroxyethyl)thiazole monophosphate (THZ-P) and 2-methyl-4-amino-5-hydroxymethyl pyrimidine pyrophosphate (HMP-PP) to form thiamine monophosphate (TMP).
TPS activity is potently inhibited by several molecules such as 4-{[(2-hydroxy-5-nitrophenyl)methylidene]amino}-5-methyl-2-(propan-2-yl)phenol (NSC compound 33472) and 2-{5-[2,4,6-(trinitrophenyl)amino]-1H-tetrazol-1-yl}ethanol (NSC compound 116720).
Activity is increased by phosphorylation.
Autophosphorylated (PubMed:19366344, PubMed:22888002, PubMed:29884774). Can be phosphorylated in vitro on threonine residues by several mycobacterial eukaryotic-like Ser/Thr protein kinases (eSTPKs), including PknA, PknD, PknF and PknK. PknD and PknK can enhance PtkA autophosphorylation activity in vitro (PubMed:26417687). Phosphorylated in vitro on serine residues by the eukaryotic serine/threonine kinase PKA (PubMed:29494752).
Belongs to the HAD-like hydrolase superfamily. CbbY/CbbZ/Gph/YieH family.
Composed of two domains: the N-terminal highly flexible intrinsically disordered domain (IDD) and the C-terminal rigid kinase core domain (KCD) (PubMed:29494752, PubMed:29884774, PubMed:32157138). IDD is unstructured and highly dynamic, allowing transient interactions with the rigid KCD. This interaction modulates the accessibility of the KCD active site (PubMed:29884774). In closed state, IDD masks the autophosphorylation site, thereby decreasing the activity of PtkA. In open state conformation, IDD is away from the autophosphorylation site, making it accessible for phosphorylation and activation of PtkA (PubMed:29884774). Phosphorylation of PtkA by serine/threonine kinase induces conformational changes of IDD, which promotes the open state (PubMed:29884774). IDD had a greater inhibitory effect on the catalytic activity of KCD in the presence of the drugs esculin and inosine pranobex (PubMed:32157138).
Deletion mutant shows impaired intracellular survival within the human THP-1 macrophage infection model, and fails to inhibit phagosome acidification. However, the mutant displays enhanced resistance against oxidative stress in vitro. Disruption of the gene increases secretion of the thioredoxin reductase TrxB.
Interacts with PtpA (PubMed:19366344, PubMed:22888002, PubMed:29724125). The presence of a phosphate donor increases the interaction affinity (PubMed:19366344). Interacts with TrxB (PubMed:29317718). Interacts with several eukaryotic-like Ser/Thr protein kinases (eSTPKs) in vivo, including PknA (PubMed:26417687).
PtkA-PtpA (TK-TP) interaction could be a good target for drug discovery program. Benzylbenzofurans and benzofuranamides disrupt the PtkA-PtpA interaction, which inhibits activation of PtpA and leads to the decrease in intracellular survival of mycobacteria.
Required for growth within macrophages (PubMed:29317718). Catalyzes the phosphorylation of PtpA on the tyrosine residues at positions 128 and 129, thereby increasing PtpA phosphatase activity and promoting pathogenicity (PubMed:19366344, PubMed:22888002, PubMed:25535696, PubMed:29724125). Also phosphorylates the thioredoxin reductase TrxB (PubMed:29317718).
Belongs to the universal ribosomal protein uL23 family.
One of the early assembly proteins it binds 23S rRNA. One of the proteins that surrounds the polypeptide exit tunnel on the outside of the ribosome. Forms the main docking site for trigger factor binding to the ribosome.
Part of the 50S ribosomal subunit. Contacts protein L29, and trigger factor when it is bound to the ribosome.
Toxic component of a type II toxin-antitoxin (TA) system. An RNase (By similarity). Upon expression in M.smegmatis inhibits translation and colony formation. Its toxic effect on colony formation is neutralized by coexpression with cognate antitoxin VapB47; the effect on translation has not been tested but is probably neutralized also.
Belongs to the SLC41A transporter family.
Belongs to the CRISPR-associated Csm4 family.
The subunit probably binds to the 5' handle of the crRNA, helping in discrimination between self- and non-self.
Belongs to the methylmalonyl-CoA mutase family.
Catalyzes the isomerization of succinyl-CoA to methylmalonyl-CoA during synthesis of propionate from tricarboxylic acid-cycle intermediates.
Heterodimer of an alpha and a beta chain.
Bacitracin is thought to be involved in the inhibition of peptidoglycan synthesis by sequestering undecaprenyl diphosphate, thereby reducing the pool of lipid carrier available.
Catalyzes the dephosphorylation of undecaprenyl diphosphate (UPP). Confers resistance to bacitracin.
Deletion mutant is partially attenuated during murine tuberculosis, but not during the chronic steps of infection. On day 28 post infection, shows a slight reduction of the bacterial burden, but on day 70, bacterial counts of the mutant are similar to the wild-type strain.
Expression is down-regulated in macrophages and infected mice.
A member of the dormancy regulon. Moderately expressed under aerobic conditions, it is strongly induced in response to reduced oxygen tension (hypoxia), low levels of nitric oxide (NO) and carbon monoxide (CO) (PubMed:11416222, PubMed:12953092, PubMed:17609369, PubMed:18474359, PubMed:18400743). It is hoped that this regulon will give insight into the latent, or dormant phase of infection. Expression under hypoxic conditions, but not aerobically, is autoregulated. Member of the Rv3134c-devR-devS operon (PubMed:10970762).
Homodimer (PubMed:18353359). Interacts with NarL (PubMed:25659431).
Member of the two-component regulatory system DevR/DevS (also called DosR/DosS) involved in onset of the dormancy response (PubMed:15033981). Regulates an approximately 48-member regulon (PubMed:12953092, PubMed:11416222, PubMed:15033981, PubMed:18400743). When phosphorylated binds and activates the promoter of DevR regulon genes in response to hypoxia (PubMed:18359816, PubMed:21764934, PubMed:28977726). The presence of target DNA increases stability of phospho-DevR in vitro (PubMed:28977726). Activates its own transcription under hypoxic but not aerobic conditions, probably binds as a dimer to tandem binding sites within the devR and hspX promoters (PubMed:18359816). Accepts a phosphate group from DevS (DosS) and from DosT (PubMed:15033981, PubMed:15073296, PubMed:21764934, PubMed:28977726). Does not regulate transcription of dosT (PubMed:19487478).
Phosphorylated on Asp-54 by both DevS (DosS) and DosT (PubMed:15033981, PubMed:15073296, PubMed:21764934). Phosphorylated on Thr-198 and Thr-205 by PknH, which enhances DevR dimerization (PubMed:20630871). Aspartate phosphorylation and threonine phosphorylation cooperatively enhance DevR binding to DNA (PubMed:20630871).
Strains deleted for this gene show hypervirulence upon intravenous inoculation in the mouse and DBA/2 model (PubMed:12595424). However contradictory results were shown for using a devR/devS deletion strain in rabbits, guinea pigs and C57BL/6 mice (PubMed:19103767). All studies agree that deletion strains fail to induce the dormancy regulon genes in response to hypoxia, NO, and CO (PubMed:11416222, PubMed:12694625, PubMed:18474359, PubMed:18400743, PubMed:19487478). Deletion has no effect on expression of dosT (PubMed:19487478).
The dev nomenclature derives from the increased expression (differentially expressed in virulent strain, dev) of these genes in virulent H37Rv versus avirulent H37Ra. The dos nomenclature derives from experiments in M.bovis showing the same genes are essential for dormancy survival (dos).
Transcriptionally repressed by IdeR and iron. Induced during infection of human THP-1 macrophages.
Antitoxin component of a possible type II toxin-antitoxin (TA) system. The cognate toxin is VapC7.
Mutant is slightly more resistant to copper. Mutation does not attenuate growth in mice.
Forms a 24-polypeptide structural core with octahedral symmetry (By similarity). Part of the BCKADH complex, consisting of multiple copies of BkdA/BkdB (E1), BkdC (E2) and Lpd (E3).
Member of the two-component regulatory system NarS/NarL involved in gene expression during aerobic nitrate metabolism (PubMed:25659431). Plays therefore a crucial role in anaerobic survival of mycobacteria in host. Functions as a sensor protein kinase which is autophosphorylated at a histidine residue and transfers its phosphate group to the conserved aspartic acid residue in the regulatory domain of NarL (PubMed:25659431). In turn, NarL binds to the upstream promoter regions of target genes to regulate their expression during aerobic nitrate metabolism (PubMed:25659431).
Belongs to the MurCDEF family. MurT subfamily.
The lipid II isoglutaminyl synthase complex catalyzes the formation of alpha-D-isoglutamine in the cell wall lipid II stem peptide. The MurT subunit catalyzes the ATP-dependent amidation of D-glutamate residue of lipid II, converting it to an isoglutamine residue.
Belongs to the bacterial ribosomal protein bS20 family.
Inhibited by bengamide derivatives and by various metalloform-selective inhibitors.
May be involved in the GO system responsible for removing an oxidatively damaged form of guanine (7,8-dihydro-8-oxoguanine, 8-oxo-dGTP) from DNA and the nucleotide pool. 8-oxo-dGTP is inserted opposite dA and dC residues of template DNA with almost equal efficiency thus leading to A.T to G.C transversions. MutT specifically degrades 8-oxo-dGTP to the monophosphate (By similarity).
Toxic component of a type II toxin-antitoxin (TA) system. An RNase. The cognate antitoxin is VapB10 (By similarity).
Belongs to the vitamin-B12 independent methionine synthase family.
Catalyzes the transfer of a methyl group from 5-methyltetrahydrofolate to homocysteine resulting in methionine formation.
Overexpression in M. smegmatis increases resistance to erythromycin, ampicillin, novobiocin and vancomycin. It also reduces accumulation of ethidium bromide in the cell.
The ATP-binding domains (NBD) and the transmembrane domains (TMD) are fused.
Belongs to the ArfC membrane protein family.
Expression in M.smegmatis leads to reduced survival capacity of human macrophage-like THP-1 cells and increase of the release of nitrogen monoxide (NO), and increase of the release of lactate dehydrogenase (LDH) and NO from mouse bone marrow macrophage line ANA-1 cells.
Part of the arfA-arfB-arfC operon. Maximal expression of ArfA requires the full operon.
Required for wild-type expression of ArfA and ammonia secretion, not however part of an ammonia transporter (PubMed:21410778). Is highly immunogenic and may play a role in virulence (PubMed:19168955).
Upon operon disruption no reduction of serine uptake at pH 6.9, no visible effect on outer membrane permeability, however severe delays in ammonia secretion, medium pH neutralization and growth also occur at pH 5.5.
Belongs to the DNA polymerase type-C family. DnaE subfamily.
DNA polymerase III is a complex, multichain enzyme responsible for most of the replicative synthesis in bacteria. Pol III also exhibits 3' to 5' exonuclease activity. The alpha chain is the DNA polymerase (By similarity).
The Pol III holoenzyme complex contains at least 10 different subunits organized into 3 functionally essential subassemblies: the Pol III core, the beta sliding clamp processivity factor and the clamp-loading complex. The Pol III core (subunits alpha, epsilon and theta) contains the polymerase and the 3'-5' exonuclease proofreading activities. The polymerase is tethered to the template via the dimeric beta sliding clamp processivity factor. The clamp loader (also called gamma complex) assembles the beta sliding clamp onto the primed template and plays a central role in the organization and communication at the replication fork. The clamp-loading complex contains delta, delta', psi and chi, and 3 copies of either or both of two different DnaX proteins, gamma and tau. The DNA replisome complex has a single clamp loader (3 tau and 1 each of delta, delta', psi and chi subunits) which binds 3 Pol III cores (1 core on the leading strand and 2 on the lagging strand) each with a beta sliding clamp dimer (By similarity). Interacts with the beta-sliding clamp (DnaN) (PubMed:21219854). Co-immunoprecipitates with DarG in the presence and absence of darT (PubMed:32634279).
Catalyzes the hydrolysis of the gamma-glutamyl amide bond of hercynyl-gamma-L-glutamyl-L-cysteine sulfoxide to produce hercynylcysteine sulfoxide, a step in the biosynthesis pathway of ergothioneine. Ergothioneine is an antioxidant that protects mycobacteria from oxidative stress.
May catalyze the biosynthesis of cardiolipin from phosphatidylglycerol (PG) and CDP-diacylglycerol. May also catalyze the synthesis of phosphatidylinositol.
May participate in the regulatory network that controls the expression of MmpL lipid transporters (PubMed:26396194). Binds to intragenic and/or promoter regions of rv1816, mmpL3, rv0204, mmpL11, mmpL7, kasA and mmpS3 (PubMed:26396194).
Belongs to the class-II DAHP synthase family.
Binds 1 divalent cation per subunit. The enzyme is active with manganese, cobalt or cadmium ions.
Catalyzes an aldol-like condensation reaction between phosphoenolpyruvate (PEP) and D-erythrose 4-phosphate (E4P) to generate 3-deoxy-D-arabino-heptulosonate 7-phosphate (DAH7P) and inorganic phosphate.
Feedback inhibited by tryptophan, tyrosine, phenylalanine and chorismate.
Belongs to the UDP-galactopyranose/dTDP-fucopyranose mutase family.
Catalyzes the interconversion through a 2-keto intermediate of uridine diphosphogalactopyranose (UDP-GalP) into uridine diphosphogalactofuranose (UDP-GalF) which is a key building block for cell wall construction in Mycobacterium tuberculosis.
Negatively regulates transcription of bacterial ribonucleotide reductase nrd genes and operons by binding to NrdR-boxes.
Belongs to the OXA1/ALB3/YidC family. Type 1 subfamily.
Interacts with the Sec translocase complex via SecD. Specifically interacts with transmembrane segments of nascent integral membrane proteins during membrane integration (By similarity).
Required for the insertion and/or proper folding and/or complex formation of integral membrane proteins into the membrane. Involved in integration of membrane proteins that insert both dependently and independently of the Sec translocase complex, as well as at least some lipoproteins. Aids folding of multispanning membrane proteins (By similarity).
ATPase activity inhibited by EDTA (PubMed:26396239).
An ATPase (PubMed:26396239). Part of the ESX-1 specialized secretion system, which delivers several virulence factors to host cells during infection, including the key virulence factors EsxA (ESAT-6) and EsxB (CFP-10) (PubMed:16368961).
Ca(2+) has 50% activity (PubMed:26396239).
Has a discontinuous central core of beta sheets stabilized by a disulfide bond that is flanked by 2 structural domain repeats on each side; the protein forms an elongated 'S'-shaped structure (PubMed:26396239, PubMed:26841765, PubMed:26922638). Repeat A2 (approximately residues 265-323) is farthest from the cell inner membrane and is quite mobile, swinging on 2 inter-repeat loops (A, residues 234-264 and B, 324-341) (PubMed:26841765).
Oligomerizes, possibly a hexamer (PubMed:26396239). Part of the ESX-1 / type VII secretion system (T7SS), which is composed of cytosolic and membrane components. The ESX-1 membrane complex is composed of EccB1, EccCa1, EccCb1, EccD1 and EccE1. Residues 72-342 interact with an artificial EsxB-EsxA heterodimer (PubMed:19854905).
Could be part of the ESX-2 / type VII secretion system (T7SS), which is composed of cytosolic and membrane components (By similarity). Residues 138-211 interact with an artificial EsxB-EsxA heterodimer from the adjacent ESX-1 locus (PubMed:19854905).
Activity of PfkB is tenfold lower than that of PfkA (PubMed:33540748). Activity with tagatose-6-phosphate suggests that PfkA and/or PfkB may substitute for tagatose-6-phosphate kinase and further support glycolysis (PubMed:33540748).
Catalyzes the phosphorylation of D-fructose 6-phosphate to fructose 1,6-bisphosphate by ATP, the first committing step of glycolysis (PubMed:33540748). Can also catalyze the phosphorylation of tagatose-6-phosphate. The catalytic efficiency with tagatose-6-phosphate is about 1.8 times lower than that with fructose 6-phosphate (PubMed:33540748). Can use phosphate donors other than ATP (GTP and ITP), with lower efficiency (PubMed:33540748). In addition, can catalyze the reverse gluconeogenic reaction, albeit with low efficiency (PubMed:33540748). May support and maintain basic glycolysis and metabolic fluxes during conditions inhibiting PfkA (PubMed:33540748).
Not inhibited by an excess of substrates and common allosteric inhibitors. Inhibited by high concentrations of the reaction products, fructose 1,6-bisphosphate and ADP.
The magnesium does not function as an allosteric effector but is essential for glycolytic reaction.
Induces an inflammatory response and cell apoptosis in the host cells. Increases expression of IL-6, NF-kappaB, TLR-2, TLR-6, TNF-alpha, and MyD88 in mouse alveolar macrophage RAW264.7 cells. Persistent expression induces RAW264.7 cell apoptosis in vitro.
Inhibited by the serine esterase inhibitors PMSF (100%), E600 (80%) and THL (22%) (PubMed:17784850). Virtual screening identified a tautomer of ZINC13451138, known inhibitor for HIV-1 integrase, as a potential inhibitor (Probable).
Involved in the hydrolysis of exogenous host lipids during chronic infection (Probable). Catalyzes the hydrolysis of both monoacylglycerols (MAG) and diacylglycerols (DAG), with a preference for MAG. It hydrolyzes 2-MAG, 1-3-MAG and MAG with short, medium and long chain fatty acids such as 1-monobutyroyl-rac-glycerol (MC4), 1-mono-octanoyl-rac-glycerol (MC8), 1-monodecanoyl-rac-glycerol (MC10), 1-monolauroyl-rac-glycerol (MC12), 1-monomyristoyl-rac-glycerol (MC14) and 1-mono-oleyl-rac-glycerol (MC18:1) (PubMed:17784850). Also able to hydrolyze DAG with short (DiC6) and medium (DiC10) fatty acid chains, but not with longest fatty acid chains (PubMed:17784850). Can also hydrolyze vinyl laurate (VC12), vinyl butyrate (VC4) and vinyl propionate (VC3) (PubMed:17784850).
Rv0183 represents a suitable and promising drug target.
The Rv0183 antigen-specific IL-6 response has the potential to be used as an immune-diagnosis test for active TB in clinical practice.
Belongs to the nucleoside triphosphate pyrophosphohydrolase family.
Required to maintain the full capacity of the mycobacterium to respond to oxidative stress via the degradation of oxidation-induced damaged nucleotides. Hydrolyzes all canonical (d)NTPs, as well as mutagenic dUTP and 8-oxo-7,8-dihydro-2'-deoxyguanosine 5'-triphosphate (8-oxo-dGTP). Also involved in the transcriptional activation of RelA in response to oxidative stress.
Belongs to the mycobacterial pilin family.
Forms a homomer composed of subunits assembled in a large structure.
Is produced during infection of the human host.
Structural subunit of M.tuberculosis pili (MTP), which are thin (2- to 3-nm wide), flexible, coiled-coil, aggregative fibers. Has a strong affinity for laminin but lacks significant binding affinity for fibronectin or type IV collagen. Mediates adhesion to the extracellular matrix, an event that would facilitate direct interaction with the host epithelium during infection in the lung or other tissues.
Belongs to the metallo-beta-lactamase superfamily.
Belongs to the major facilitator superfamily. TCR/Tet family.
The glycine cleavage system catalyzes the degradation of glycine.
Catalyzes the addition of isopentenyl diphosphate (IPP) onto dimethylallyl diphosphate (DMAPP) to form geranyl pyrophosphate (GPP) (PubMed:21237161, PubMed:30301210). Is probably involved in the biosynthesis of decaprenyl diphosphate, which is required for mycobacterial cell wall synthesis (PubMed:21237161). Could be required for host endothelial-cell invasion and/or intracellular survival (PubMed:16586367).
Contains two aspartate-rich motifs, designated as FARM (the first aspartate-rich motif) and SARM (the second aspartate-rich motif). Rv0989c contains arginine in place of the second Asp in its FARM and first Asp in its SARM. The primary role of the FARM and SARM is the chelation of the divalent magnesium ion cofactors that assist substrate binding and catalysis, but it may also play a role in determining product chain length.
Belongs to the pseudouridine synthase TruB family. Type 1 subfamily.
Responsible for synthesis of pseudouridine from uracil-55 in the psi GC loop of transfer RNAs.
Alternative, nonproton pumping NADH:quinone oxidoreductase that delivers electrons to the respiratory chain by oxidation of NADH and reduction of quinones (PubMed:15767566, PubMed:29382761, PubMed:29522317). Ndh is probably the main NADH dehydrogenase of M.tuberculosis (PubMed:29382761).
Deletion mutant is attenuated for growth and virulence in mice (PubMed:29382761). Deletion of the gene alters the NADH/NAD(+) ratio, suggesting that this enzyme has an important function in maintaining the redox status of the cell (PubMed:29382761). Mutant shows growth defects in vitro and is more susceptible to oxidative stress reagents, but not to potential NADH dehydrogenase inhibitors (PubMed:29382761). Was considered as an essential gene in vitro, but later studies show that ndh is not essential individually (PubMed:25128581, PubMed:29382761). The ndh-ndhA double knockout could not be obtained, suggesting that at least one type II NADH dehydrogenase is required for M.tuberculosis growth (PubMed:29382761).
Inhibited by phenothiazine analogs (PubMed:15767566). Inhibited by 2-mercapto-quinazolinones (PubMed:29522317). Not inhibited by classic inhibitors of type I NADH dehydrogenase, such as rotenone, piericidin A and pyridaben (PubMed:15767566).
Homodimer. Hexamer formed by 3 homodimers.
Involved in the catabolism of quinolinic acid (QA).
Expressed during infection. Expressed during exponential growth in vitro.
Immunodominant antigen that could be used for serological diagnosis to distinguish patients with active tuberculosis from M.bovis BCG-vaccinated individuals (PubMed:17328725, PubMed:19467342, PubMed:23136116). Candidate for development of a vaccine for the control of tuberculosis (PubMed:18426397, PubMed:25586105).
Plays a key role in regulating innate and adaptive immune responses through human Toll-like receptor 2 (TLR2). Interacts with TLR2, leading to the subsequent activation of the mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NF-kappa-B) signaling pathways. Induces macrophage activation by augmenting the expression of several cell surface molecules (CD40, CD80, CD86 and MHC class II) and pro-inflammatory cytokines (TNF-alpha, IL-6 and IL-12p40) within macrophages. Also participates in adaptive immunity by directing Th1-polarised immune responses (PubMed:25586105). Stimulates specific humoral and cellular immune responses in tuberculosis (TB) patients (PubMed:17328725, PubMed:19467342, PubMed:23136116). Induces a strong IgG(1) antibody response and an increased Th1/Th2 type immune response in mice (PubMed:18426397).
Contributes to spectinomycin and tetracycline resistance.
Contains an unusual winged helix-turn-helix (wHTH) DNA-binding motif missing the typical third helix.
Monomer in solution. May form homodimers. Interacts with phosphorylated PknL.
Phosphorylated by PknL. Phosphorylation negatively regulates DNA-binding activity.
Toxic component of a type II toxin-antitoxin (TA) system. An RNase (By similarity). Upon expression in M.smegmatis inhibits colony formation. Its toxic effect is neutralized by coexpression with cognate antitoxin VapB3.
Induced by cholesterol and repressed by KtsR (PubMed:17635188). Up-regulated in vitro by acid shock and ex vivo by macrophage challenge (PubMed:18486437).
Involved in the third cycle of side chain dehydrogenation in the beta-oxidation of cholesterol catabolism (PubMed:26161441). May play an important role for the initial macrophage invasion, possibly in response to the acidification of phagosome (PubMed:18486437). It contributes partly to the virulence by increasing the efficiency of beta-oxidation (PubMed:18486437, PubMed:22045806). Catalyzes the dehydrogenation of 2'-propanoyl-CoA ester side chains of 3-oxo-4-pregnene-20-carboxyl-CoA (3-OPC-CoA) to yield 3-oxo-4,17-pregnadiene-20-carboxyl-CoA (3-OPDC-CoA). Also able to dehydrogenate steroyl-CoA such as 3-oxo-chol-4-en-24-oyl-CoA (3-OCO-CoA), 1beta-(2'-propanoyl-CoA)-3a-alpha-H-7a-beta-methylhexahydro-4-indanone (indanone-CoA ester), hexahydroindanone and pregenenone (PubMed:22045806, PubMed:23560677, PubMed:26161441).
Appears to bind only one FMN molecule per homodimer.
Belongs to the pyridoxamine 5'-phosphate oxidase family.
Catalyzes the oxidation of pyridoxine 5'-phosphate (PNP) into pyridoxal 5'-phosphate (PLP). Unlike many PNPOx enzymes, Rv2607 does not recognize pyridoxamine 5'-phosphate (PMP) as a substrate.
The electron density for the FMN cofactor is weak in the crystal structure (PDB 2A2J), which does not allow FMN to be definitively placed in the M.tuberculosis PNPOx active site, but the residues known to interact with FMN in the E.coli and human PNPOx enzymes are found to be conserved.
Belongs to the DNA glycosylase MPG family.
Removes 5-oxoproline from various penultimate amino acid residues except L-proline.
Possibly the antitoxin component of a type II toxin-antitoxin (TA) system. Its cognate toxin is VapC48.
Part of the SecDF-YidC-YajC translocase complex. The SecDF-YidC-YajC translocase forms a supercomplex with SecYEG, called the holo-translocon (HTL).
The SecYEG-SecDF-YajC-YidC holo-translocon (HTL) protein secretase/insertase is a supercomplex required for protein secretion, insertion of proteins into membranes, and assembly of membrane protein complexes. While the SecYEG complex is essential for assembly of a number of proteins and complexes, the SecDF-YajC-YidC subcomplex facilitates these functions.
Homodimer. Forms an heterotetramer composed of two aldolase (HsaF) and two dehydrogenase (HsaG) subunits.
Involved in cholesterol degradation. Catalyzes the retro-aldol cleavage of 4-hydroxy-2-oxohexanoate (HOHA) to pyruvate and propanal. Can also catalyze the cleavage of 4-hydroxy-2-oxopentanoate (HOPA) to pyruvate and acetaldehyde. The aldehydes produced by this reaction are directly channeled to the dehydrogenase HsaG.
Requires a divalent metal cation. Activity is highest in the presence of Mn(2+), followed by Co(2+) and Ni(2+). Mg(2+) and Ca(2+) are poor metal cofactors. No activity with Cd(2+), Zn(2+) or Cu(2+).
Shows aldolase activity only when expressed and copurified with HsaG. This arrangement probably prevents the deleterious formation and release of toxic aldehydes in the absence of the partner dehydrogenase.
Belongs to the metallophosphoesterase superfamily. YfcE family.
4'-phosphopantetheine is transferred from CoA to specific serines of apo-Pks13 by PptT.
Identified as a drug target (PubMed:23770708, PubMed:28669536, PubMed:29328655, PubMed:30875203). Fatty acyl-AMP loading is inhibited by thiophene (TP) compounds, which kill Mycobacterium tuberculosis. Overexpression of wild-type Pks13 results in TP resistance, and overexpression of the F79S mutant confers high resistance (PubMed:23770708). Structure-guided methods identified a highly potent and very safe lead compound, TAM16, a benzofuran class inhibitor that targets the thioesterase activity (PubMed:28669536). The thioesterase-like domain is inhibited by coumestan derivatives that possess excellent anti-tuberculosis activity against both the drug-susceptible and drug-resistant Mtb strains (PubMed:29328655, PubMed:30875203).
Involved in the biosynthesis of mycolic acids (PubMed:19436070, PubMed:23770708, PubMed:25467124). Forms, with FadD32, the initiation module of the mycolic condensation system (PubMed:19436070, PubMed:19477415, PubMed:25467124). Synthesizes, in coupled reaction with FadD32, the biosynthetic precursors of mycolic acids, alpha-alkyl beta-ketoacids, via the condensation of two long chain fatty acid derivatives, a very long meromycoloyl-AMP and a shorter 2-carboxyacyl-CoA (PubMed:19436070, PubMed:25467124). The acyl chain of the acyl-AMP produced by FadD32 is specifically transferred onto the N-terminal ACP domain of Pks13, and then transferred onto the KS domain. The extender unit carboxyacyl-CoA is specifically loaded onto the AT domain, which catalyzes the covalent attachment of the carboxyacyl chain to its active site, and its subsequent transfer onto the P-pant arm of the C-terminal ACP domain. The KS domain catalyzes the condensation between the two loaded fatty acyl chains to produce an alpha-alkyl beta-ketothioester linked to the C-ACP domain (PubMed:19436070). Then, the thioesterase-like domain acts as a transacylase and is responsible for both the release and the transfer of the alpha-alkyl beta-ketoacyl chain onto a polyol acceptor molecule, particularly trehalose, leading to the formation of the trehalose monomycolate precursor (PubMed:25467124).
Made of a minimal module holding ketosynthase (KS), acyltransferase (AT), and C-terminal acyl carrier protein (C-ACP) domains, and additional N-terminal ACP (N-ACP) and C-terminal thioesterase-like domains.
The presence of FadD32 is necessary for the transfer of the acyl chain from the AMP carrier onto Pks13.
Belongs to the thymidine/pyrimidine-nucleoside phosphorylase family.
The enzymes which catalyze the reversible phosphorolysis of pyrimidine nucleosides are involved in the degradation of these compounds and in their utilization as carbon and energy sources, or in the rescue of pyrimidine bases for nucleotide synthesis.
Component of the DprE1-DprE2 complex that catalyzes the 2-step epimerization of decaprenyl-phospho-ribose (DPR) to decaprenyl-phospho-arabinose (DPA), a key precursor that serves as the arabinose donor required for the synthesis of cell-wall arabinans (PubMed:16291675, PubMed:19299584). DprE1 catalyzes the first step of epimerization, namely FAD-dependent oxidation of the C2' hydroxyl of DPR to yield the keto intermediate decaprenyl-phospho-2'-keto-D-arabinose (DPX) (PubMed:22733761). The intermediate DPX is then transferred to DprE2 subunit of the epimerase complex, most probably through a 'substrate channel' at the interface of DprE1-DprE2 complex (PubMed:25789990). DprE2 then catalyzes the second step of epimerization, the NAD(+)-dependent reduction of DPX that leads to the formation of DPA (PubMed:22733761, PubMed:25789990). Appears to be essential for the growth and survival of M.tuberculosis (PubMed:12657046, PubMed:24517327).
Interacts with DprE1 to form an epimerase complex.
Traditional knockout mutant with dprE2 disruption could not be achieved, suggesting this gene is essential (PubMed:24517327). Conditional knock-down mutant of dprE2 show that down-regulation of DprE2 results in growth arrest in vitro (PubMed:24517327). Cells lacking this gene display impaired growth (PubMed:12657046).
Major role in the synthesis of nucleoside triphosphates other than ATP. The ATP gamma phosphate is transferred to the NDP beta phosphate via a ping-pong mechanism, using a phosphorylated active-site intermediate.
Belongs to the phosphoenolpyruvate carboxykinase [GTP] family.
Cells lacking this gene are unable to grow in the absence of an external carbon source when grown with fatty acids acetate, valerate, or butyrate as the sole carbon source. This mutant also fails to replicate in mouse lungs. PEPCK depletion during the chronic phase of infection results in mycobacterial clearance.
Involved in the gluconeogenesis, in growth on fatty acids and is important for initiation of infection in the macrophages. Catalyzes the GTP-dependent conversion of oxaloacetate (OAA) to phosphoenolpyruvate (PEP), the rate-limiting step in the metabolic pathway that produces glucose from lactate and other precursors derived from the citric acid cycle.
The number of CD4 T-cells is increased in the PEPCK immunized mice although the change of the number of CD8 T-cells is not significant. The cytokines IFN-gamma (IFNG), IL-12 (IL12A or IL12B) and TNF-alpha (TNF) are increased significantly in the mice immunized with PEPCK relative to those immunized with incomplete adjuvant.