MODEL1207300000
type: SBMLModel
notes: This model is from the article: A model of flux regulation in the cholesterol biosynthesis pathway: Immune mediated graduated flux reduction versus statin-like led stepped flux reduction. Watterson S, Guerriero ML, Blanc M, Mazein A, Loewe L, Robertson KA, Gibbs H, Shui G, Wenk MR, Hillston J, Ghazal P. Biochimie. 2012 Jun 1. 22664637 , Abstract: The cholesterol biosynthesis pathway has recently been shown to play an important role in the innate immune response to viral infection with host protection occurring through a coordinate down regulation of the enzymes catalysing each metabolic step. In contrast, statin based drugs, which form the principle pharmaceutical agents for decreasing the activity of this pathway, target a single enzyme. Here, we build an ordinary differential equation model of the cholesterol biosynthesis pathway in order to investigate how the two regulatory strategies impact upon the behaviour of the pathway. We employ a modest set of assumptions: that the pathway operates away from saturation, that each metabolite is involved in multiple cellular interactions and that mRNA levels reflect enzyme concentrations. Using data taken from primary bone marrow derived macrophage cells infected with murine cytomegalovirus or treated with IFNγ, we show that, under these assumptions, coordinate down-regulation of enzyme activity imparts a graduated reduction in flux along the pathway. In contrast, modelling a statin-like treatment that achieves the same degree of down-regulation in cholesterol production, we show that this delivers a step change in flux along the pathway. The graduated reduction mediated by physiological coordinate regulation of multiple enzymes supports a mechanism that allows a greater level of specificity, altering cholesterol levels with less impact upon interactions branching from the pathway, than pharmacological step reductions. We argue that coordinate regulation is likely to show a long-term evolutionary advantage over single enzy…
species: s35
reaction: re23
species: s55
reaction: re21
length unit: length
species: s30
species: s50
is described by: http://identifiers.org/pubmed/22664637
reaction: re20
species: s16
species: s14
species: s62
species: s12
species: s32
time units: time
reaction: re38
species: s60
reaction: re36
species: s8
species: s6
species: s4
reaction: re15
reaction: re4
species: s49
species: s29
species: s31
reaction: re31
species: s67
reaction: re10
reaction: re47
species: s28
species: s26
compartment: default
species: s24
reaction: re46
reaction: re44
reaction: re18
reaction: re9
reaction: re7
units def: substance
species: s38
species: s18
species: s58
species: s56
reaction: re34
reaction: re32
reaction: re17
reaction: re6
species: s51
species: s21
species: s17
species: s13
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species: s20
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reaction: re43
reaction: re28
species: s5
reaction: re26
reaction: re42
volume units: volume
species: s40
species: s10
reaction: re40
reaction: re16
reaction: re5
reaction: re14
area units: area
reaction: re3
reaction: re30
units def: length
reaction: re13
reaction: re2
species: s47
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units def: area
reaction: re29

s35
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name: SC4MOL

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spatial dimensions: 3.0

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re23
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CDMT00069
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re21
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re20
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CDMT00061
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s21
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CDMT00060
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s20
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re38
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CDMT00125
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CDMT00124
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re36
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CDMT00121
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CDMT00120
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re15
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CDMT00047
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s15
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CDMT00046
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re4
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s3
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re31
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s7
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CDMT00110
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re47
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CDMT00143
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CDMT00142
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re46
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CDMT00141
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s66
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CDMT00140
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re44
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CDMT00137
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CDMT00136
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re18
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CDMT00054
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s17
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CDMT00055
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s19
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re9
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CDMT00029
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CDMT00028
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re7
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CDMT00022
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CDMT00023
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substance
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s38
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s56
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re34
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CDMT00117
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CDMT00116
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re32
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CDMT00113
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CDMT00112
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re17
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CDMT00052
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CDMT00051
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re6
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CDMT00020
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s5
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CDMT00019
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re43
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CDMT00135
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CDMT00134
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re28
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CDMT00105
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re26
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re42
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CDMT00133
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s40
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re40
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CDMT00129
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CDMT00128
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re16
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CDMT00050
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CDMT00049
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re5
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CDMT00017
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CDMT00016
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s27
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re14
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s36
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CDMT00043
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CDMT00044
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re3
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s25
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CDMT00010
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CDMT00011
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re30
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reactant: CDMT00108
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reversible: false

CDMT00109
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CDMT00108
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re13
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modifier: 354995
product: CDMT00041
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CDMT00041
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CDMT00040
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re2
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reversible: false
modifier: CDMT00009
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kinetic law: CDMT00073

s1
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CDMT00008
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CDMT00007
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re29
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reactant: CDMT00106
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reversible: false

CDMT00107
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CDMT00106
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re45
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kinetic law: CDMT00162
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CDMT00139
type: SpeciesReference
stoichiometry: 1.0
species: s65

s65
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: NaN
initial amount: 0.0
in compartment: default
name: s65

CDMT00138
type: SpeciesReference
stoichiometry: 1.0
species: s18

s57
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: NaN
initial amount: 0.0
in compartment: default
name: s57

re22
type: Reaction
kinetic law: CDMT00093
modifier: 355202
product: CDMT00067
reactant: CDMT00066
fast: false
reversible: false

CDMT00067
type: SpeciesReference
stoichiometry: 1.0
species: s22

CDMT00066
type: SpeciesReference
stoichiometry: 1.0
species: s18

s64
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: NaN
initial amount: 0.0
in compartment: default
name: s64

s34
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: NaN
initial amount: 0.0
in compartment: default
name: TM7SF2

re39
type: Reaction
kinetic law: CDMT00156
modifier: 355418
product: CDMT00127
reactant: CDMT00126
fast: false
reversible: false

CDMT00127
type: SpeciesReference
stoichiometry: 1.0
species: s64

CDMT00126
type: SpeciesReference
stoichiometry: 1.0
species: s15

re37
type: Reaction
kinetic law: CDMT00154
modifier: 355394
product: CDMT00123
reactant: CDMT00122
fast: false
reversible: false

CDMT00123
type: SpeciesReference
stoichiometry: 1.0
species: s53

s53
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: NaN
initial amount: 0.0
in compartment: default
name: s53

CDMT00122
type: SpeciesReference
stoichiometry: 1.0
species: s13

s11
type: Species
constant: false
boundary condition: false
has only substance units: false
initial concentration: NaN
initial amount: 0.0
in compartment: default
name: 44Di

re27
type: Reaction
kinetic law: CDMT00144
modifier: 355274
product: CDMT00103
reactant: CDMT00102
fast: false
reversible: false

CDMT00103
type: SpeciesReference
stoichiometry: 1.0
species: s47

CDMT00102
type: SpeciesReference
stoichiometry: 1.0
species: s3

re25
type: Reaction
kinetic law: CDMT00098
modifier: 355250
product: CDMT00097
reactant: CDMT00096
fast: false
reversible: false

CDMT00097
type: SpeciesReference
stoichiometry: 1.0
species: s45

CDMT00096
type: SpeciesReference
stoichiometry: 1.0
species: s1

re41
type: Reaction
kinetic law: CDMT00158
modifier: 355442
product: CDMT00131
reactant: CDMT00130
fast: false
reversible: false

CDMT00131
type: SpeciesReference
stoichiometry: 1.0
species: s62

CDMT00130
type: SpeciesReference
stoichiometry: 1.0
species: s17

re24
type: Reaction
kinetic law: CDMT00095
modifier: 355226
modifier: 355238
fast: false
modifier: CDMT00072
reactant: CDMT00070
reversible: false
product: CDMT00071

CDMT00070
type: SpeciesReference
stoichiometry: 1.0
species: s23

CDMT00071
type: SpeciesReference
stoichiometry: 1.0
species: s21

re11
type: Reaction
modifier: 354958
modifier: 354946
kinetic law: CDMT00082
reversible: false
product: CDMT00035
fast: false
modifier: CDMT00036
reactant: CDMT00034

CDMT00035
type: SpeciesReference
stoichiometry: 1.0
species: s11

CDMT00034
type: SpeciesReference
stoichiometry: 1.0
species: s10

re12
type: Reaction
kinetic law: CDMT00083
product: CDMT00038
reactant: CDMT00037
fast: false
modifier: CDMT00039
reversible: false
modifier: 354970
modifier: 354983

CDMT00038
type: SpeciesReference
stoichiometry: 1.0
species: s12

CDMT00037
type: SpeciesReference
stoichiometry: 1.0
species: s11

re19
type: Reaction
modifier: 355140
kinetic law: CDMT00090
modifier: CDMT00059
fast: false
product: CDMT00058
modifier: 355128
reactant: CDMT00057
reversible: false

CDMT00058
type: SpeciesReference
stoichiometry: 1.0
species: s20

CDMT00057
type: SpeciesReference
stoichiometry: 1.0
species: s19

re8
type: Reaction
modifier: 354886
modifier: 354874
product: CDMT00026
kinetic law: CDMT00079
reversible: false
fast: false
modifier: CDMT00027
reactant: CDMT00025

CDMT00026
type: SpeciesReference
stoichiometry: 1.0
species: s8

CDMT00025
type: SpeciesReference
stoichiometry: 1.0
species: s7

re35
type: Reaction
kinetic law: CDMT00152
modifier: 355370
product: CDMT00119
reactant: CDMT00118
fast: false
reversible: false

CDMT00119
type: SpeciesReference
stoichiometry: 1.0
species: s55

CDMT00118
type: SpeciesReference
stoichiometry: 1.0
species: s11

re33
type: Reaction
kinetic law: CDMT00150
modifier: 355346
product: CDMT00115
reactant: CDMT00114
fast: false
reversible: false

CDMT00115
type: SpeciesReference
stoichiometry: 1.0
species: s57

CDMT00114
type: SpeciesReference
stoichiometry: 1.0
species: s9