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BIOMD0000000218 - Singh2006_TCA_mtu_model2

 

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Reference Publication
Publication ID: 16887020
Singh VK, Ghosh I.
Kinetic modeling of tricarboxylic acid cycle and glyoxylate bypass in Mycobacterium tuberculosis, and its application to assessment of drug targets.
Theor Biol Med Model 2006; 3: 27
Bioinformatics Centre, University of Pune, Pune-411007, India. vivek@bioinfo.ernet.in  [more]
Model
Original Model: BIOMD0000000218.xml.origin
Submitter: Indira Ghosh
Submission ID: MODEL8584468482
Submission Date: 29 Sep 2006 22:49:52 UTC
Last Modification Date: 05 Jul 2012 14:45:35 UTC
Creation Date: 29 Sep 2006 22:49:52 UTC
Encoders:  Lukas Endler
   Vijayalakshmi Chelliah
   Vivek Kumar Singh
set #1
bqbiol:occursIn Taxonomy Mycobacterium tuberculosis
bqbiol:isHomologTo Reactome REACT_1785
bqbiol:hasVersion Gene Ontology tricarboxylic acid cycle
Gene Ontology glyoxylate cycle
bqbiol:isVersionOf KEGG Pathway ko00020
Notes

This a model from the article:
Kinetic modeling of tricarboxylic acid cycle and glyoxylate bypass in Mycobacterium tuberculosis, and its application to assessment of drug targets.
Singh VK , Ghosh I Theor Biol Med Model 2006 Aug 3;3:27 16887020 ,
Abstract:
BACKGROUND: Targeting persistent tubercule bacilli has become an important challenge in the development of anti-tuberculous drugs. As the glyoxylate bypass is essential for persistent bacilli, interference with it holds the potential for designing new antibacterial drugs. We have developed kinetic models of the tricarboxylic acid cycle and glyoxylate bypass in Escherichia coli and Mycobacterium tuberculosis, and studied the effects of inhibition of various enzymes in the M. tuberculosis model. RESULTS: We used E. coli to validate the pathway-modeling protocol and showed that changes in metabolic flux can be estimated from gene expression data. The M. tuberculosis model reproduced the observation that deletion of one ofthe two isocitrate lyase genes has little effect on bacterial growth in macrophages, but deletion of both genes leads to the elimination of the bacilli from the lungs. It also substantiated the inhibition of isocitrate lyases by 3-nitropropionate. On the basis of our simulation studies, we propose that: (i) fractional inactivation of both isocitrate dehydrogenase 1 and isocitrate dehydrogenase 2 is required for a flux through the glyoxylate bypass in persistent mycobacteria; and (ii) increasing the amount of active isocitrate dehydrogenases can stop the flux through the glyoxylate bypass, so the kinase that inactivates isocitrate dehydrogenase 1 and/or the proposed inactivator of isocitrate dehydrogenase 2 is a potential target for drugs against persistent mycobacteria. In addition, competitive inhibition of isocitrate lyases along with a reduction in the inactivation of isocitrate dehydrogenases appears to be a feasible strategy for targeting persistent mycobacteria. CONCLUSION: We used kinetic modeling of biochemical pathways to assess various potential anti-tuberculous drug targets that interfere with the glyoxylate bypass flux, and indicated the type of inhibition needed to eliminate the pathogen. The advantage of such an approach to the assessment of drug targets is that it facilitates the study of systemic effect(s) of the modulation of the target enzyme(s) in the cellular environment.


To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

In summary, you are entitled to use this encoded model in absolutely any manner you deem suitable, verbatim, or with modification, alone or embedded it in a larger context, redistribute it, commercially or not, in a restricted way or not.


To cite BioModels Database, please use: Li C, Donizelli M, Rodriguez N, Dharuri H, Endler L, Chelliah V, Li L, He E, Henry A, Stefan MI, Snoep JL, Hucka M, Le Novère N, Laibe C (2010) BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. BMC Syst Biol., 4:92.

Model
Publication ID: 16887020 Submission Date: 29 Sep 2006 22:49:52 UTC Last Modification Date: 05 Jul 2012 14:45:35 UTC Creation Date: 29 Sep 2006 22:49:52 UTC
Mathematical expressions
Reactions
CS ACN ICD1 ICD2
KGD SSADH ScAS SDH
FUM MDH ICL1 ICL2
MS SYN    
Physical entities
Compartments Species
cell aca oaa coa
cit icit akg
ssa suc sca
fa mal gly
biosyn    
Reactions (14)
 
 CS [aca] + [oaa] ↔ [coa] + [cit];  
 
 ACN [cit] ↔ [icit];  
 
 ICD1 [icit] ↔ [akg];  
 
 ICD2 [icit] ↔ [akg];  
 
 KGD [akg] ↔ [ssa];  
 
 SSADH [ssa] ↔ [suc];  
 
 ScAS [sca] ↔ [suc];  
 
 SDH [suc] ↔ [fa];  
 
 FUM [fa] ↔ [mal];  
 
 MDH [mal] ↔ [oaa];  
 
 ICL1 [icit] ↔ [suc] + [gly];  
 
 ICL2 [icit] ↔ [suc] + [gly];  
 
 MS [gly] + [aca] ↔ [mal] + [coa];  
 
 SYN [akg] ↔ [biosyn];   {icit}
 
  Spatial dimensions: 3.0  Compartment size: 1.0
 
 aca
Compartment: cell
Initial concentration: 0.5
 
 oaa
Compartment: cell
Initial concentration: 3.0E-4
 
 coa
Compartment: cell
Initial concentration: 1.0E-4
 
 cit
Compartment: cell
Initial concentration: 3.4
 
 icit
Compartment: cell
Initial concentration: 0.06
 
 akg
Compartment: cell
Initial concentration: 0.96
 
 ssa
Compartment: cell
Initial concentration: 0.03
 
 suc
Compartment: cell
Initial concentration: 2.464
 
 sca
Compartment: cell
Initial concentration: 0.04
 
 fa
Compartment: cell
Initial concentration: 0.08528
 
 mal
Compartment: cell
Initial concentration: 0.408
 
 gly
Compartment: cell
Initial concentration: 0.114
 
   biosyn
Compartment: cell
Initial concentration: 0.1
 
CS (6)
 
 Vf_cs
Value: 64.8   (Units: mM_per_min)
Constant
 
 Kaca_cs
Value: 0.05   (Units: mM)
Constant
 
 Koaa_cs
Value: 0.012   (Units: mM)
Constant
 
 Vr_cs
Value: 0.648   (Units: mM_per_min)
Constant
 
 Kcoa_cs
Value: 0.5   (Units: mM)
Constant
 
 Kcit_cs
Value: 0.12   (Units: mM)
Constant
 
ACN (4)
 
 Vf_acn
Value: 31.2   (Units: mM_per_min)
Constant
 
 Kcit_acn
Value: 1.7   (Units: mM)
Constant
 
 Vr_acn
Value: 0.312   (Units: mM_per_min)
Constant
 
 Kicit_acn
Value: 0.7   (Units: mM)
Constant
 
ICD1 (4)
 
 Vf_icd1
Value: 10.2   (Units: mM_per_min)
Constant
 
 Kicit_icd1
Value: 0.03   (Units: mM)
Constant
 
 Vr_icd1
Value: 0.102   (Units: mM_per_min)
Constant
 
 Kakg_icd1
Value: 0.3   (Units: mM)
Constant
 
ICD2 (4)
 
 Vf_icd2
Value: 9.965   (Units: mM_per_min)
Constant
 
 Kicit_icd2
Value: 0.06   (Units: mM)
Constant
 
 Vr_icd2
Value: 0.09965   (Units: mM_per_min)
Constant
 
 Kakg_icd2
Value: 0.6   (Units: mM)
Constant
 
KGD (4)
 
 Vf_kgd
Value: 48.3   (Units: mM_per_min)
Constant
 
 Kakg_kgd
Value: 0.48   (Units: mM)
Constant
 
 Vr_kgd
Value: 0.483   (Units: mM_per_min)
Constant
 
 Kssa_kgd
Value: 4.8   (Units: mM)
Constant
 
SSADH (4)
 
 Vf_ssadh
Value: 6.51   (Units: mM_per_min)
Constant
 
 Kssa_ssadh
Value: 0.015   (Units: mM)
Constant
 
 Vr_ssadh
Value: 0.0651   (Units: mM_per_min)
Constant
 
 Ksuc_ssadh
Value: 0.15   (Units: mM)
Constant
 
ScAS (4)
 
 Vf_scas
Value: 1.2   (Units: mM_per_min)
Constant
 
 Ksca_scas
Value: 0.02   (Units: mM)
Constant
 
 Vr_scas
Value: 0.012   (Units: mM_per_min)
Constant
 
 Ksuc_scas
Value: 5.0   (Units: mM)
Constant
 
SDH (4)
 
 Vf_sdh
Value: 1.02   (Units: mM_per_min)
Constant
 
 Ksuc_sdh
Value: 0.12   (Units: mM)
Constant
 
 Vr_sdh
Value: 1.02   (Units: mM_per_min)
Constant
 
 Kfa_sdh
Value: 0.15   (Units: mM)
Constant
 
FUM (4)
 
 Vf_fum
Value: 87.7   (Units: mM_per_min)
Constant
 
 Kfa_fum
Value: 0.25   (Units: mM)
Constant
 
 Vr_fum
Value: 87.7   (Units: mM_per_min)
Constant
 
 Kmal_fum
Value: 2.38   (Units: mM)
Constant
 
MDH (4)
 
 Vf_mdh
Value: 184.0   (Units: mM_per_min)
Constant
 
 Kmal_mdh
Value: 0.833   (Units: mM)
Constant
 
 Vr_mdh
Value: 184.0   (Units: mM_per_min)
Constant
 
 Koaa_mdh
Value: 0.0443   (Units: mM)
Constant
 
ICL1 (5)
 
 Vf_icl1
Value: 1.172   (Units: mM_per_min)
Constant
 
 Kicit_icl1
Value: 0.145   (Units: mM)
Constant
 
 Vr_icl1
Value: 0.01172   (Units: mM_per_min)
Constant
 
 Ksuc_icl1
Value: 0.59   (Units: mM)
Constant
 
 Kgly_icl1
Value: 0.13   (Units: mM)
Constant
 
ICL2 (5)
 
 Vf_icl2
Value: 0.391   (Units: mM_per_min)
Constant
 
 Kicit_icl2
Value: 1.3   (Units: mM)
Constant
 
 Vr_icl2
Value: 0.00391   (Units: mM_per_min)
Constant
 
 Ksuc_icl2
Value: 5.9   (Units: mM)
Constant
 
 Kgly_icl2
Value: 1.3   (Units: mM)
Constant
 
MS (6)
 
 Vf_ms
Value: 20.0   (Units: mM_per_min)
Constant
 
 Kgly_ms
Value: 0.057   (Units: mM)
Constant
 
 Kaca_ms
Value: 0.03   (Units: mM)
Constant
 
 Vr_ms
Value: 0.2   (Units: mM_per_min)
Constant
 
 Kmal_ms
Value: 1.0   (Units: mM)
Constant
 
 Kcoa_ms
Value: 0.1   (Units: mM)
Constant
 
SYN (8)
 
 Vf_icd1
Value: 10.2   (Units: mM_per_min)
Constant
 
 Kicit_icd1
Value: 0.03   (Units: mM)
Constant
 
 Vr_icd1
Value: 0.102   (Units: mM_per_min)
Constant
 
 Kakg_icd1
Value: 0.3   (Units: mM)
Constant
 
 Vf_icd2
Value: 9.965   (Units: mM_per_min)
Constant
 
 Kicit_icd2
Value: 0.06   (Units: mM)
Constant
 
 Vr_icd2
Value: 0.09965   (Units: mM_per_min)
Constant
 
 Kakg_icd2
Value: 0.6   (Units: mM)
Constant
 
Representative curation result(s)
Representative curation result(s) of BIOMD0000000218

Curator's comment: (updated: 27 Jul 2009 17:37:02 BST)

This model corresponds to the Mycobacterium tuberculosis model2 (i.e. model with no KDH activity) reported in the publication.Figure 2 (Effect on the
fluxthrough ICDs and ICLs with varying VfICD1 and VfICD2) of the reference publication is reproduced here. The effect of varying VfICD1 alone and both
VfICD1 and VfICD2 simultaneously, are illustrated in figures A and B. Figure C denote the effect of varying VfICD1 and VfICD2 simultaneously, with reaction
ICL1 removed. Figure D denote the effect of varying VfICD1 and VfICD2 simultaneously, with reaction ICL2 removed. The model was simulated and run
using Copasi v4.5.

To generate Figure 2A, 2B, 2C and 2D the users need to do the following while simulating the model in Copasi.

1. To generate Figure 2A:

(i) Assign global parameters jICD and jICL:
jICD = (ICD1)Flux + (ICD2)Flux
jICL = (ICL1)Flux + (ICL2)Flux

(ii) and plot VfICD1 against jICD and jICL.

2. To generate Figure 2B:

(i) Assign global parameters jICD and jICL:
jICD = (ICD1)Flux + (ICD2)Flux
jICL = (ICL1)Flux + (ICL2)Flux

(ii) Assign a global (fixed) parameter "f" and
assign global parameters V_ICD1 and V_ICD2 as a factor of "f".
i.e. V_ICD1 = f * VfICD1(=10.2)
V_ICD2 = f * VfICD2(=9.965)

(iii) and plot "f" against jICD and jICL.

3. To generate Figure 2C (ICL1 reaction removed):

(i) Assign a global parameter jICD
jICD = (ICD1)Flux + (ICD2)Flux

(ii) Assign a global (fixed) parameter "f" and
assign global parameters V_ICD1 and V_ICD2 as a factor of "f".
i.e. V_ICD1 = f * VfICD1(=10.2)
V_ICD2 = f * VfICD2(=9.965)

(iii) and plot "f" against jICD and (ICL2)Flux.

4. To generate Figure 2D (ICL2 reaction removed):

(i) Assign a global parameter jICD
jICD = (ICD1)Flux + (ICD2)Flux

(ii) Assign a global (fixed) parameter "f" and
assign global parameters V_ICD1 and V_ICD2 as a factor of "f".
i.e. V_ICD1 = f * VfICD1(=10.2)
V_ICD2 = f * VfICD2(=9.965)

(iii) and plot "f" against jICD and (ICL1)Flux.

Note:

Though the model can be encoded in SBML, with assignment rules using reaction fluxes (jICD and jICL), the model cannot be imported in Copasi and hence cannot be simulated. Similarly, Copasi allows the
generation of the above assignments (jICD and jICL), but cannot be exported in SBML format. (Since, object that refers to the "Flux" of Reaction " referenced in a mathematical expression, cannot be expressed in
SBML. Mathematical Expressions in SBML files can only reference the transient values of compartments, species, global parameters and reaction fluxes. In COPASI references to other objects, e.g. the initial value of a species, are also allowed and these references can not be expressed in an SBML file.).
So, one needs to do the above to generate the figures.

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