Singh2006_TCA_Ecoli_acetate

  public model
Model Identifier
BIOMD0000000221
Short description

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.


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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.

Format
SBML (L2V4)
Related Publication
  • Kinetic modeling of tricarboxylic acid cycle and glyoxylate bypass in Mycobacterium tuberculosis, and its application to assessment of drug targets.
  • Singh VK, Ghosh I
  • Theoretical biology & medical modelling , 0/ 2006 , Volume 3 , pages: 27 , PubMed ID: 16887020
  • Bioinformatics Centre, University of Pune, Pune-411007, India. vivek@bioinfo.ernet.in
  • 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 of the 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.
Contributors
Indira Ghosh

Metadata information

is
BioModels Database MODEL8584137422
BioModels Database BIOMD0000000221
isDescribedBy
PubMed 16887020
hasTaxon
Taxonomy Escherichia coli
hasVersion
Gene Ontology GO:0006099
Gene Ontology GO:0006097
isVersionOf
isHomologTo

Curation status
Curated

Tags
Name Description Size Actions

Model files

BIOMD0000000221_url.xml SBML L2V4 representation of Singh2006_TCA_Ecoli_acetate 46.65 KB Preview | Download

Additional files

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BIOMD0000000221_urn.xml Auto-generated SBML file with URNs 48.85 KB Preview | Download
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  • Model originally submitted by : Indira Ghosh
  • Submitted: Sep 29, 2006 11:47:20 PM
  • Last Modified: Jul 5, 2012 3:47:17 PM
Revisions
  • Version: 2 public model Download this version
    • Submitted on: Jul 5, 2012 3:47:17 PM
    • Submitted by: Indira Ghosh
    • With comment: Current version of Singh2006_TCA_Ecoli_acetate
  • Version: 1 public model Download this version
    • Submitted on: Sep 29, 2006 11:47:20 PM
    • Submitted by: Indira Ghosh
    • With comment: Original import of Singh_Ghosh2006_TCA_eco_acetate

(*) You might be seeing discontinuous revisions as only public revisions are displayed here. Any private revisions unpublished model revision of this model will only be shown to the submitter and their collaborators.

Legends
: Variable used inside SBML models


Species
Species Initial Concentration/Amount
aca

acetyl-CoA ; Acetyl-CoA
0.5 mmol
oaa

oxaloacetic acid ; Oxaloacetate
0.0014 mmol
coa

coenzyme A ; CoA
1.0E-4 mmol
cit

citric acid ; Citrate
9.0 mmol
icit

isocitric acid ; Isocitrate
0.15 mmol
akg

2-oxoglutaric acid ; 2-Oxoglutarate
0.2 mmol
suc

succinic acid ; Succinate
6.0 mmol
fa

fumaric acid ; Fumarate
0.3 mmol
mal

malic acid ; Malate
5.0 mmol
gly

glyoxylic acid ; Glyoxylate
4.0 mmol
Reactions
Reactions Rate Parameters
gly + aca => mal + coa cell*(Vf_ms*gly/Kgly_ms*aca/Kaca_ms-Vr_ms*mal/Kmal_ms*coa/Kcoa_ms)/((1+gly/Kgly_ms+mal/Kmal_ms)*(1+aca/Kaca_ms+coa/Kcoa_ms)) Kgly_ms=2.0 mmol*l^(-1); Vr_ms=0.285 mmol*l^(-1)*(60*s)^(-1); Kmal_ms=1.0 mmol*l^(-1); Kaca_ms=0.01 mmol*l^(-1); Vf_ms=28.5 mmol*l^(-1)*(60*s)^(-1); Kcoa_ms=0.1 mmol*l^(-1)
aca + oaa => coa + cit cell*(Vf_cs*aca/Kaca_cs*oaa/Koaa_cs-Vr_cs*coa/Kcoa_cs*cit/Kcit_cs)/((1+aca/Kaca_cs+coa/Kcoa_cs)*(1+oaa/Koaa_cs+cit/Kcit_cs)) Kaca_cs=0.03 mmol*l^(-1); Kcit_cs=0.7 mmol*l^(-1); Vf_cs=446.88 mmol*l^(-1)*(60*s)^(-1); Koaa_cs=0.07 mmol*l^(-1); Vr_cs=4.4688 mmol*l^(-1)*(60*s)^(-1); Kcoa_cs=0.3 mmol*l^(-1)
mal => oaa cell*(Vf_mdh*mal/Kmal_mdh-Vr_mdh*oaa/Koaa_mdh)/(1+mal/Kmal_mdh+oaa/Koaa_mdh) Vf_mdh=1390.9 mmol*l^(-1)*(60*s)^(-1); Koaa_mdh=0.04 mmol*l^(-1); Kmal_mdh=2.6 mmol*l^(-1); Vr_mdh=1276.06 mmol*l^(-1)*(60*s)^(-1)
cit => icit cell*(Vf_acn*cit/Kcit_acn-Vr_acn*icit/Kicit_acn)/(1+cit/Kcit_acn+icit/Kicit_acn) Vr_acn=6.2928 mmol*l^(-1)*(60*s)^(-1); Kcit_acn=1.7 mmol*l^(-1); Kicit_acn=3.33 mmol*l^(-1); Vf_acn=629.28 mmol*l^(-1)*(60*s)^(-1)
icit => akg cell*(Vf_icd*icit/Kicit_icd-Vr_icd*akg/Kakg_icd)/(1+icit/Kicit_icd+akg/Kakg_icd) Vf_icd=6.625 mmol*l^(-1)*(60*s)^(-1); Vr_icd=0.06625 mmol*l^(-1)*(60*s)^(-1); Kakg_icd=0.13 mmol*l^(-1); Kicit_icd=0.008 mmol*l^(-1)
akg => sca cell*(Vf_kdh*akg/Kakg_kdh-Vr_kdh*sca/Ksca_kdh)/(1+akg/Kakg_kdh+sca/Ksca_kdh) Ksca_kdh=1.0 mmol*l^(-1); Kakg_kdh=0.1 mmol*l^(-1); Vr_kdh=0.57344 mmol*l^(-1)*(60*s)^(-1); Vf_kdh=57.344 mmol*l^(-1)*(60*s)^(-1)
suc => fa cell*(Vf_sdh*suc/Ksuc_sdh-Vr_sdh*fa/Kfa_sdh)/(1+suc/Ksuc_sdh+fa/Kfa_sdh) Vr_sdh=16.24 mmol*l^(-1)*(60*s)^(-1); Vf_sdh=17.7 mmol*l^(-1)*(60*s)^(-1); Ksuc_sdh=0.02 mmol*l^(-1); Kfa_sdh=0.4 mmol*l^(-1)
icit => suc + gly cell*(Vf_icl*icit/Kicit_icl-Vr_icl*suc/Ksuc_icl*gly/Kgly_icl)/(1+icit/Kicit_icl+suc/Ksuc_icl+gly/Kgly_icl+icit/Kicit_icl*suc/Ksuc_icl+suc/Ksuc_icl*gly/Kgly_icl) Vr_icl=0.285 mmol*l^(-1)*(60*s)^(-1); Vf_icl=28.5 mmol*l^(-1)*(60*s)^(-1); Kicit_icl=0.604 mmol*l^(-1); Kgly_icl=0.13 mmol*l^(-1); Ksuc_icl=0.59 mmol*l^(-1)
fa => mal cell*(Vf_fum*fa/Kfa_fum-Vr_fum*mal/Kmal_fum)/(1+fa/Kfa_fum+mal/Kmal_fum) Vr_fum=144.67 mmol*l^(-1)*(60*s)^(-1); Kmal_fum=0.04 mmol*l^(-1); Vf_fum=156.24 mmol*l^(-1)*(60*s)^(-1); Kfa_fum=0.15 mmol*l^(-1)
Curator's comment:
(added: 07 Jul 2009, 16:13:56, updated: 07 Jul 2009, 16:13:56)
This model corresponds to the E.coli growth on acetate model, reported in the publication. Steady state fluxes computed based on the simulation (Table 2 - Column 3)and that compared to the experimental fluxes (Table 3 - Column 5), reported in the reference publication is reproduced here.