Cargando…

Flux Balance Analysis of Mycolic Acid Pathway: Targets for Anti-Tubercular Drugs

Mycobacterium tuberculosis is the focus of several investigations for design of newer drugs, as tuberculosis remains a major epidemic despite the availability of several drugs and a vaccine. Mycobacteria owe many of their unique qualities to mycolic acids, which are known to be important for their g...

Descripción completa

Detalles Bibliográficos
Autores principales: Raman, Karthik, Rajagopalan, Preethi, Chandra, Nagasuma
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2005
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1246807/
https://www.ncbi.nlm.nih.gov/pubmed/16261191
http://dx.doi.org/10.1371/journal.pcbi.0010046
_version_ 1782125636766138368
author Raman, Karthik
Rajagopalan, Preethi
Chandra, Nagasuma
author_facet Raman, Karthik
Rajagopalan, Preethi
Chandra, Nagasuma
author_sort Raman, Karthik
collection PubMed
description Mycobacterium tuberculosis is the focus of several investigations for design of newer drugs, as tuberculosis remains a major epidemic despite the availability of several drugs and a vaccine. Mycobacteria owe many of their unique qualities to mycolic acids, which are known to be important for their growth, survival, and pathogenicity. Mycolic acid biosynthesis has therefore been the focus of a number of biochemical and genetic studies. It also turns out to be the pathway inhibited by front-line anti-tubercular drugs such as isoniazid and ethionamide. Recent years have seen the emergence of systems-based methodologies that can be used to study microbial metabolism. Here, we seek to apply insights from flux balance analyses of the mycolic acid pathway (MAP) for the identification of anti-tubercular drug targets. We present a comprehensive model of mycolic acid synthesis in the pathogen M. tuberculosis involving 197 metabolites participating in 219 reactions catalysed by 28 proteins. Flux balance analysis (FBA) has been performed on the MAP model, which has provided insights into the metabolic capabilities of the pathway. In silico systematic gene deletions and inhibition of InhA by isoniazid, studied here, provide clues about proteins essential for the pathway and hence lead to a rational identification of possible drug targets. Feasibility studies using sequence analysis of the M. tuberculosis H37Rv and human proteomes indicate that, apart from the known InhA, potential targets for anti-tubercular drug design are AccD3, Fas, FabH, Pks13, DesA1/2, and DesA3. Proteins identified as essential by FBA correlate well with those previously identified experimentally through transposon site hybridisation mutagenesis. This study demonstrates the application of FBA for rational identification of potential anti-tubercular drug targets, which can indeed be a general strategy in drug design. The targets, chosen based on the critical points in the pathway, form a ready shortlist for experimental testing.
format Text
id pubmed-1246807
institution National Center for Biotechnology Information
language English
publishDate 2005
publisher Public Library of Science
record_format MEDLINE/PubMed
spelling pubmed-12468072005-10-14 Flux Balance Analysis of Mycolic Acid Pathway: Targets for Anti-Tubercular Drugs Raman, Karthik Rajagopalan, Preethi Chandra, Nagasuma PLoS Comput Biol Research Article Mycobacterium tuberculosis is the focus of several investigations for design of newer drugs, as tuberculosis remains a major epidemic despite the availability of several drugs and a vaccine. Mycobacteria owe many of their unique qualities to mycolic acids, which are known to be important for their growth, survival, and pathogenicity. Mycolic acid biosynthesis has therefore been the focus of a number of biochemical and genetic studies. It also turns out to be the pathway inhibited by front-line anti-tubercular drugs such as isoniazid and ethionamide. Recent years have seen the emergence of systems-based methodologies that can be used to study microbial metabolism. Here, we seek to apply insights from flux balance analyses of the mycolic acid pathway (MAP) for the identification of anti-tubercular drug targets. We present a comprehensive model of mycolic acid synthesis in the pathogen M. tuberculosis involving 197 metabolites participating in 219 reactions catalysed by 28 proteins. Flux balance analysis (FBA) has been performed on the MAP model, which has provided insights into the metabolic capabilities of the pathway. In silico systematic gene deletions and inhibition of InhA by isoniazid, studied here, provide clues about proteins essential for the pathway and hence lead to a rational identification of possible drug targets. Feasibility studies using sequence analysis of the M. tuberculosis H37Rv and human proteomes indicate that, apart from the known InhA, potential targets for anti-tubercular drug design are AccD3, Fas, FabH, Pks13, DesA1/2, and DesA3. Proteins identified as essential by FBA correlate well with those previously identified experimentally through transposon site hybridisation mutagenesis. This study demonstrates the application of FBA for rational identification of potential anti-tubercular drug targets, which can indeed be a general strategy in drug design. The targets, chosen based on the critical points in the pathway, form a ready shortlist for experimental testing. Public Library of Science 2005-10 2005-10-14 /pmc/articles/PMC1246807/ /pubmed/16261191 http://dx.doi.org/10.1371/journal.pcbi.0010046 Text en Copyright: © 2005 Raman et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Raman, Karthik
Rajagopalan, Preethi
Chandra, Nagasuma
Flux Balance Analysis of Mycolic Acid Pathway: Targets for Anti-Tubercular Drugs
title Flux Balance Analysis of Mycolic Acid Pathway: Targets for Anti-Tubercular Drugs
title_full Flux Balance Analysis of Mycolic Acid Pathway: Targets for Anti-Tubercular Drugs
title_fullStr Flux Balance Analysis of Mycolic Acid Pathway: Targets for Anti-Tubercular Drugs
title_full_unstemmed Flux Balance Analysis of Mycolic Acid Pathway: Targets for Anti-Tubercular Drugs
title_short Flux Balance Analysis of Mycolic Acid Pathway: Targets for Anti-Tubercular Drugs
title_sort flux balance analysis of mycolic acid pathway: targets for anti-tubercular drugs
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1246807/
https://www.ncbi.nlm.nih.gov/pubmed/16261191
http://dx.doi.org/10.1371/journal.pcbi.0010046
work_keys_str_mv AT ramankarthik fluxbalanceanalysisofmycolicacidpathwaytargetsforantituberculardrugs
AT rajagopalanpreethi fluxbalanceanalysisofmycolicacidpathwaytargetsforantituberculardrugs
AT chandranagasuma fluxbalanceanalysisofmycolicacidpathwaytargetsforantituberculardrugs