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Systems analysis of metabolism in the pathogenic trypanosomatid Leishmania major

Systems analyses have facilitated the characterization of metabolic networks of several organisms. We have reconstructed the metabolic network of Leishmania major, a poorly characterized organism that causes cutaneous leishmaniasis in mammalian hosts. This network reconstruction accounts for 560 gen...

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Autores principales: Chavali, Arvind K, Whittemore, Jeffrey D, Eddy, James A, Williams, Kyle T, Papin, Jason A
Formato: Texto
Lenguaje:English
Publicado: Nature Publishing Group 2008
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2290936/
https://www.ncbi.nlm.nih.gov/pubmed/18364711
http://dx.doi.org/10.1038/msb.2008.15
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author Chavali, Arvind K
Whittemore, Jeffrey D
Eddy, James A
Williams, Kyle T
Papin, Jason A
author_facet Chavali, Arvind K
Whittemore, Jeffrey D
Eddy, James A
Williams, Kyle T
Papin, Jason A
author_sort Chavali, Arvind K
collection PubMed
description Systems analyses have facilitated the characterization of metabolic networks of several organisms. We have reconstructed the metabolic network of Leishmania major, a poorly characterized organism that causes cutaneous leishmaniasis in mammalian hosts. This network reconstruction accounts for 560 genes, 1112 reactions, 1101 metabolites and 8 unique subcellular localizations. Using a systems-based approach, we hypothesized a comprehensive set of lethal single and double gene deletions, some of which were validated using published data with approximately 70% accuracy. Additionally, we generated hypothetical annotations to dozens of previously uncharacterized genes in the L. major genome and proposed a minimal medium for growth. We further demonstrated the utility of a network reconstruction with two proof-of-concept examples that yielded insight into robustness of the network in the presence of enzymatic inhibitors and delineation of promastigote/amastigote stage-specific metabolism. This reconstruction and the associated network analyses of L. major is the first of its kind for a protozoan. It can serve as a tool for clarifying discrepancies between data sources, generating hypotheses that can be experimentally validated and identifying ideal therapeutic targets.
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spelling pubmed-22909362008-04-10 Systems analysis of metabolism in the pathogenic trypanosomatid Leishmania major Chavali, Arvind K Whittemore, Jeffrey D Eddy, James A Williams, Kyle T Papin, Jason A Mol Syst Biol Article Systems analyses have facilitated the characterization of metabolic networks of several organisms. We have reconstructed the metabolic network of Leishmania major, a poorly characterized organism that causes cutaneous leishmaniasis in mammalian hosts. This network reconstruction accounts for 560 genes, 1112 reactions, 1101 metabolites and 8 unique subcellular localizations. Using a systems-based approach, we hypothesized a comprehensive set of lethal single and double gene deletions, some of which were validated using published data with approximately 70% accuracy. Additionally, we generated hypothetical annotations to dozens of previously uncharacterized genes in the L. major genome and proposed a minimal medium for growth. We further demonstrated the utility of a network reconstruction with two proof-of-concept examples that yielded insight into robustness of the network in the presence of enzymatic inhibitors and delineation of promastigote/amastigote stage-specific metabolism. This reconstruction and the associated network analyses of L. major is the first of its kind for a protozoan. It can serve as a tool for clarifying discrepancies between data sources, generating hypotheses that can be experimentally validated and identifying ideal therapeutic targets. Nature Publishing Group 2008-03-25 /pmc/articles/PMC2290936/ /pubmed/18364711 http://dx.doi.org/10.1038/msb.2008.15 Text en Copyright © 2008, EMBO and Nature Publishing Group http://creativecommons.org/licenses/by-nc-nd/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution Licence, which permits distribution and reproduction in any medium, provided the original author and source are credited. This licence does not permit commercial exploitation or the creation of derivative works without specific permission.
spellingShingle Article
Chavali, Arvind K
Whittemore, Jeffrey D
Eddy, James A
Williams, Kyle T
Papin, Jason A
Systems analysis of metabolism in the pathogenic trypanosomatid Leishmania major
title Systems analysis of metabolism in the pathogenic trypanosomatid Leishmania major
title_full Systems analysis of metabolism in the pathogenic trypanosomatid Leishmania major
title_fullStr Systems analysis of metabolism in the pathogenic trypanosomatid Leishmania major
title_full_unstemmed Systems analysis of metabolism in the pathogenic trypanosomatid Leishmania major
title_short Systems analysis of metabolism in the pathogenic trypanosomatid Leishmania major
title_sort systems analysis of metabolism in the pathogenic trypanosomatid leishmania major
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2290936/
https://www.ncbi.nlm.nih.gov/pubmed/18364711
http://dx.doi.org/10.1038/msb.2008.15
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