title: Systems analysis of metabolism in the pathogenic trypanosomatid Leishmania major.
abstract: 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.
authors: Department of Biomedical Engineering, University of Virginia, Charlottesville, VA 22908, USA.
authors: Arvind K
authors: AK
authors: Chavali
authors: Jeffrey D
authors: JD
authors: Whittemore
authors: James A
authors: JA
authors: Eddy
authors: Kyle T
authors: KT
authors: Williams
authors: Jason A
authors: JA
authors: Papin
mesh_terms: D000818:Animals; D018533:Biomass; D019295:Computational Biology; D017353:Gene Deletion; D018503:Genome, Protozoan; D018320:Leishmania major / Q000201:enzymology / Q000235:genetics / Q000254:growth & development / Q000378:metabolism*; D008018:Life Cycle Stages; D053858:Metabolic Networks and Pathways / Q000235:genetics; D008954:Models, Biological; D006180:Proton-Translocating ATPases / Q000378:metabolism; D015203:Reproducibility of Results; D013597:Systems Analysis
chemical_list: D006180:Proton-Translocating ATPases