Abstract
BackgroundTrypanosoma cruzi is a Kinetoplastid parasite of humans and is the cause of Chagas disease, a potentially lethal condition affecting the cardiovascular, gastrointestinal, and nervous systems of the human host. Constraint-based modeling has emerged in the last decade as a useful approach to integrating genomic and other high-throughput data sets with more traditional, experimental data acquired through decades of research and published in the literature.ResultsWe present a validated, constraint-based model of the core metabolism of Trypanosoma cruzi strain CL Brener. The model includes four compartments (extracellular space, cytosol, mitochondrion, glycosome), 51 transport reactions, and 93 metabolic reactions covering carbohydrate, amino acid, and energy metabolism. In addition, we make use of several replicate high-throughput proteomic data sets to specifically examine metabolism of the morphological form of T. cruzi in the insect gut (epimastigote stage).ConclusionThis work demonstrates the utility of constraint-based models for integrating various sources of data (e.g., genomics, primary biochemical literature, proteomics) to generate testable hypotheses. This model represents an approach for the systematic study of T. cruzi metabolism under a wide range of conditions and perturbations, and should eventually aid in the identification of urgently needed novel chemotherapeutic targets.
Highlights
Trypanosoma cruzi is a Kinetoplastid parasite of humans and is the cause of Chagas disease, a potentially lethal condition affecting the cardiovascular, gastrointestinal, and nervous systems of the human host
Constraint-based modeling has emerged in the last decade as a useful approach to the integration of genomic and other high-throughput data sets with more traditional, experimental data acquired through decades of biochemical and molecular research [3,4]
17 are input-output exchanges that allow metabolites to enter and/or leave the model system, and one is the biomass demand reaction used to drain metabolites assumed critical to the growth of T. cruzi
Summary
Trypanosoma cruzi is a Kinetoplastid parasite of humans and is the cause of Chagas disease, a potentially lethal condition affecting the cardiovascular, gastrointestinal, and nervous systems of the human host. Constraint-based modeling has emerged in the last decade as a useful approach to integrating genomic and other high-throughput data sets with more traditional, experimental data acquired through decades of research and published in the literature. Constraint-based modeling has emerged in the last decade as a useful approach to the integration of genomic and other high-throughput data sets with more traditional, experimental data acquired through decades of biochemical and molecular research [3,4]. When combined with a specific method of analysis, e.g., flux balance analysis (FBA), constraint-based models can be used to generate quantitative predictions (e.g., growth rate of an organism) and yield testable hypotheses for future experimental investigations [7]. Validated constraint-based models are providing integrative, systems-level views of the functioning of different metabolic networks of various organisms across a wide range of specific conditions (e.g., gene deletions, pharmacological interventions and environmental perturbations) [1114]
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