Proteomic and network analysis characterize stage-specific metabolism in Trypanosoma cruzi

We 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).This 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.The increasing availability of complete genome sequences has spurred efforts to model biological systems on a comprehensive scale [1,2]. 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]. To date, constraint-based modeling has been extensively applied to probe the function of intracellular metabolism, although the constraint-based framework is in principle applicable to any set of chemical transformations, including signal transduction networks [5] and transcription or translation [6]. 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]. This permits an iterative process of model development, hypothesis generation and testing, and further