Metabolic control analysis of the oxidation and biosynthesis of proline in Trypanosoma cruzi

Abstract

Trypanosoma cruzi is the etiological agent for Chagas´ Disease, which is one of the main tropical illnesses in Latin America, and is also among the most neglected ones in the world. Furthermore, currently used drugs present significant toxicity and show little effectiveness in the chronic phase of the disease, when most of the cases are diagnosed. These facts illustrate the urgent need for studies improving current knowledge of the parasite's metabolism, revealing new targets for treatment. In this context, Metabolic Control Analysis (MCA) surfaces as a powerful technique for in silico analyses of metabolic pathways with predictive capabilities that can speed up the drug development workflow. Even though the computational models must be validated experimentally, MCA may result in costs reduction for the identification of putative targets for new drugs, since this approach minimizes trial and error in favor of preliminary in silico tests. The aim of this project is to develop, test and validate a computational model of the proline metabolic pathway that presents the aforementioned characteristics. Proline is involved in several processes in the parasite's biology, including osmoregulation, cellular invasion, differentiation, energy metabolism and resistance to different types of stress, oxidative imbalance in particular. In addition to having contributed to establishing the vital role of proline in T. cruzi, our lab has already characterized the proline metabolic pathway and collected biochemical data for all its enzymes, which is an important step to ensure the success of the project. (AU)