The relevance of the enzymes isovaleril-CoA dehydrogenase (1.3.8.4) and Enoil-CoA hidratase (4.2.1.17) in the metabolism of Leucine in Trypanosoma cruzi.

• Grant number: 17/14334-9
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date until: May 01, 2018
• End date until: January 31, 2023
• Field of knowledge: Biological Sciences - Parasitology - Protozoology of Parasites
• Principal Investigator: Ariel Mariano Silber
• Grantee: Sabrina Del Carmen Marsiccobetre Castaneda
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 16/06034-2 - The biological role of amino acids and their metabolites in Trypanosoma cruzi, AP.TEM

Abstract

Chagas disease is caused by the parasite Trypanosoma cruzi. Amino acids participate of several biological processes in T. cruzi, beyond their obvious role as constituents of proteins, such as differentiation, mammalian host-cells invasion, cell cycle regulation and resistence to different types of stresses. We already found in the T. cruzi genome the presence of ORFs enconding enzymes associated to the catabolism of the Branched Chains AMino Acids (BCAA) Leucine (Leu), Valine (Val) and Isoleucine) (Ile). Leu, differently from Val and Ile, presents in principle two alternative degradation pathways in T. cruzi: the third product of the Leu degradation could be substrate of both, Metylcrotonoil-CoA Carboxylase (rendering metylglutaconyl-CoA) or Enoyl-CoA hydratase, rendering Hydroxyvaleryl-CoA. In the former case, the degradation could proceed to the formation of Acetoacetyl_CoA and finally Acetyl_CoA, fueling the Tricarboxylic Acids Cycle. In the latter case, it is predictable a derivation of carbons to the biosynthesis of lipids and/or isoprenoids. In this project we propose: i. to evaluate the contribution of Leu to the production of ATP, as well as the lipids and/or isoprenoids throught the pathways mentined above ii. to evaluate the reflexes of these metabolic pathways on the different aspects of T. cruzi biology that are critical for the establishment of the parasite infection in their hosts.