The metabolic connection between metionine and cysteine: a relevant aspect of the S metabolism in T. cruzi

• Grant number: 18/12660-9
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• Start date: September 01, 2018
• End date: August 31, 2022
• Field of knowledge: Biological Sciences - Parasitology - Protozoology of Parasites
• Principal Investigator: Ariel Mariano Silber
• Grantee: Mayke Bezerra Alencar
• 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

Trypanosoma cruzi, the etiologic agent of Chagas Disease, is a flagellate parasite that alternates its life cycle between invertebrate and vertebrate hosts, including humans. This parasite needs to survive in different environmental conditions, which expose it to different energy and carbon sources, such as carbohydrates and amino acids. Previous studies have shown the participation of amino acid metabolism in several biological vital processes (beyond their obvious involvement in protein synthesis). Thus, the characterization of the amino acids and their intermediates biosynthesis and degradation pathways has an increased relevance to understand the biology of T. cruzi. Metabolites containing -SH groups (such as cystein and some of its intermediates) are relevant to buffer the redox state of the different sub-cellular compartments. At the same time, the redox metabolism is directly "wired" with the oxidative and energetics metabolism. In this sense, the study of the pathways involving cystein (Cys) are relevant. There are two pathways: i) the methionine trans-sulfuration; and ii) the reverse trans-sulfuraction. In the present work we propose to study the first enzymatic steps of the latter, in which serine (Ser) is a precursor for the synthesis of Cys, and SH2 is the source of sulfur. This choice is due to the fact that this pathway is directly connected to glycolisis through the enzyme Ser hidroximetiltransferase, already studied by our group. Ser can be initially acetylated by Ser-O-acetiltranferase (SAT) and probably this step is determinant in its metabolic fate. In a second step, the acetyl group is substituted by -SH, this reaction being catalysed by a Cys Sintase (CS). For both enzymes we already have identified the putative genes in T. cruzi genome databases (TriTryps). The present project has as a main goal to characterize the biological role of the enzymes SAT and CS of T.cruzi in the different stages, as well as in the different biological processes that are critical for the parasite to complete its life cycle. (AU)