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Relevance of L-asparagine and its catabolism in the cell biology and bioenergetics of Trypanosoma cruzi

Grant number: 17/10256-3
Support type:Scholarships in Brazil - Post-Doctorate
Effective date (Start): December 01, 2018
Effective date (End): March 31, 2022
Field of knowledge:Biological Sciences - Parasitology - Protozoology of Parasites
Principal researcher:Ariel Mariano Silber
Grantee:Letícia Marchese
Home 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
Associated scholarship(s):19/24707-2 - Understanding the metabolism of aspartate and asparagine and its role on the biosynthesis of nucleotides in Leishmania mexicana, BE.EP.PD

Abstract

The energetic metabolism in Trypanosoma cruzi, the etiological agent of Chagas disease, is well adapted to the consumption of a diversity of carbon and energy sources available in their hosts. In the absence of glucose, amino acids such as glutamate, proline, histidine and aspartate are relevant energy and carbon sources. In addition, other amino acids such as asparagine, glutamine, leucine, isoleucine seem to participate of these processes as well. Besides its role as a precursor of the tricarboxylic acid cycle intermediate oxaloacetate through the aspartate aminotransferase (mASAT), aspartate is involved in metacyclogenesis, in the detoxification of NH3 and in the de novo synthesis of pyrimidins and purins. Its is known that aspartate is taken up more efficiently at acidic pH. However, little information is available on its intracellular synthesis, which can happens through mASAT (a reversible enzyme) or through an asparaginase, which uses asparagine as substrate. Noteworthy, in spite of being structurally and metabolically related with aspartate, almost nothing is known about the relevance of asparagine in trypanossomatids. We propose as a hypothesis for this Project that this amino acid is a relevant source of aspartate in environmental conditions in which aspartate uptake does not supply the metabolic requirements of the parasite. From this hypothesis we predict for asparagine similar functions to those for aspartate in T. cruzi: participation in the bioenergetics, in the resistance to nutritional stress, and in the cell differentiation. The possible involvement of this amino acid in other biological processes in the parasite will be evaluated as well. Based on the considerations above, this Project has as a main goal to characterize the uptake of asparagine, to evaluate its relevance for the parasite in the bioenergetics and resistance to nutritional stress, to characterize the enzyme Asnase, and to investigate the biological role of both, Asnase and mASAT by producing knock out lineages of T. cruzi for these genes by CRISPR/cas9 technology.

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