Scholarship 22/12315-5 - Bioquímica, Metabolismo de aminoácidos - BV FAPESP
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Biochemical and functional characterization of the asparagine synthetases of Trypanosoma cruzi

Grant number: 22/12315-5
Support Opportunities:Scholarships in Brazil - Doctorate (Direct)
Start date until: April 01, 2023
End date until: December 31, 2023
Field of knowledge:Biological Sciences - Parasitology - Protozoology of Parasites
Principal Investigator:Ariel Mariano Silber
Grantee:Andrea Katherine Pinto Martinez
Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Associated research grant:18/14432-3 - A network for an integrative biology in neglected diseases: bridging epigenetics, metabolism and cell cycle in pathogenic trypanosomatids, AP.TEM

Abstract

The absence of an efficient treatment against Chagas disease rises the need to broaden our knowledge about the biology of this parasite, with the aim of identifying new targets and compounds as a therapeutic alternative. On this regard, aminoacid metabolism is a rational study proposal owed to its fundamental importance. Aminoacids, besides being precursors of protein biosynthesis, they serve as sources of carbon and energy and are involved in several critical processes of T. cruzi biology, such as cellular differentiation, host cell invasion, cell cycle regulation and resistance to different types of stress. In this sense, the asparagine synthetase (AsnS) is an enzyme that catalyzes the interconvertion of aspartate (Asp) and glutamine (Gln) to produce asparagine (Asn) and glutamate (Glu). Besides the envolvement of this enzyme in the metabolism of the forementioned aminoacids, we propose that ASnS is also relevant in the administration and availability of other metabolites of great importance derived from the previously mentioned aminoacids, and are indispensable for mitochondrial function. Among the derivatives of such metabolic pathways can be mentioned ±-ketoglutarate produced by deamination of Glu, and oxaloacetate produced by deamination of Asp. Our research team has previously reported the characterization of a Gln synthetase from T. cruzi, which catalyzes the production of Gln using Glu as substrate, also showing this enzyme is involved in the recruitment of the NH„z generated by aminoacid metabolism. In this proposal, we rise the hypothesis that just like Glu acts as a NH„z acceptor, the transference of amino (-NH‚) groups to Asp with the resulting production of Asn by the AsnS, would be an essential component of the resistance mechanism against NH4 accumulation, allowing the control of the relative quantities of the four aminoacids involved in this process. (AU)

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