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Understanding the metabolism of aspartate and asparagine and its role on the biosynthesis of nucleotides in Leishmania mexicana

Grant number: 19/24707-2
Support type:Scholarships abroad - Research Internship - Post-doctor
Effective date (Start): August 01, 2020
Effective date (End): July 31, 2021
Field of knowledge:Biological Sciences - Parasitology - Protozoology of Parasites
Principal researcher:Ariel Mariano Silber
Grantee:Letícia Marchese
Supervisor abroad: Brian Alejandro Suarez Mantilla
Home Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Research place: Durham University (DU), England  
Associated to the scholarship:17/10256-3 - Relevance of L-asparagine and its catabolism in the cell biology and bioenergetics of Trypanosoma cruzi, BP.PD

Abstract

Amino acids and nucleotides constitute essential building blocks of macromolecules for any living organism. Aspartate (the deaminated form of asparagine) and glutamine serve as precursors for pyrimidine nucleotides biosynthesis by forming N-carbamoyl aspartate (through aspartate carbamoyltransferase), which can be further transformed into uridine monophosphate (UMPS) through de novo pathway for pyrimidines biosynthesis. Importantly, for the production of UMPS the presence of phosphoribosyl-1-pyrophosphate (PRPP) is critical. PRPP in turn is a product of the pentose phosphate pathway. Therefore, PRPP is involved in both purine and pyrimidine nucleotides biosynthetic routes. Trypanosomatids have the enzymatic machinery for de novo biosynthesis of pyrimidine nucleotides but no purines. In addition, in Leishmania parasites it has been recently identified a single PRPP synthase whose activity can be regulated by inositol pyrophosphates. Summarizing, all the data available until now point to a close relationship between the aspartate/asparagine and nucleotide metabolism. However, there are still no clear evidences on how aspartate feeds the nucleotides synthesis requirements. This proposal aims to define the role of aspartate/asparagine metabolism and the aspartate carbamoyltransferase to the whole pool of pyrimidines nucleotides in Leishmania parasites.

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