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Cloning, expression and charactherization of L-asparaginases from Saccharomyces cerevisiae and comparison with bacterial L-asparaginases used to treat Leukemia

Grant number: 13/08139-8
Support type:Scholarships in Brazil - Scientific Initiation
Effective date (Start): July 01, 2013
Effective date (End): December 31, 2014
Field of knowledge:Biological Sciences - Pharmacology - Biochemical and Molecular Pharmacology
Principal researcher:Gisele Monteiro
Grantee:Mariana Silva Moreira Leite
Home Institution: Faculdade de Ciências Farmacêuticas (FCF). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Associated research grant:09/01303-1 - Characterization of unknown function ORFs involved in Saccharomyces cerevisiae antioxidant response, AP.JP

Abstract

The L-asparaginase (ASPase) was discovered in the 1960s and it is used until the present day as a leading biopharmaceutical to treat leukemia. It is an enzyme capable of catalyzing the cleavage of the amino acid asparagine (Asn) to form aspartic acid and ammonia. This prevents the uptake of extracellular Asn by tumor cells, causing decreased protein production and consequently a decrease in DNA, and RNA levels, altering the cell cycle and inducing apoptosis. Leukemic cells, unlike normal cells, possess little or no presence of asparagine synthetase, making them completely dependent upon the intake of this amino acid from extracellular media. The ATPases commercially available are of bacterial origin and they induce remission of acute lymphoblastic leukemia in children - ALL, and others. Currently, the greatest difficulty is the allergic reaction and the induction of an immune response caused by the administration of a bacterial protein in humans. Furthermore, and perhaps more importantly, despite its importance in the treatment of leukemia juvenile, the overseas company supplying the product to Brazil discontinued the production of the ATPase. The phases obtained from the yeast S. cerevisiae, produced by genes ASP1 and ASP3 are still poorly studied and could be another option for antitumor therapy. This study aims to produce large quantities of the ATPases from S. cerevisiae and characterize their enzyme kinetics in comparison with the bacterial isoforms to assess whether they are possible to use for the treatment of ALL. (AU)

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Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
RODRIGUES, MARIANE A. D.; PIMENTA, MARCELA V.; COSTA, IRIS M.; ZENATTI, PRISCILA P.; MIGITA, NATACHA A.; YUNES, JOSE A.; RANGEL-YAGUI, CARLOTA O.; DE SA, MATHEUS M.; PESSOA, ADALBERTO; COSTA-SILVA, TALES A.; et al. Influence of lysosomal protease sensitivity in the immunogenicity of the antitumor biopharmaceutical asparaginase. Biochemical Pharmacology, v. 182, . (14/06863-3, 18/18257-1, 13/08617-7, 16/25896-5, 15/07749-2, 18/15104-0, 13/08139-8, 18/15549-1)

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