Elucidation of the mechanism of action of fumarate hydratase from Leishmania major

• Grant number: 13/14988-8
• Support Opportunities: Scholarships in Brazil - Post-Doctorate
• Effective date (Start): November 01, 2013
• Effective date (End): May 31, 2016
• Field of knowledge: Biological Sciences - Biophysics - Molecular Biophysics
• Principal Investigator: Maria Cristina Nonato
• Grantee: Patrícia Rosa Feliciano
• Host Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated scholarship(s): 14/22246-4 - Mutational analysis of active site residues in fumarate hydratase from Leishmania major, BE.EP.PD

Abstract

Fumarate hydratases catalyze the stereospecific reversible hydration of fumarate to S-malate. The project aims to elucidate the mechanism of action of fumarate hydratase from Leishmania major by site directed mutagenesis, single crystal x-ray diffraction and electron paramagnetic resonance. Leishmania is a parasite that causes Leishmaniases, classified as neglected tropical deseases and threatening 350 million people around the world. Recent studies in trypanosomatids, using Trypanosoma brucei as a model, suggest that fumarate hydratase may be exploited as a potential target for the development of anti-trypanosomatid drugs. Mechanism of action studies, proposed in this work, associated to our previous kinetic, cell localization and structural studies will be used to further to establish the structure-function relationship of both fumarate hydratase enzymes in Leishmania major. The results obtained during the development of this project will provide valuable information for the development of specific inhibitors as an important tool in the fight against Leishmaniasis.

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)

FELICIANO, PATRICIA R.; RUSTIGUEL, JOANE K.; SOARES, RICARDO O. S.; SAMPAIO, SUELY V.; CRISTINA NONATO, M.. Crystal structure and molecular dynamics studies of L-amino acid oxidase from Bothrops atrox. Toxicon, v. 128, p. 50-59, MAR 15 2017. (15/24010-0, 09/10454-3, 13/14988-8)

FELICIANO, PATRICIA R.; DRENNAN, CATHERINE L.; NONATO, MARIA CRISTINA. Crystal Structures of Fumarate Hydratases from Leishmania major in a Complex with Inhibitor 2-Thiomalate. ACS Chemical Biology, v. 14, n. 2, p. 266-275, FEB 2019. (08/08262-6, 14/22246-4, 13/14988-8)