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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

Characterization of class II fumarase from Schistosoma mansoni provides the molecular basis for selective inhibition

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Author(s):
Cardoso, Iara Aime [1] ; Luiz de Souza, Aline Kusumota [1] ; Burgess, Adam Muslem George [2] ; Chalmers, Iain Wyllie [2] ; Hoffmann, Karl Francis [2] ; Nonato, Maria Cristina [1]
Total Authors: 6
Affiliation:
[1] Univ Sao Paulo, Fac Ciencias Farmaceut Ribeirao Preto, Dept Ciencias BioMol, Lab Cristalog Proteinas, Ribeirao Preto, SP - Brazil
[2] Aberystwyth Univ, Inst Biol Environm & Rural Sci IBERS, Aberystwyth, Dyfed - Wales
Total Affiliations: 2
Document type: Journal article
Source: International Journal of Biological Macromolecules; v. 175, p. 406-421, APR 1 2021.
Web of Science Citations: 0
Abstract

Schistosomiasis is a neglected tropical disease that affects more than 250 million people worldwide. The only drug available for its treatment undergoes first-pass hepatic metabolism and is not capable of preventing reinfection, which makes the search of new therapies urgently needed. Due to the essential role of fumarases in metabolism, these enzymes represent potential targets for developing novel schistosomiasis treatments. Here, we evaluate the expression profiles for class I and class II fumarases from Schistosoma mansoni (SmFHI and SmFHII, respectively), and report the complete characterization of SmFHII. The first SmFHII structure in complex with L-malate was determined at 1.85 angstrom resolution. The significant thermo shift observed for SmFHII in the presence of identified ligands makes the differential scanning fluorimetry an adequate technique for ligand screening. A complete kinetic characterization of SmFHII was performed, and comparison with the human fumarase (HsFH) revealed differences regarding the turnover number (k(cat)). Structural characterization allowed us to identify differences between SmFHII and HsFH that could be explored to design new selective inhibitors. This work represents the very first step towards validate the fumarases as drug targets to treat schistosomiasis. Our results provide the structural basis to rational search for selective ligands. (C) 2021 Elsevier B.V. All rights reserved. (AU)

FAPESP's process: 11/01495-8 - Cloning, expression, purification, crystallization and kinetics studies of fumarate hydratase from Schistosoma mansoni
Grantee:Aline Luiz de Souza
Support Opportunities: Scholarships in Brazil - Master
FAPESP's process: 08/08262-6 - Kinetic, Structural and functional characterization of LmjF24.0320. e LmjF29.1960 genes that code for fumarate hydratase in Leishmania major
Grantee:Maria Cristina Nonato
Support Opportunities: Regular Research Grants