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

Autor(es)

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]

Afiliação do(s) autor(es)

^[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

• Tipo de documento: Artigo Científico
• Fonte: International Journal of Biological Macromolecules; v. 175, p. 406-421, APR 1 2021.
• Citações Web of Science: 0

Resumo

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)

• Processo FAPESP: 11/01495-8 - Clonagem, expressão, purificação, cristalização e caracterização cinética da enzima fumarato hidratase de Schistosoma mansoni
• Beneficiário: Aline Luiz de Souza
• Modalidade de apoio: Bolsas no Brasil - Mestrado
• Processo FAPESP: 08/08262-6 - Caracterização cinética, estrutural e funcional dos genes LmjF24.0320. e LmjF29.1960 que codificam a enzima fumarato hidratase em Leishmania major
• Beneficiário: Maria Cristina Nonato
• Modalidade de apoio: Auxílio à Pesquisa - Regular