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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.)

Characterisation of the fumarate hydratase repertoire in Trypanosoma cruzi

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de Padua, Ricardo A. P. ; Kia, Ali Martin ; Costa-Filho, Antonio J. ; Wilkinson, Shane R. ; Nonato, M. Cristina
Total Authors: 5
Document type: Journal article
Source: International Journal of Biological Macromolecules; v. 102, p. 42-51, SEP 2017.
Web of Science Citations: 4

Nifurtimox and benznidazole represent the only treatments options available targeting Chagas disease, the most important parasitic infection in the Americas. However, use of these is problematic as they are toxic and ineffective against the more severe stages of the disease. In this work, we used a multidisciplinary approach to characterise the fumarases from Trypanosoma cruzi, the causative agent of Chagas Disease. We showed this trypanosome expresses cytosolic and mitochondrial fumarases that via an iron-sulfur cluster mediate the reversible conversion of fumarate to S-malate. Based on sequence, biochemical properties and co-factor binding, both T. cruzi proteins share characteristics with class I fumarases, enzymes found in bacteria and some other protozoa but absent from humans, that possess class II isoforms instead. Gene disruption suggested that although the cytosolic or mitochondrial fumarase activities are individually dispensable their combined activity is essential for parasite viability. Finally, based on the mechanistic differences with the human (host) fumarase, we designed and validated a selective inhibitor targeting the parasite enzyme. This study showed that T. cruzi fumarases should be exploited as targets for the development of new chemotherapeutic interventions against Chagas disease. (C) 2017 Elsevier B.V. All rights reserved. (AU)

FAPESP's process: 15/18390-5 - Electron magnetic resonance in molecular biophysics: new and old looks to new and old problems
Grantee:Antonio José da Costa Filho
Support type: Regular Research Grants
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 type: Regular Research Grants
FAPESP's process: 08/11644-8 - Structural and functional characterization of Trypanosoma cruzi fumarate hydratase isoforms
Grantee:Ricardo Augusto Pereira de Pádua
Support type: Scholarships in Brazil - Doctorate (Direct)