Characterisation of the fumarate hydratase repertoire in Trypanosoma cruzi

Autor(es)

de Padua, Ricardo A. P. ; Kia, Ali Martin ; Costa-Filho, Antonio J. ; Wilkinson, Shane R. ; Nonato, M. Cristina

• Tipo de documento: Artigo Científico
• Fonte: International Journal of Biological Macromolecules; v. 102, p. 42-51, SEP 2017.
• Citações Web of Science: 4

Resumo

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)

• 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
• Processo FAPESP: 15/18390-5 - Ressonância magnética eletrônica em biofísica molecular: novos e velhos olhares para novos e velhos problemas
• Beneficiário: Antonio José da Costa Filho
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 08/11644-8 - Caracterização estrutural e funcional das isoformas da enzima fumarato hidratase de Trypanosoma cruzi
• Beneficiário: Ricardo Augusto Pereira de Pádua
• Modalidade de apoio: Bolsas no Brasil - Doutorado Direto