Characterization and role of the 3-methylglutaconyl coenzyme A hidratase in Trypanosoma brucei

Autor(es)

de Lima Stein, Mariana Ledo ; Icimoto, Marcelo Yudi ; de Castro Levatti, Erica Valadares ; Oliveira, Vitor ; Straus, Anita Hilda ; Schenkman, Sergio

• Tipo de documento: Artigo Científico
• Fonte: Molecular and Biochemical Parasitology; v. 214, p. 36-46, JUN 2017.
• Citações Web of Science: 2

Resumo

Trypanosoma brucei, the agent of African Trypanosomiasis, is a flagellated protozoan parasite that develops in tsetse flies and in the blood of various mammals. The parasite acquires nutrients such as sugars, lipids and amino acids from their hosts. Amino acids are used to generate energy and for protein and lipid synthesis. However, it is still unknown how T. brucei catabolizes most of the acquired amino acids. Here we explored the role of an enzyme of the leucine catabolism, the 3-methylglutaconyl-Coenzyme A hydratase (3-MGCoA-H). It catalyzes the hydration of 3-methylglutaconyl-Coenzyme A (3-MGCoA) into 3-hydroxymethylglutaryl-Coenzyme A (3-HMGCoA). We found that 3-MGCoA-H localizes in the mitochondria) matrix and is expressed in both insect and mammalian bloodstream forms of the parasite. The depletion of 3-MGCoA-H by RNA interference affected minimally the proliferation of both forms. However, an excess of leucine in the culture medium caused growth defects in cells depleted of 3-MGCoA-H, which could be reestablished by mevalonate, a precursor of isoprenoids and steroids. Indeed, procyclics depleted of the 3-MGCoA-H presented reduced levels of synthesized steroids relative to cholesterol that is scavenged by the parasite, and these levels were also reestablished by mevalonate. These results suggest that accumulation of leucine catabolites could affect the level of mevalonate and consequently inhibit the sterol biosynthesis, required for T. brucei growth. (C) 2017 Elsevier B.V. All rights reserved. (AU)

• Processo FAPESP: 15/22031-0 - Sinalização celular em Trypanosoma durante a interação do parasita com o hospedeiro
• Beneficiário: Sergio Schenkman
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 11/51973-3 - Mecanismo de sinalização celular de Trypanosoma em resposta a alterações nutricionais e agentes genotóxicos
• Beneficiário: Sergio Schenkman
• Modalidade de apoio: Auxílio à Pesquisa - Temático