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

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

Author de Lima Stein, Mariana Ledo Autor UNIFESP Google Scholar
Icimoto, Marcelo Yudi Autor UNIFESP Google Scholar
de Castro Levatti, Erica Valadares Autor UNIFESP Google Scholar
Oliveira, Vitor Autor UNIFESP Google Scholar
Straus, Anita Hilda Autor UNIFESP Google Scholar
Schenkman, Sergio Autor UNIFESP Google Scholar
Abstract 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.
Keywords Trypanosoma brucei
Leucine
3-methylglutaconyl CoA
RNAi
Ergosterol
Mevalonate
xmlui.dri2xhtml.METS-1.0.item-coverage Amsterdam
Language English
Sponsor Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP)
Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq)
Grant number FAPESP: 11/51973-3
FAPESP: 2015/22031-0
CNPq: 445655/2014-3
CNPq: 306815/2015-0
Date 2017
Published in Molecular And Biochemical Parasitology. Amsterdam, v. 214, p. 36-46, 2017.
ISSN 0166-6851 (Sherpa/Romeo, impact factor)
Publisher Elsevier Science Bv
Extent 36-46
Origin http://dx.doi.org/10.1016/j.molbiopara.2017.03.007
Access rights ACESSO RESTRITO
Type Article
Web of Science ID WOS:000404795200005
URI https://repositorio.unifesp.br/handle/11600/53704

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