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Artículo

Functional reconstitution of the Mycobacterium tuberculosis long-chain acyl-CoA carboxylase from multiple acyl-CoA subunits

Bazet Lyonnet, BernardoIcon ; Diacovich, LautaroIcon ; Gago, Gabriela MarisaIcon ; Spina, Lucie; Bardou, Fabienne; Lemassu, Anne; Quemard, Annaïk; Gramajo, Hugo CesarIcon
Fecha de publicación: 21/04/2017
Editorial: Wiley Blackwell Publishing, Inc
Revista: Febs Journal
ISSN: 1742-464X
Idioma: Inglés
Tipo de recurso: Artículo publicado
Clasificación temática:
Otras Ciencias Biológicas

Resumen

Mycobacterium tuberculosis produces a large number of structurally diverse lipids that have been implicated in the pathogenicity, persistence and antibiotic resistance of this organism. Most building blocks involved in the biosynthesis of all these lipids are generated by acyl-CoA carboxylases whose subunit composition and physiological roles have not yet been clearly established. Inconclusive data in the literature refer to the exact protein composition and substrate specificity of the enzyme complex that produces the long-chain α-carboxy-acyl-CoAs, which are substrates involved in the last step of condensation mediated by the polyketide synthase 13 to synthesize mature mycolic acids. Here we have successfully reconstituted the long-chain acyl-CoA carboxylase (LCC) complex from its purified components, the α subunit (AccA3), the ε subunit (AccE5) and the two β subunits (AccD4 and AccD5), and demonstrated that the four subunits are essential for its activity. Furthermore, we also showed by substrate competition experiments and the use of a specific inhibitor that the AccD5 subunit's role in the carboxylation of the long acyl-CoAs, as part of the LCC complex, was structural rather than catalytic. Moreover, AccD5 was also able to carboxylate its natural substrates, acetyl-CoA and propionyl-CoA, in the context of the LCC enzyme complex. Thus, the supercomplex formed by these four subunits has the potential to generate the main substrates, malonyl-CoA, methylmalonyl-CoA and α-carboxy-C24–26-CoA, used as condensing units for the biosynthesis of all the lipids present in this pathogen.
Palabras clave: Acyl-Coa Carboxylase , Lipid Biosynthesis , Mycobacterium Tuberculosis , Mycolic Acids
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info:eu-repo/semantics/openAccess Excepto donde se diga explícitamente, este item se publica bajo la siguiente descripción: Creative Commons Attribution-NonCommercial-ShareAlike 2.5 Unported (CC BY-NC-SA 2.5)
Identificadores
URI: http://hdl.handle.net/11336/65215
URL: http://onlinelibrary.wiley.com/doi/10.1111/febs.14046/abstract
DOI: http://dx.doi.org/10.1111/febs.14046
URL: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5393044/
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Articulos(IBR)
Articulos de INST.DE BIOLOGIA MOLECULAR Y CELULAR DE ROSARIO
Citación
Bazet Lyonnet, Bernardo; Diacovich, Lautaro; Gago, Gabriela Marisa; Spina, Lucie; Bardou, Fabienne; et al.; Functional reconstitution of the Mycobacterium tuberculosis long-chain acyl-CoA carboxylase from multiple acyl-CoA subunits; Wiley Blackwell Publishing, Inc; Febs Journal; 284; 7; 21-4-2017; 1110-1125
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