Pleiotropic effect of AccD5 and AccE5 depletion in acyl-coenzyme a carboxylase activity and in lipid biosynthesis in mycobacteria

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dc.citation.titlePLoS ONE
dc.citation.volume9
dc.creatorBazet Lyonnet, Bernardo
dc.creatorDiacovich, Lautaro
dc.creatorCabruja, Matías Ezequiel
dc.creatorBardou, Fabienne
dc.creatorQuémard, Annaïk
dc.creatorGago, Gabriela
dc.creatorGramajo, Hugo Cesar
dc.date.accessioned2024-11-07T18:48:31Z
dc.date.available2024-11-07T18:48:31Z
dc.date.issued2014-06-20
dc.description.abstractMycobacteria contain a large variety of fatty acids which are used for the biosynthesis of several complex cell wall lipids that have been implicated in the ability of the organism to resist host defenses. The building blocks for the biosynthesis of all these lipids are provided by a fairly complex set of acyl-CoA carboxylases (ACCases) whose subunit composition and roles within these organisms have not yet been clearly established. Previous biochemical and structural studies provided strong evidences that ACCase 5 from Mycobacterium tuberculosis is formed by the AccA3, AccD5 and AccE5 subunits and that this enzyme complex carboxylates acetyl-CoA and propionyl-CoA with a clear substrate preference for the latest. In this work we used a genetic approach to unambiguously demonstrate that the products of both accD5 and accE5 genes are essential for the viability of Mycobacterium smegmatis. By obtaining a conditional mutant on the accD5-accE5 operon, we also demonstrated that the main physiological role of this enzyme complex was to provide the substrates for fatty acid and mycolic acid biosynthesis. Furthermore, enzymatic and biochemical analysis of the conditional mutant provided strong evidences supporting the notion that AccD5 and/or AccE5 have an additional role in the carboxylation of long chain acylCoA prior to mycolic acid condensation. These studies represent a significant step towards a better understanding of the roles of ACCases in mycobacteria and confirm ACCase 5 as an interesting target for the development of new antimycobacterial drugs.
dc.description.filFil: Bazet Lyonnet, Bernardo. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario. Laboratory of Physiology and Genetcs of Actinomycetes (IBR-CONICET); Argentina.
dc.description.filFil: Diacovich, Lautaro. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario. Laboratory of Physiology and Genetcs of Actinomycetes (IBR-CONICET); Argentina.
dc.description.filFil: Cabruja, Matías Ezequiel. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario. Laboratory of Physiology and Genetcs of Actinomycetes (IBR-CONICET); Argentina.
dc.description.filFil: Bardou, Fabienne. Institut de Pharmacologie et de Biologie Structurale. Département Tuberculose et Biologie des Infections; France.
dc.description.filFil: Bardou, Fabienne. Université de Toulouse; France.
dc.description.filFil: Quémard, Annaïk. Institut de Pharmacologie et de Biologie Structurale. Département Tuberculose et Biologie des Infections; France.
dc.description.filFil: Quémard, Annaïk. Université de Toulouse; France.
dc.description.filFil: Gago, Gabriela. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario. Laboratory of Physiology and Genetcs of Actinomycetes (IBR-CONICET); Argentina.
dc.description.filFil: Gramajo, Hugo Cesar. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario. Laboratory of Physiology and Genetcs of Actinomycetes (IBR-CONICET); Argentina.
dc.description.sponsorshipNational Institutes of Health (NIH): 1R01AI095183-01
dc.description.sponsorshipMinisterio de Ciencia, Tecnología e Innovación Productiva de la República Argentina (MINCYT)/ECOS-Sud France: A11B04
dc.description.sponsorshipAgencia Nacional de Promoción Científica y Tecnológica: PICT 2008-1640, PICTO 2011-0047, PICT 2011-0245
dc.description.versionpeerreviewed
dc.format.extent1-10
dc.identifier.citationBazet Lyonnet, Bernardo; Diacovich, Lautaro; Cabruja, Matias Ezequiel; Bardou, Fabienne; Quémard, Annaïk; et al.; Pleiotropic effect of AccD5 and AccE5 depletion in acyl-coenzyme a carboxylase activity and in lipid biosynthesis in mycobacteria; Public Library of Science; Plos One; 9; 6; 6-2014; 1-10
dc.identifier.issn1932-6203
dc.identifier.urihttps://hdl.handle.net/2133/28062
dc.language.isoen
dc.publisherPublic Library of Science
dc.relation.publisherversionhttps://doi.org/10.1371/journal.pone.0099853
dc.relation.publisherversionhttps://journals.plos.org/plosone/article?id=10.1371/journal.pone.0099853
dc.rightsopenAccess
dc.rights.holderBazet Lyonnet, Bernardo
dc.rights.holderDiacovich, Lautaro
dc.rights.holderCabruja, Matías Ezequiel
dc.rights.holderBardou, Fabienne
dc.rights.holderQuémard, Annaïk
dc.rights.holderGago, Gabriela
dc.rights.holderGramajo, Hugo Cesar
dc.rights.textAttribution 4.0 International CC BY 4.0 Deed
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectMycobacterium
dc.subjectMycolic acids
dc.subjectAnti-bacterial agents
dc.titlePleiotropic effect of AccD5 and AccE5 depletion in acyl-coenzyme a carboxylase activity and in lipid biosynthesis in mycobacteria
dc.typearticulo
dc.type.collectionarticulo
dc.type.versionpublishedVersion

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