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dc.contributor.author
Lin, Ting-Wan
dc.contributor.author
Melgar, Melrose M
dc.contributor.author
Kurth, Daniel German
dc.contributor.author
Swamidass, S Joshua
dc.contributor.author
Purdon, John
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Tseng, Teresa
dc.contributor.author
Gago, Gabriela Marisa
dc.contributor.author
Baldi, Pierre
dc.contributor.author
Gramajo, Hugo Cesar
dc.contributor.author
Tsai, Shiou Chan
dc.date.available
2018-09-28T20:22:15Z
dc.date.issued
2006-02
dc.identifier.citation
Lin, Ting-Wan; Melgar, Melrose M; Kurth, Daniel German; Swamidass, S Joshua; Purdon, John; et al.; Structure-based inhibitor design of AccD5, an essential acyl-CoA carboxylase carboxyltransferase domain of Mycobacterium tuberculosis; National Academy of Sciences; Proceedings of the National Academy of Sciences of The United States of America; 103; 9; 2-2006; 3072-3077
dc.identifier.issn
0027-8424
dc.identifier.uri
http://hdl.handle.net/11336/61315
dc.description.abstract
Mycolic acids and multimethyl-branched fatty acids are found uniquely in the cell envelope of pathogenic mycobacteria. These unusually long fatty acids are essential for the survival, virulence, and antibiotic resistance of Mycobacterium tuberculosis. Acyl-CoA carboxylases (ACCases) commit acyl-CoAs to the biosynthesis of these unique fatty acids. Unlike other organisms such as Escherichia coli or humans that have only one or two ACCases, M. tuberculosis contains six ACCase carboxyltransferase domains, AccD1-6, whose specific roles in the pathogen are not well defined. Previous studies indicate that AccD4, AccD5, and AccD6 are important for cell envelope lipid biosynthesis and that its disruption leads to pathogen death. We have determined the 2.9-Å crystal structure of AccD5, whose sequence, structure, and active site are highly conserved with respect to the carboxyltransferase domain of the Streptomyces coelicolor propionyl-CoA carboxylase. Contrary to the previous proposal that AccD4-5 accept long-chain acyl-CoAs as their substrates, both crystal structure and kinetic assay indicate that AccD5 prefers propionyl-CoA as its substrate and produces methylmalonyl-CoA, the substrate for the biosyntheses of multimethyl-branched fatty acids such as mycocerosic, phthioceranic, hydroxyphthioceranic, mycosanoic, and mycolipenic acids. Extensive in silico screening of National Cancer Institute compounds and the University of California, Irvine, ChemDB database resulted in the identification of one inhibitor with a Ki of 13.1 μM. Our results pave the way toward understanding the biological roles of key ACCases that commit acyl-CoAs to the biosynthesis of cell envelope fatty acids, in addition to providing a target for structure-based development of antituberculosis therapeutics.
dc.format
application/pdf
dc.language.iso
eng
dc.publisher
National Academy of Sciences
dc.rights
info:eu-repo/semantics/restrictedAccess
dc.rights.uri
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.subject
Cell Wall Lipid
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Multimethyl-Branched Fatty Acid
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Mycocerosic Acid
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Mycolic Acid
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Tuberculosis
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Otras Ciencias Biológicas
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Ciencias Biológicas
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CIENCIAS NATURALES Y EXACTAS
dc.title
Structure-based inhibitor design of AccD5, an essential acyl-CoA carboxylase carboxyltransferase domain of Mycobacterium tuberculosis
dc.type
info:eu-repo/semantics/article
dc.type
info:ar-repo/semantics/artículo
dc.type
info:eu-repo/semantics/publishedVersion
dc.date.updated
2018-08-30T15:48:35Z
dc.journal.volume
103
dc.journal.number
9
dc.journal.pagination
3072-3077
dc.journal.pais
Estados Unidos
dc.journal.ciudad
Washington
dc.description.fil
Fil: Lin, Ting-Wan. University of California at Irvine; Estados Unidos
dc.description.fil
Fil: Melgar, Melrose M. University of California at Irvine; Estados Unidos
dc.description.fil
Fil: Kurth, Daniel German. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Biología Molecular y Celular de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario; Argentina
dc.description.fil
Fil: Swamidass, S Joshua. University of California at Irvine; Estados Unidos
dc.description.fil
Fil: Purdon, John. University of California at Irvine; Estados Unidos
dc.description.fil
Fil: Tseng, Teresa. University of California at Irvine; Estados Unidos
dc.description.fil
Fil: Gago, Gabriela Marisa. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Biología Molecular y Celular de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario; Argentina
dc.description.fil
Fil: Baldi, Pierre. University of California at Irvine; Estados Unidos
dc.description.fil
Fil: Gramajo, Hugo Cesar. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Biología Molecular y Celular de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario; Argentina
dc.description.fil
Fil: Tsai, Shiou Chan. University of California at Irvine; Estados Unidos
dc.journal.title
Proceedings of the National Academy of Sciences of The United States of America
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/url/http://www.pnas.org/content/103/9/3072
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/doi/https://doi.org/10.1073/pnas.0510580103


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  • Articulos(IBR) [353]
    Articulos de INST.DE BIOLOGIA MOLECULAR Y CELULAR DE ROSARIO
  • Articulos(PROIMI) [488]
    Articulos de PLANTA PILOTO DE PROC.IND.MICROBIOLOGICOS (I)

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