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Structure-based inhibitor design of AccD5, an essential acyl-CoA carboxylase carboxyltransferase domain of Mycobacterium tuberculosis.

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Title: Structure-based inhibitor design of AccD5, an essential acyl-CoA carboxylase carboxyltransferase domain of Mycobacterium tuberculosis.
Authors: Ting-Wan Lin1,2,3, MeIgar, Melrose M.1,2,3, Kurth, Daniel4, Swamidass, S. Joshua3,5,6, Purdon, John1,2,3, Tseng, Teresa1,2,3, Gago, Gabriela4, BaIdi, Pierre3,5,6, Gramajo, Hugo4, Shiou-Chuan Tsai1,2,3,7 sctsai@uci.edu
Source: Proceedings of the National Academy of Sciences of the United States of America. 2/28/2006, Vol. 103 Issue 9, p3072-3077. 6p. 4 Diagrams, 1 Graph.
Subjects: Fatty acids, Mycobacteria, Mycobacterium tuberculosis, Escherichia coli, Streptomyces coelicolor, Biosynthesis, Tuberculin, Pathogenic microorganisms, National Cancer Institute (U.S.)
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-C0A 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. [ABSTRACT FROM AUTHOR]
Copyright of Proceedings of the National Academy of Sciences of the United States of America is the property of National Academy of Sciences and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
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  Data: Structure-based inhibitor design of AccD5, an essential acyl-CoA carboxylase carboxyltransferase domain of Mycobacterium tuberculosis.
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  Data: <searchLink fieldCode="AR" term="%22Ting-Wan+Lin%22">Ting-Wan Lin</searchLink><relatesTo>1,2,3</relatesTo><br /><searchLink fieldCode="AR" term="%22MeIgar%2C+Melrose+M%2E%22">MeIgar, Melrose M.</searchLink><relatesTo>1,2,3</relatesTo><br /><searchLink fieldCode="AR" term="%22Kurth%2C+Daniel%22">Kurth, Daniel</searchLink><relatesTo>4</relatesTo><br /><searchLink fieldCode="AR" term="%22Swamidass%2C+S%2E+Joshua%22">Swamidass, S. Joshua</searchLink><relatesTo>3,5,6</relatesTo><br /><searchLink fieldCode="AR" term="%22Purdon%2C+John%22">Purdon, John</searchLink><relatesTo>1,2,3</relatesTo><br /><searchLink fieldCode="AR" term="%22Tseng%2C+Teresa%22">Tseng, Teresa</searchLink><relatesTo>1,2,3</relatesTo><br /><searchLink fieldCode="AR" term="%22Gago%2C+Gabriela%22">Gago, Gabriela</searchLink><relatesTo>4</relatesTo><br /><searchLink fieldCode="AR" term="%22BaIdi%2C+Pierre%22">BaIdi, Pierre</searchLink><relatesTo>3,5,6</relatesTo><br /><searchLink fieldCode="AR" term="%22Gramajo%2C+Hugo%22">Gramajo, Hugo</searchLink><relatesTo>4</relatesTo><br /><searchLink fieldCode="AR" term="%22Shiou-Chuan+Tsai%22">Shiou-Chuan Tsai</searchLink><relatesTo>1,2,3,7</relatesTo><i> sctsai@uci.edu</i>
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  Data: 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-C0A 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. [ABSTRACT FROM AUTHOR]
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  Data: <i>Copyright of Proceedings of the National Academy of Sciences of the United States of America is the property of National Academy of Sciences and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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      – Type: doi
        Value: 10.1073/pnas.0510580103
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      – Code: eng
        Text: English
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      Pagination:
        PageCount: 6
        StartPage: 3072
    Subjects:
      – SubjectFull: Fatty acids
        Type: general
      – SubjectFull: Mycobacteria
        Type: general
      – SubjectFull: Mycobacterium tuberculosis
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      – SubjectFull: Escherichia coli
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      – SubjectFull: Streptomyces coelicolor
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      – SubjectFull: Biosynthesis
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      – SubjectFull: Tuberculin
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      – SubjectFull: Pathogenic microorganisms
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      – SubjectFull: National Cancer Institute (U.S.)
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      – TitleFull: Structure-based inhibitor design of AccD5, an essential acyl-CoA carboxylase carboxyltransferase domain of Mycobacterium tuberculosis.
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              Text: 2/28/2006
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