2A7S

Crystal Structure of the Acyl-CoA Carboxylase, AccD5, from Mycobacterium tuberculosis

2A7S の概要

• エントリーDOI: 10.2210/pdb2a7s/pdb
• 分子名称: Probable propionyl-CoA carboxylase beta chain 5 (2 entities in total)
• 機能のキーワード: carboxylase, carboxyltransferase, acetyl-coa carboxylase, propionyl-coa carboxylase, acyl-coa carboxylase, mycolic acid, fatty acid, polyketide, ligase
• 由来する生物種: Mycobacterium tuberculosis
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 356519.81

構造登録者

Lin, T.,Melgar, M.,Purdon, J.,Tseng, T.,Tsai, S.C. (登録日: 2005-07-06, 公開日: 2006-02-21, 最終更新日: 2024-04-03)

主引用文献

Lin, T.W.,Melgar, M.M.,Kurth, D.,Swamidass, S.J.,Purdon, J.,Tseng, T.,Gago, G.,Baldi, P.,Gramajo, H.,Tsai, S.C.
Structure-based inhibitor design of AccD5, an essential acyl-CoA carboxylase carboxyltransferase domain of Mycobacterium tuberculosis.
Proc.Natl.Acad.Sci.Usa, 103:3072-3077, 2006

PubMed 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-Angstroms 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 K(i) of 13.1 microM. 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.

PubMed: 16492739
DOI: 10.1073/pnas.0510580103

実験手法

X-RAY DIFFRACTION (2.9 Å)