'''Crystal Structure of the Acyl-CoA Carboxylase, AccD5, from Mycobacterium tuberculosis'''
===Crystal Structure of the Acyl-CoA Carboxylase, AccD5, from Mycobacterium tuberculosis===
==Overview==
<!--
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.
The line below this paragraph, {{ABSTRACT_PUBMED_16492739}}, adds the Publication Abstract to the page
(as it appears on PubMed at http://www.pubmed.gov), where 16492739 is the PubMed ID number.
-->
{{ABSTRACT_PUBMED_16492739}}
==About this Structure==
==About this Structure==
Line 36:
Line 40:
[[Category: Polyketide]]
[[Category: Polyketide]]
[[Category: Propionyl-coa carboxylase]]
[[Category: Propionyl-coa carboxylase]]
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 18:43:08 2008''
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun Jul 27 20:36:26 2008''
Revision as of 20:36, 27 July 2008
This article has been automatically seeded. Changes to this page should pertain to the PDB entry only and not to the protein or biomolecule in general.
Crystal Structure of the Acyl-CoA Carboxylase, AccD5, from Mycobacterium tuberculosisCrystal Structure of the Acyl-CoA Carboxylase, AccD5, from Mycobacterium tuberculosis
Structure-based inhibitor design of AccD5, an essential acyl-CoA carboxylase carboxyltransferase domain of Mycobacterium tuberculosis., Lin TW, Melgar MM, Kurth D, Swamidass SJ, Purdon J, Tseng T, Gago G, Baldi P, Gramajo H, Tsai SC, Proc Natl Acad Sci U S A. 2006 Feb 28;103(9):3072-7. Epub 2006 Feb 21. PMID:16492739
