2gp6
X-ray crystal structure of Mycobacterium tuberculosis beta-ketoacyl acyl carrier protein synthase II (mtKasB)
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OverviewOverview
Mycolic acids are long chain alpha-alkyl branched, beta-hydroxy fatty, acids that represent a characteristic component of the Mycobacterium, tuberculosis cell wall. Through their covalent attachment to peptidoglycan, via an arabinogalactan polysaccharide, they provide the basis for an, essential outer envelope membrane. Mycobacteria possess two fatty acid, synthases (FAS); FAS-I carries out de novo synthesis of fatty acids while, FAS-II is considered to elongate medium chain length fatty acyl primers to, provide long chain (C(56)) precursors of mycolic acids. Here we report the, crystal structure of Mycobacterium tuberculosis beta-ketoacyl acyl carrier, protein synthase (ACP) II mtKasB, a mycobacterial elongation condensing, enzyme involved in FAS-II. This enzyme, along with the M. tuberculosis, beta-ketoacyl ACP synthase I mtKasA, catalyzes the Claisen-type, condensation reaction responsible for fatty acyl elongation in FAS-II and, are potential targets for development of novel anti-tubercular drugs. The, crystal structure refined to 2.4 A resolution revealed that, like other, KAS-II enzymes, mtKasB adopts a thiolase fold but contains unique, structural features in the capping region that may be crucial to its, preference for longer fatty acyl chains than its counterparts from other, bacteria. Modeling of mtKasA using the mtKasB structure as a template, predicts the overall structures to be almost identical, but a larger, entrance to the active site tunnel is envisaged that might contribute to, the greater sensitivity of mtKasA to the inhibitor thiolactomycin (TLM)., Modeling of TLM binding in mtKasB shows that the drug fits the active site, poorly and results of enzyme inhibition assays using TLM analogues are, wholly consistent with our structural observations. Consequently, the, structure described here further highlights the potential of TLM as an, anti-tubercular lead compound and will aid further exploration of the TLM, scaffold towards the design of novel compounds, which inhibit, mycobacterial KAS enzymes more effectively.
About this StructureAbout this Structure
2GP6 is a Single protein structure of sequence from Mycobacterium tuberculosis. Active as Beta-ketoacyl-acyl-carrier-protein synthase I, with EC number 2.3.1.41 Full crystallographic information is available from OCA.
ReferenceReference
X-ray crystal structure of Mycobacterium tuberculosis beta-ketoacyl acyl carrier protein synthase II (mtKasB)., Sridharan S, Wang L, Brown AK, Dover LG, Kremer L, Besra GS, Sacchettini JC, J Mol Biol. 2007 Feb 16;366(2):469-80. Epub 2006 Nov 7. PMID:17174327
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