2ahb
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X-ray crystal structure of R46A,R161A mutant of Mycobacterium tuberculosis FabH
OverviewOverview
Mycolic acids are the dominant feature of the Mycobacterium tuberculosis, cell wall. These alpha-alkyl, beta-hydroxy fatty acids are formed by the, condensation of two fatty acids, a long meromycolic acid and a shorter, C(24)-C(26) fatty acid. The component fatty acids are produced via a, combination of type I and II fatty acid synthases (FAS) with FAS-I, products being elongated by FAS-II toward meromycolic acids. The, beta-ketoacyl-acyl carrier protein (ACP) synthase III encoded by mtfabH, (mtFabH) links FAS-I and FAS-II, catalyzing the condensation of, FAS-I-derived acyl-CoAs with malonyl-acyl carrier protein (ACP). The, acyl-CoA chain length specificity of mtFabH was assessed in vitro; the, enzyme extended longer, physiologically relevant acyl-CoA primers when, paired with AcpM, its natural partner, than with Escherichia coli ACP. The, ability of the enzyme to use E. coli ACP suggests that a similar mode of, binding is likely with both ACPs, yet it is clear that unique factors, inherent to AcpM modulate the substrate specificity of mtFabH. Mutation of, proposed key mtFabH residues was used to define their catalytic roles., Substitution of supposed acyl-CoA binding residues reduced transacylation, with double substitutions totally abrogating activity. Mutation of Arg(46), revealed its more critical role in malonyl-AcpM decarboxylation than in, the acyl-CoA binding role. Interestingly, this effect was suppressed, intragenically by Arg(161) --> Ala substitution. Our structural studies, suggested that His(258), previously implicated in malonyl-ACP, decarboxylation, also acts as an anchor point for a network of water, molecules that we propose promotes deprotonation and transacylation of, Cys(122).
About this StructureAbout this Structure
2AHB 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
Probing the mechanism of the Mycobacterium tuberculosis beta-ketoacyl-acyl carrier protein synthase III mtFabH: factors influencing catalysis and substrate specificity., Brown AK, Sridharan S, Kremer L, Lindenberg S, Dover LG, Sacchettini JC, Besra GS, J Biol Chem. 2005 Sep 16;280(37):32539-47. Epub 2005 Jul 22. PMID:16040614 [[Category: 3-oxoacyl-[acyl-carrier-protein] synthase iii]]
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