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Papers In Press, published online ahead of print July 22, 2005
School of Biosciences, The University of Birmingham, Birmingham B15 2TT
Corresponding Author: g.besra{at}bham.ac.uk
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 C24-C26 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 towards meromycolic acids. The beta-ketoacyl-ACP synthase III (KAS-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 E. coli ACP. The enzyme’s ability to use ecACP 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 Arg46 revealed its more critical role in malonyl-AcpM decarboxylation than in acyl-CoA binding role. Interestingly, this effect was suppressed intragenically by Arg161‡Ala substitution. Our structural studies suggested that His258, 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 Cys122.
J. Biol. Chem, 10.1074/jbc.M413216200
Submitted on November 23, 2004
Revised on July 21, 2005
Accepted on July 22, 2005
Probing the mechanism of the mycobacterium tuberculosis
-ketoacyl-ACP synthase III mtFabH: Factors influencing catalysis and substrate specificity
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