1hzp

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Crystal Structure of the Myobacterium Tuberculosis Beta-Ketoacyl-Acyl Carrier Protein Synthase III

Overview

Mycolic acids (alpha-alkyl-beta-hydroxy long chain fatty acids) cover the, surface of mycobacteria, and inhibition of their biosynthesis is an, established mechanism of action for several key front-line, anti-tuberculosis drugs. In mycobacteria, long chain acyl-CoA products, (C(14)-C(26)) generated by a type I fatty-acid synthase can be used, directly for the alpha-branch of mycolic acid or can be extended by a type, II fatty-acid synthase to make the meromycolic acid (C(50)-C(56)))-derived, component. An unusual Mycobacterium tuberculosis beta-ketoacyl-acyl, carrier protein (ACP) synthase III (mtFabH) has been identified, purified, and shown to catalyze a Claisen-type condensation between long chain, acyl-CoA substrates such as myristoyl-CoA (C(14)) and malonyl-ACP. This, enzyme, presumed to play a key role in initiating meromycolic acid, biosynthesis, was crystallized, and its structure was determined at 2.1-A, resolution. The mtFabH homodimer is closely similar in topology and, active-site structure to Escherichia coli FabH (ecFabH), with a, CoA/malonyl-ACP-binding channel leading from the enzyme surface to the, buried active-site cysteine residue. Unlike ecFabH, mtFabH contains a, second hydrophobic channel leading from the active site. In the ecFabH, structure, this channel is blocked by a phenylalanine residue, which, constrains specificity to acetyl-CoA, whereas in mtFabH, this residue is a, threonine, which permits binding of longer acyl chains. This same channel, in mtFabH is capped by an alpha-helix formed adjacent to a 4-amino acid, sequence insertion, which limits bound acyl chain length to 16 carbons., These observations offer a molecular basis for understanding the unusual, substrate specificity of mtFabH and its probable role in regulating the, biosynthesis of the two different length acyl chains required for, generation of mycolic acids. This mtFabH presents a new target for, structure-based design of novel antimycobacterial agents.

About this Structure

1HZP is a Single protein structure of sequence from Mycobacterium tuberculosis with DAO and GOL as ligands. Active as Beta-ketoacyl-acyl-carrier-protein synthase I, with EC number 2.3.1.41 Full crystallographic information is available from OCA.

Reference

Crystal structure of the Mycobacterium tuberculosis beta-ketoacyl-acyl carrier protein synthase III., Scarsdale JN, Kazanina G, He X, Reynolds KA, Wright HT, J Biol Chem. 2001 Jun 8;276(23):20516-22. Epub 2001 Mar 8. PMID:11278743

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