1HZP

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

Summary for 1HZP

• Entry DOI: 10.2210/pdb1hzp/pdb
• Related: 1EBL 1HNJ
• Descriptor: 3-OXOACYL-[ACYL-CARRIER-PROTEIN] SYNTHASE III, LAURIC ACID, GLYCEROL, ... (4 entities in total)
• Functional Keywords: fatty acid biosynthesis, myobacterium tuberculosis, structural basis for substrate specificity, structural genomics, psi, protein structure initiative, tb structural genomics consortium, tbsgc, transferase
• Biological source: Mycobacterium tuberculosis
• Total number of polymer chains: 2
• Total formula weight: 70651.76

Authors

Scarsdale, J.N.,Kazanina, G.,He, X.,Reynolds, K.A.,Wright, H.T.,TB Structural Genomics Consortium (TBSGC) (deposition date: 2001-01-25, release date: 2001-06-13, Last modification date: 2023-08-09)

Primary citation

Scarsdale, J.N.,Kazanina, G.,He, X.,Reynolds, K.A.,Wright, H.T.
Crystal structure of the Mycobacterium tuberculosis beta-ketoacyl-acyl carrier protein synthase III
J.Biol.Chem., 276:20516-20522, 2001

PubMed Abstract: 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.

PubMed: 11278743
DOI: 10.1074/jbc.M010762200

Experimental method

X-RAY DIFFRACTION (2.1 Å)