Beta-ketoacyl-(acyl-carrier-protein) Synthase III - Structure and Substrates

Structure and Substrates

Crystal structures of FabH have been reported from Mycobacterium tuberculosis, Staphylococcus aureus, Escherichia coli, and Thermus thermophilus.

The catalytic activity and substrate specificity of mtFabH has been measured then further probed using crystallographic and directed mutagenesis methods Structures have been determined of ecFabH bound with substrates, (CoA, malonyl CoA, degraded CoA). Specific inhibitors developed using rational design have recently been reported. In 2005, the structure of a catalytically disabled mtFabH mutant with lauroyl-CoA was reported.

Native mtFabH is a homodimer with M_r = 77 ± 25 kDa. Although there is substantial structural homology among all bacterial FabH enzymes determined thus far, with two channels for binding of acyl-CoA and malonyl-ACP substrates and a conserved catalytic triad (C122, H258, N289 in mtFabH), mtFabH contains residues along the acyl-CoA binding channel that preferentially select for longer chain substrates peaking with lauroyl-CoA (C₁₂). Inhibition strategies based on rational design could include competitive displacement of the substrates or disruption of the catalytic site. Phosphorylation of Thr45, which is located at the entrance of the substrate channel, inhibits activity, perhaps by altering accessibility of substrates.