Beta-ketoacyl-[acyl-carrier-protein] synthase III (FabH) (FabH)

Beta-ketoacyl-[acyl-carrier-protein] synthase III (FabH) is a pivotal enzyme in the bacterial Type II fatty acid synthesis (FAS II) pathway, responsible for initiating the fatty acid elongation cycle (UniProt P0A6R0). It catalyzes the decarboxylative condensation of acetyl-CoA with malonyl-acyl carrier protein (malonyl-ACP) to produce acetoacetyl-ACP, a critical precursor for membrane lipid formation (PMID: 25515508). Because the FAS II system is distinct from the Type I fatty acid synthase found in humans, FabH represents a selective and essential target for the development of novel antibacterial agents (PMC4413734). Inhibitors of FabH, such as the natural product thiolactomycin and various synthetic covalent inhibitors like Oxa1, have demonstrated potent activity against a range of pathogens, including multidrug-resistant Staphylococcus aureus (MRSA) and Mycobacterium tuberculosis (PMID: 32554194). However, therapeutic challenges include the potential for some bacteria to bypass FAS II inhibition by utilizing host-derived fatty acids and the structural diversity of FabH isoforms across different bacterial species, which can limit the spectrum of activity for certain inhibitors (PMC4413734).

Other names

3-oxoacyl-[acyl-carrier-protein] synthase IIIBeta-ketoacyl-ACP synthase IIIKAS IIIAcetoacetyl-ACP synthase3-oxoacyl-ACP synthase IIIMtFabHEcFabH

Inhibition of the initiation step of bacterial Type II fatty acid biosynthesis by blocking the condensation of acetyl-CoA and malonyl-ACP (PMID: 25515508).