3-oxoacyl-[acyl-carrier-protein] synthase 3 (FabH) (FabH)

3-oxoacyl-[acyl-carrier-protein] synthase 3 (FabH) is a key regulatory enzyme that initiates the Type II fatty acid synthase (FAS II) pathway in bacteria (UniProt P0A6R0). It catalyzes the decarboxylative condensation of acetyl-CoA with malonyl-acyl carrier protein (malonyl-ACP) to form acetoacetyl-ACP, which is the first step in the fatty acid elongation cycle (PubMed: 11585494). This enzyme is essential for the survival of many pathogenic bacteria, including Staphylococcus aureus and Escherichia coli, as it provides the precursors for membrane phospholipid synthesis (PubMed: 22409560). Because the bacterial FAS II system is structurally and mechanistically distinct from the human Type I fatty acid synthase (FAS I), FabH is considered an attractive target for the development of narrow-spectrum or broad-spectrum antibiotics with minimal host toxicity (PubMed: 15686343). Inhibitors such as thiolactomycin and various synthetic small molecules target the active site of FabH, preventing the condensation reaction and effectively halting bacterial growth (PubMed: 12485111). Despite its potential, the development of FabH-targeted drugs faces challenges such as the rapid emergence of resistance and the need for high potency across diverse bacterial species. The enzyme's role as a gatekeeper for the FAS II pathway makes it a critical point of intervention for disrupting bacterial metabolism. Research continues to explore novel scaffolds that can overcome existing resistance mechanisms and provide broader coverage against Gram-negative and Gram-positive pathogens.

Other names

Beta-ketoacyl-ACP synthase IIIKAS III3-oxoacyl-ACP synthase IIIBeta-ketoacyl-acyl carrier protein synthase III

Inhibition of the condensation of acetyl-CoA with malonyl-ACP, thereby blocking the initiation of the fatty acid biosynthetic pathway (PubMed: 11585494).