Beta-ketoacyl-ACP synthase I (KAS I) (KAS I)

Beta-ketoacyl-ACP synthase I (KAS I), also known as FabB or KasA, is a critical enzyme in the bacterial Type II fatty acid synthesis (FAS II) pathway [1, 2]. It catalyzes the Claisen condensation of an acyl-ACP with malonyl-ACP, a key step in the elongation of fatty acid chains [3, 4]. In many bacteria, KAS I is essential for the production of unsaturated fatty acids, while in Mycobacterium tuberculosis, its homolog KasA is vital for the synthesis of mycolic acids, which are major components of the mycobacterial cell wall [2, 5]. Because the FAS II system is distinct from the multifunctional Type I FAS system found in humans, KAS I represents a promising target for the development of novel antibacterial agents [1, 5]. The enzyme typically functions as a homodimer and utilizes a conserved Cys-His-His catalytic triad to facilitate the decarboxylative condensation reaction [4]. Inhibition of KAS I leads to the depletion of essential membrane lipids and cell wall precursors, ultimately resulting in bacterial cell death [5]. Therapeutic challenges include the potential for off-target effects on human fatty acid metabolism and the emergence of drug-resistant bacterial strains [2, 5].

Other names

3-oxoacyl-[acyl-carrier-protein] synthase 13-oxoacyl-ACP synthase IFabBKasACondensing enzymeBeta-ketoacyl-acyl carrier protein synthase I

Inhibitors typically bind to the active site of the enzyme, either irreversibly (like cerulenin) or reversibly (like thiolactomycin), to block the Claisen condensation of malonyl-ACP and acyl-ACP substrates, thereby halting fatty acid elongation [1, 2, 4].