Ketosynthase

Ketosynthase refers to a class of enzymes that catalyze carbon–carbon bond formation during fatty acid and polyketide biosynthesis. In both systems, the key step is a condensation that extends a growing acyl chain by two carbons from a malonyl-ACP donor. The beta-ketoacyl-ACP synthase (KS) domain or enzyme accepts an acyl group bound to a carrier protein and condenses it with malonyl-ACP, releasing CO2 and forming a beta-ketoacyl-ACP product. The reaction is typically mediated by a catalytic cysteine that forms an acyl thioester, with other active-site residues organizing the condensation and decarboxylation steps.

In bacteria and fungi, KS enzymes are organized differently in fatty acid synthases. Type II fatty acid synthases use discrete KS enzymes such as FabB and FabF to extend the growing chain, each with specific substrate specificities. In type I fatty acid synthases, a single multi-domain polypeptide carries a KS domain as part of a larger assembly line. In modular polyketide synthases, KS domains reside in modules that also contain acyltransferase (AT) and acyl carrier protein (ACP) domains; these KS modules drive successive condensations to build complex polyketide backbones.

The KS family is a common target in biotechnology and medicine. Inhibitors such as cerulenin and platensimycin block KS activity and impede fatty acid biosynthesis. Beyond inhibition, KS domains are used as markers in genome mining to identify polyketide gene clusters and in engineering efforts to create novel bioactive compounds.