ketosynthases

Ketosynthases are enzymes that catalyze the carbon–carbon bond-forming steps in fatty acid and polyketide biosynthesis. They belong to the thiolase superfamily and act as condensing enzymes that extend acyl chains by two-carbon units donated from malonyl-ACP or malonyl-CoA during chain elongation.

In type II fatty acid synthesis, ketosynthases mediate a Claisen-like condensation between an acyl-ACP donor and malonyl-ACP, producing a β-ketoacyl-ACP and releasing CO2. Similar condensations occur in modular or iterative polyketide synthases to extend the growing polyketide chain.

Bacteria commonly express three main condensing enzymes: KAS I, KAS II, and KAS III. KAS I and II differ in substrate preferences, helping determine typical fatty-acid chain lengths; KAS III initiates chain elongation by condensing an acetyl unit with malonyl-ACP. PKS KS domains function analogously within assembly lines.

Catalysis proceeds via a nucleophilic cysteine that forms a thioester with the donor substrate, followed by decarboxylative condensation with malonyl-ACP. A histidine and asparagine residues participate in proton transfer and stabilization of intermediates.

Structurally, KS enzymes are typically homodimers with a conserved active-site channel for acyl- and malonyl-ACP substrates. Their central role in lipid and polyketide biosynthesis makes them targets for antibiotic development and for engineering biosynthetic pathways.