PKSs

Polyketide synthases (PKSs) are large, multi-enzyme complexes that assemble polyketides, a diverse class of natural products with wide-ranging biological activities, including antibiotic, anticancer, and immunosuppressive properties. PKSs operate as assembly lines that join simple acyl-CoA starter units with extender units such as malonyl-CoA or methylmalonyl-CoA, through decarboxylative Claisen condensations, to form complex carbon backbones that are then modified by tailoring enzymes.

Type I PKSs are giant, single polypeptides or multi-subunit complexes. They are further categorized as modular or iterative. Modular Type I PKSs have discrete modules; each module typically contains domains for condensation (ketosynthase KS), acyl transfer (AT), and carrier function (ACP), along with optional processing domains such as ketoreductase (KR), dehydratase (DH), enoyl reductase (ER), and methyltransferase (MT). Each module adds one extender unit to the growing chain and often culminates in product release by a thioesterase (TE). Iterative Type I PKSs reuse the same catalytic domains to build products over multiple cycles, a strategy common in fungal pathways.

Type II PKSs are dissociated, iterative enzymes found mainly in bacteria. A minimal KS-CLF-ACP core works with separate, domain-specific enzymes (KR, DH, ER) to iteratively construct aromatic polyketides. Type II systems typically generate more highly oxidized, often ring-structured compounds.

Type III PKSs are small, homodimeric, and do not use ACP carriers. They catalyze direct condensation of primary CoA starters with extender units and are widespread in plants, producing simple to moderately complex polyketides such as chalcones and related compounds.

PKSs share evolutionary links with fatty acid synthases and underpin the biosynthesis of many clinically important natural products. They are targets for metabolic engineering and combinatorial biosynthesis to create novel compounds.