PKSNRPS

PKSNRPS refers to natural product biosynthetic assemblies that integrate polyketide synthase (PKS) and nonribosomal peptide synthetase (NRPS) modules to construct molecules containing both polyketide and amino acid–derived elements. These hybrid megasynthases are encoded by gene clusters primarily in bacteria and fungi and enable the cooperative use of PKS and NRPS chemistry within a single assembly line.

Typically, PKS-NRPS systems resemble concatenations of PKS and NRPS modules connected through dedicated docking domains. The PKS portion builds the carbon backbone from starter and extender units using domains such as ketosynthase, acyltransferase, and acyl carrier protein, with optional processing domains like ketoreductase, dehydratase, and enoylreductase. The NRPS portion adds amino acid-derived fragments via adenylation, peptidyl carrier protein, and condensation domains, with optional epimerization or heterocyclization. In hybrids, the growing chain may transfer between PKS and NRPS modules, yielding hybrid backbones that are further modified by tailoring enzymes or released by a thioesterase domain.

Prominent PKS-NRPS natural products include epothilones, potent microtubule stabilizers produced by myxobacteria; rapamycin and tacrolimus (FK-506), macrolide immunosuppressants formed through PKS-NRPS architectures; and salinamides among others. These molecules exhibit features derived from both polyketide and peptide origins and have significant clinical or research relevance.

Research on PKS-NRPS systems informs genome mining and synthetic biology approaches to drug discovery. Challenges include coordinating large multi-domain complexes and ensuring compatibility between PKS and NRPS modules, but advances in docking-domain engineering and heterologous expression are expanding the potential to create novel hybrids with desired properties.