Hybrid Peptide–Polyketide Natural Products: Biosynthesis and Prospects toward Engineering Novel Molecules

The structural and catalytic similarities between modular nonribosomal peptide synthetase (NRPS) and polyketide synthase (PKS) inspired us to search for hybrid NRPS–PKS systems. By examining the biochemical and genetic data known to date for the biosynthesis of hybrid peptide–polyketide natural products, we show (1) that the same catalytic sites are conserved between the hybrid NRPS–PKS and normal NRPS or PKS systems, although the ketoacyl synthase domain in NRPS/PKS hybrids is unique, and (2) that specific interpolypeptide linkers exist at both the C- and N-termini of the NRPS and PKS proteins, which presumably play a critical role in facilitating the transfer of the growing peptide or polyketide intermediate between NRPS and PKS modules in hybrid NRPS–PKS systems. These findings provide new insights for intermodular communications in hybrid NRPS–PKS systems and should now be taken into consideration in engineering hybrid peptide–polyketide biosynthetic pathways for making novel “unnatural” natural products.