Peptidepolyketides

Peptidepolyketides, or peptide-polyketide hybrids, are natural products produced by bacteria, fungi, and some marine organisms that combine elements derived from amino acids (peptides) and polyketide-derived units. They are assembled by hybrid megasynthase enzymes that integrate nonribosomal peptide synthetase (NRPS) and polyketide synthase (PKS) machinery, enabling iterative or modular extension with amino- and acyl-derived building blocks. The resulting molecules frequently feature macrocyclic scaffolds, unusual amino acids, and polyketide-derived moieties, often linked by amide and ester (depsipeptide) bonds.

Biosynthesis uses co-operating PKS and NRPS modules; in hybrid pathways, modules from both systems cooperate in a single assembly line. Domain architectures may include NRPS modules for amino acid activation (A domains) and condensation (C domains) alongside PKS modules for acyl-CoA elongation (KS, AT, ACP) and enoyl reductase (ER) tailoring. Tailoring enzymes introduce modifications such as methylation, glycosylation, hydroxylation, or epoxidation. The final product is typically released via a thioesterase or a dedicated cyclization domain, yielding linear or macrocyclic structures.

Structural diversity underpins broad biological activities. Peptidepolyketides can act as antibiotics, antifungals, cytotoxics, or immunosuppressants, with activities arising from the combined peptide interactions and the reactive polyketide fragments. The complexity of their assembly lines presents challenges for genetic and chemical analysis but also opportunities for engineering.

Research and applications: advances in genome sequencing and bioinformatics have accelerated discovery through genome mining for PKS-NRPS gene clusters. Heterologous expression, precursor feeding, and synthetic biology approaches are used to study biosynthesis and to create novel compounds with potential pharmaceutical uses.