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.
Du
L
L
Department of Chemistry, University of California, One Shields Avenue, Davis, California 95616, USA.
Sánchez
C
C
Shen
B
B
D000595:Amino Acid Sequence; D001688:Biological Products / Q000096:biosynthesis* / Q000138:chemical synthesis* / Q000235:genetics; D002240:Carbohydrate Sequence; D008969:Molecular Sequence Data; D009097:Multienzyme Complexes / Q000378:metabolism*; D010453:Peptide Synthases / Q000096:biosynthesis*; D015202:Protein Engineering / Q000379:methods* / Q000639:trends
D001688:Biological Products; D009097:Multienzyme Complexes; D010453:Peptide Synthases; C104385:non-ribosomal peptide synthase