The biosynthetic gene cluster for the anticancer drug bleomycin from <i>Streptomyces verticillus</i> ATCC15003 as a model for hybrid peptide–polyketide natural product biosynthesis

The hybrid peptide–polyketide backbone of bleomycin (BLM) is assembled by the BLM megasynthetase that consists of both nonribosomal peptide synthetase (NRPS) and polyketide synthase (PKS) modules. BlmIX/BlmVIII/BlmVII constitute a natural hybrid NRPS/PKS/NRPS system, serving as a model for both hybrid NRPS/PKS and PKS/NRPS systems. Sequence analysis and functional comparison of domains and modules of BlmIX/BlmVIII/BlmVII with those of nonhybrid NRPS and PKS systems suggest that (1) the same catalytic sites appear to be conserved in both hybrid NRPS–PKS and nonhybrid NRPS or PKS systems, with the exception of the KS domains in the hybrid NRPS/PKS systems that are unique; (2) specifi c interpolypeptide linkers may play a critical role in intermodular communication to facilitate transfer of the growing intermediates between the interacting NRPS and/or PKS modules; and (3) posttranslational modifi cation of the BLM megasynthetase has been accomplished by a single PPTase with a broad substrate specifi city toward the apo forms of both acyl carrier proteins (ACPs) and peptidyl carrier proteins (PCPs).