The biosynthetic gene cluster for the anticancer drug bleomycin from Streptomyces verticillus 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) specific 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 modification of the BLM megasynthetase has been accomplished by a single PPTase with a broad substrate specificity toward the apo forms of both acyl carrier proteins (ACPs) and peptidyl carrier proteins (PCPs).
Shen
B
B
Department of Chemistry, University of California, Davis, One Shields Avenue, Davis, CA 95616, USA.
Du
L
L
Sanchez
C
C
Edwards
D J
DJ
Chen
M
M
Murrell
J M
JM
D000903:Antibiotics, Antineoplastic / Q000096:biosynthesis*; D001761:Bleomycin / Q000096:biosynthesis*; D005798:Genes, Bacterial; D009097:Multienzyme Complexes / Q000235:genetics / Q000378:metabolism; D005810:Multigene Family; D010453:Peptide Synthases / Q000235:genetics / Q000378:metabolism; D013302:Streptomyces / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism
D000903:Antibiotics, Antineoplastic; D009097:Multienzyme Complexes; D001761:Bleomycin; D010453:Peptide Synthases; C104385:non-ribosomal peptide synthase