The biosynthetic gene cluster for the anticancer drug bleomycin from Streptomyces verticillus ATCC15003 as a model for hybrid peptide-polyketide natural product biosynthesis

Abstract

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).

Genome Sequence of Dickeya solani, a New soft Rot Pathogen of Potato, Suggests its Emergence May Be Related to a Novel Combination of Non-Ribosomal Peptide/Polyketide Synthetase Clusters

“…However, the organization of the ORFs, the domains within the ORFs and the predicted amino acids in the predicted product of the D. solani FAS/PKS/NRPS cluster are very similar to the S. plymuthica RVH1 zeamine cluster and zeamine, suggesting that D. solani D s0432-1 may synthesize a molecule with similarity to zeamine. The combination of ORFs suggests that this is a second PKS/NRPS hybrid system present in D. solani and lacking from D. dadantii [51]. Although NRPS modules are usually conserved, the KS domain of the PKS module in ORF 1374 seems to be unique in this hybrid, and it was not found in any other Pectobacterium or Dickeya spp.…”

“…The synthesized molecules can have antibiotic and phytotoxic effects and are found to increase the virulence in bacterial plant pathogens [50]. In this operon, PKS and NRPS modules are combined together to form a PKS/NRPS hybrid system that might be able to produce compounds of even greater chemical structural diversity compared to the ones produced by the single PKS and NRPS [51]. The D. solani ORF 2691 codes for a large multidomain protein, a type I PKS, where no acyltransferase (AT) domain could be identified; instead, an ORF 2687 may code for a free-standing acyl transferase protein, suggesting that ORF 2691 codes for a trans-AT PKS [52].…”

Functional Analysis of All Nonribosomal Peptide Synthetases in Cochliobolus heterostrophus Reveals a Factor, NPS6, Involved in Virulence and Resistance to Oxidative Stress

“…In addition to structural diversity, nonribosomal peptides have a broad spectrum of biological activities, some of which have been useful in medicine, agriculture, and biological research (24,37,40,47). Products made by nonribosomal peptide synthetases or nonribosomal peptide synthetase/polyketide synthase hybrid enzymes include well-known antibiotics (penicillin, erythromycin, and vancomycin), immunosuppressants (cyclosporin and rapamycin), antitumor agents (actinomycin, bleomycin, and epothilone) (39,47), and toxins involved in pathogenesis (HC-toxin, enniatin, AM-toxin, and probably victorin) (17,22,32,38,48,49).…”

The Phosphopantetheinyl Transferase Superfamily: Phylogenetic Analysis and Functional Implications in Cyanobacteria

“…Members of this family are approximately 230 amino acids in length and are often found associated with a biosynthetic pathway. This family includes PPTs involved in cyanobacterial heterocyst differentiation (1), fungal lysine biosynthesis (33), ␤-alanine conjugation (38), hybrid peptide synthetase/polyketide synthase complexes (43,44), and other enzymes whose exact functions have not been elucidated. They display a broad range of specificity toward carrier protein substrates and have been used in diverse applications, such as Sfp catalyzed phagemid display and Sfp labeling of carrier proteins (25,46,50).…”