Cloning and characterization of the bleomycin biosynthetic gene cluster from Streptomyces verticillus ATCC15003

Ben Shen, Liangcheng Du, Cesar Sanchez, Daniel J. Edwards, Mei Chen, Jeffrey M. Murrell

Research output: Contribution to journalReview article

55 Citations (Scopus)

Abstract

Bleomycin (BLM) biosynthesis has been studied as a model for hybrid peptide-polyketide natural product biosynthesis. Cloning, sequencing, and biochemical characterization of the blm biosynthetic gene cluster from Streptomyces verticillus ATCC 15003 revealed that (1) the BLM hybrid peptide-polyketide aglycon is assembled by the BLM megasynthetase that consists of both nonribosomal peptide synthetase (NRPS) and polyketide synthase (PKS) modules; (2) BlmIX/BlmVII/BlmVII constitute a natural hybrid NRPS/PKS/NRPS system, serving as a model for both hybrid NRPS/PKS and PKS/NRPS systems; (3) the 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; (4) specific interpolypeptide linkers may play a critical role in intermodular communication to facilitate the transfer of the growing intermediates between the interacting NRPS and/or PKS modules; (5) post-translational modification of the BLM megasynthetase has been accomplished by a single PPTase with broad carrier protein specificity; and (6) BlmIV/BlmIII-templated assembly of the BLM bithiazole moiety requires intriguing protein juxtaposition and modular recognition. These results lay the foundation to investigate the molecular basis for intermodular communication between NRPS and PKS in hybrid peptide-polyketide natural product biosynthesis and set the stage for engineering novel BLM analogues by genetic manipulation of genes governing BLM biosynthesis.

Original languageEnglish (US)
Pages (from-to)422-431
Number of pages10
JournalJournal of Natural Products
Volume65
Issue number3
DOIs
StatePublished - Apr 9 2002

Fingerprint

Streptomyces verticillus
Peptide Synthases
Polyketide Synthases
Cloning
Bleomycin
Streptomyces
Multigene Family
multigene family
polyketide synthases
Organism Cloning
molecular cloning
Genes
ligases
peptides
Biosynthesis
Polyketides
polyketides
biosynthesis
Biological Products
Peptides

ASJC Scopus subject areas

  • Analytical Chemistry
  • Molecular Medicine
  • Pharmacology
  • Pharmaceutical Science
  • Drug Discovery
  • Complementary and alternative medicine
  • Organic Chemistry

Cite this

Cloning and characterization of the bleomycin biosynthetic gene cluster from Streptomyces verticillus ATCC15003. / Shen, Ben; Du, Liangcheng; Sanchez, Cesar; Edwards, Daniel J.; Chen, Mei; Murrell, Jeffrey M.

In: Journal of Natural Products, Vol. 65, No. 3, 09.04.2002, p. 422-431.

Research output: Contribution to journalReview article

Shen, Ben ; Du, Liangcheng ; Sanchez, Cesar ; Edwards, Daniel J. ; Chen, Mei ; Murrell, Jeffrey M. / Cloning and characterization of the bleomycin biosynthetic gene cluster from Streptomyces verticillus ATCC15003. In: Journal of Natural Products. 2002 ; Vol. 65, No. 3. pp. 422-431.
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