The neocarzinostatin biosynthetic gene cluster from Streptomyces carzinostaticus ATCC 15944 involving two iterative type I polyketide synthases

Wen Liu, Koichi Nonaka, Liping Nie, Jian Zhang, Steven D. Christenson, Juyun Bae, Steven G. Van Lanen, Emmanuel Zazopoulos, Chris M. Farnet, Catherine F. Yang, Ben Shen

Research output: Contribution to journalArticlepeer-review

109 Scopus citations

Abstract

The biosynthetic gene cluster for the enediyne antitumor antibiotic neocarzinostatin (NCS) was localized to 130 kb continuous DNA from Streptomyces carzinostaticus ATCC15944 and confirmed by gene inactivation. DNA sequence analysis of 92 kb of the cloned region revealed 68 open reading frames (ORFs), 47 of which were determined to constitute the NCS cluster. Sequence analysis of the genes within the NCS cluster suggested dNDP-D-mannose as a precursor for the deoxy aminosugar, revealed two distinct type I polyketide synthases (PKSs), and supported a convergent model for NCS chromophore biosynthesis from the deoxy aminosugar, naphthoic acid, and enediyne core building blocks. These findings shed light into deoxysugar biosynthesis, further support the iterative type I PKS paradigm for enediyne core biosynthesis, and unveil a mechanism for microbial polycyclic aromatic polyketide biosynthesis by an iterative type I PKS.

Original languageEnglish
Pages (from-to)293-302
Number of pages10
JournalChemistry and Biology
Volume12
Issue number3
DOIs
StatePublished - Mar 2005

Bibliographical note

Funding Information:
We thank Dr. Hiroshi Sugiyama, Tokyo Medical and Dental University, Japan for an authentic sample of neocarzinostatin and the Analytical Instrumentation Center of the School of Pharmacy, University of Wisconsin-Madison for support in obtaining mass spectrometric data. This work is supported in part by the National Institutes of Health grant CA78747. S.V.L is supported by National Institutes of Health postdoctoral fellowship CA105984. B.S. is the recipient of National Science Foundation CAREER Award MCB9733938 and National Institutes of Health Independent Scientist Award AI51687.

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry

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