A phosphopantetheinylating polyketide synthase producing a linear polyene to initiate enediyne antitumor antibiotic biosynthesis

Jian Zhang, Steven G. Van Lanen, Jianhua Ju, Wen Liu, Pieter C. Dorrestein, Wenli Li, Neil L. Kelleher, Ben Shen*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

74 Scopus citations

Abstract

The enediynes, unified by their unique molecular architecture and mode of action, represent some of the most potent anticancer drugs ever discovered. The biosynthesis of the enediyne core has been predicted to be initiated by a polyketide synthase (PKS) that is distinct from all known PKSs. Characterization of the enediyne PKS involved in C-1027 (SgcE) and neocarzinostatin (NcsE) biosynthesis has now revealed that (i) the PKSs contain a central acyl carrier protein domain and C-terminal phosphopantetheinyl transferase domain; (ii) the PKSs are functional in heterologous hosts, and coexpression with an enediyne thioesterase gene produces the first isolable compound, 1,3,5,7,9,11,13- pentadecaheptaene, in enediyne core biosynthesis; and (iii) the findings for SgcE and NcsE are likely shared among all nine-membered enediynes, thereby supporting a common mechanism to initiate enediyne biosynthesis.

Original languageEnglish (US)
Pages (from-to)1460-1465
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume105
Issue number5
DOIs
StatePublished - Feb 5 2008

Keywords

  • C-1027
  • Neocarzinostatin
  • Phosphopantetheinyl transferase

ASJC Scopus subject areas

  • General

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