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

doi:10.1073/pnas.0711625105

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

^†Department of Chemistry,
^‡Division of Pharmaceutical Sciences, and
^¶University of Wisconsin National Cooperative Drug Discovery Group, University of Wisconsin, Madison, WI 53705; and
^§Department of Chemistry, University of Illinois at Urbana–Champaign, Urbana, IL 61801

Communicated by Arnold L. Demain, Drew University, Madison, NJ, December 11, 2007 (received for review November 29, 2007)

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.

Footnotes

^‖To whom correspondence should be addressed. E-mail: bshen{at}pharmacy.wisc.edu
Author contributions: J.Z. and S.G.V.L. contributed equally to this work; B.S. designed research; J.Z., S.G.V.L., J.J., W. Liu, and P.C.D. performed research; ; P.C.D., W. Li, and N.L.K. contributed new reagents/analytic tools; J.Z., S.G.V.L., J.J., P.C.D., N.L.K., and B.S. analyzed data; and S.G.V.L. and B.S. wrote the paper.
The authors declare no conflict of interest.
This article contains supporting information online at www.pnas.org/cgi/content/full/0711625105/DC1.