Enediyne biosynthesis and self-resistance: A progress report

Jon S. Thorson, Ben Shen, Ross E. Whitwam, Wen Liu, Yuan Li, Joachim Ahlert

Research output: Contribution to journalArticlepeer-review

50 Scopus citations

Abstract

The enediyne antitumor antibiotics are appreciated for their novel molecular architecture, remarkable biological activity, and fascinating mode of action, and many have spawned considerable interest as anticancer agents in the pharmaceutical industry. Of equal importance to these astonishing properties, the enediynes also offer a distinct opportunity to study the unparalleled biosyntheses of their unique molecular scaffolds and what promises to be unprecedented modes of self-resistance to highly reactive natural products. Elucidation of these aspects should unveil novel mechanistic enzymology and may provide access to the rational biosynthetic modification of enediyne structure for new drug leads, the construction of enediyne overproducing strains, and eventually lead to an enediyne combinatorial biosynthesis program. This article reviews the published enediyne biosynthetic labeling and blocked mutant studies and provides a brief account of efforts in the Shen laboratory to elucidate the route to C- 1027 biosynthesis and efforts in the Thorson laboratory to elucidate the calicheamicin biosynthetic cascade.

Original languageEnglish
Pages (from-to)172-188
Number of pages17
JournalBioorganic Chemistry
Volume27
Issue number2
DOIs
StatePublished - Apr 1999

Bibliographical note

Funding Information:
J.S.T gratefully acknowledges Dr. David Rothstein and Dr. Micheal Ryan (Wyeth-Ayerst Laboratories) for graciously providing the M. echinospora genomic library and putative resistance clones used in this work and for helpful discussion; Dr. George Ellestad (Wyeth-Ayerst Laboratories) for the generous gift of 9; and Professor Hung-wen Liu (Department of Chemistry, University of Minnesota) for helpful discussion and encouragement. J.S.T. is a Rita Allen Foundation Scholar. R.E.W. is a postdoctoral fellow of The Charles A. Dana Foundation. Research in the JST laboratories was supported in part by the Cancer Center Support Grant (CA-08748) and a grant from the Special Projects Committee of The Society of Memorial Sloan-Kettering Cancer Center. B.S. thanks Professor C. Richard Hutchinson, University of Wisconsin, Madison, for helpful discussion and encouragement. Research in B.S. laboratories was supported in part by a grant from the Cancer Research Coordinating Committee, University of California and by the Searle Scholars Program/The Chicago Community Trust.

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Drug Discovery
  • Organic Chemistry

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