Enediyne Biosynthesis and Self-Resistance: A Progress Report

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.