Studies to understand and exploit 10-membered enediyne biosynthesis

Natural products (NPs) and NP derivatives are an unrivaled, but highly under-represented, resource. The 10- membered enediynes [exemplified by calicheamicin (CLM), esperamicin (ESP) and dynemicins (DYN)] are arguably among the most infamous natural products discovered to date by virtue of their unprecedented complex molecular architectures, notable anticancer and anti-infective potencies and, in the case of CLM, demonstrated clinical utility. The current study builds on a longstanding collaborative effort of achievement and discovery relating to key aspects of 10-membered enediyne biosynthesis as well as parallel innovative efforts to co-opt key biosynthetic catalysts for synthetic applications. The studies put forth will take advantage of this strong foundation and a powerful combination of genetic, biochemical, chemical and protein structural tools to elucidate remaining novel biosynthetic transformations and to exploit select catalysts for enediyne non-native modification. Specifically, aims 1 and 2 will focus on extending our understanding of the fundamental steps of enediyne core biosynthesis and subsequent novel tailoring reactions, respectively, while aim 3 will focus on tactical structural studies to augment both. Additional studies in aim 2 with key catalysts and corresponding non-native substrates are designed to assess for potential strategic installation of chemoselective handles to enable novel approaches for facile, mild bioconjugation of CLM to tumor-targeting mAbs via a collaboration with Pfizer.