Cancer causes 1 of every 4 deaths in the US, and it is therefore a critical research goal to develop fundamentally new and clinically useful anticancer drugs. The enediynes are potent anticancer agents, and their use as anticancer drugs has been demonstrated clinically. A great challenge is to develop innovative methods to make enediynes and analogs and to discover new enediyne natural products for further mechanistic studies and clinical developments. We propose in this Competitive Renewal application to continue (i) to study enediyne biosynthesis to discover novel chemistry and enzymology and (ii) to apply combinatorial biosynthesis methods to selected enediyne biosynthetic machineries for discovery of new enediynes and production of novel analogs. Our hypotheses are (i) enediyne core biosynthesis is controlled by the enediyne PKS and associated enzymes, studies of which will ultimately reveal the molecular mechanism for both the 9- and 10-membered enediyne core formation, (ii) many other aspects in biosynthesis of the enediynes are unprecedented, the characterization of which will uncover new chemistry, enzymology, and molecular logic for furnishing the myriad of functionalities found in the enediynes, and (iii) enediynes are excellent anticancer leads with novel modes of action, engineered analogs of which, as well as new enediyne natural products, could be realistically developed into new anticancer drugs.
The specific aims for this grant period are: (i) functional characterization of selected 10-membered enediyne biosynthetic machineries in genetically amenable producers; (ii) in vivo and in vitro characterization of selected enediyne PKSs and associated enzymes and their roles in 9- and 10-membered enediyne core biosynthesis; (iii) in vivo and in vitro characterization of novel enzymes from the C-1027, neocarzinostatin (NCS), maduropeptin (MDP), uncialamycin (UCM), and the Streptomyces citricolor enediyne biosynthetic machineries; and (iv) application of combinatorial biosynthetic methods to C-1027, UCM, and the S. citricolor enediyne biosynthetic machineries for titer improvement and analog generation. The outcomes of these studies include (i) fundamental contributions to mechanistic enzymology and natural product chemistry and (ii) enhanced understanding of the enediyne biosynthetic machineries that can be exploited to discover new enediynes and engineer novel analogs. The long-term goal of our research is to understand how microorganisms synthesize complex natural products and to develop and apply combinatorial biosynthesis methods to natural products for anticancer drug discovery and development.
Cancer causes 1 of every 4 deaths in the US, and 562,340 Americans are expected to die of cancer in 2009. It is therefore a critical research goal to develop fundamentally new, clinically useful anticancer drugs. The enediynes are the most potent, highly active anticancer agents in existence today, and their use as anticancer drugs has been demonstrated clinically. A great challenge is to develop innovative methods to make enediynes and their analogs and to discover new enediyne natural products for further mechanistic studies and clinical developments. This research will study enediyne biosynthesis to discover novel chemistry and enzymology and apply combinatorial biosynthesis methods to selected enediyne biosynthetic machineries for discovery of new enediyne natural products and production of novel enediyne analogs. The outcomes include the discovery and development of novel anticancer drug leads and potentially clinically useful anticancer drugs.
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