Harnessing synthesis and biosynthesis to access complex molecules

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Enzymatic chemistry is a powerful tool for the production of complex molecules such as fine and research chemicals, nutraceuticals, and pharmaceuticals. A major limitation to the use of enzymes for research and industrial synthesis is the restricted chemical diversity currently accessible through known enzymatic reactions. This is in stark contrast to synthetic organic chemistry. The structures of natural products show that enzymatic reactions can access incredible chemical diversity. My research program examines the biosynthetic pathways responsible for natural product production to identify and harness enzymes capable of expanding our enzymatic toolbox. Our long term goal is to use biosynthetic enzymes and their mutants to enable rapid production of diverse molecules in vivo and in vitro. To achieve this our immediate goals are to developing new catalysts that can be used in chemoenzymatic synthesis of natural products. As natural product total synthesis is a rigorous testing ground for new chemical methodology, successful integration of new enzymes in this arena will facilitate their broader application in research and manufacturing. To meet our long-term goal of expanding the toolbox of available enzymatic reactions, we propose three short-term objectives. 1) Development of macrocyclization biocatalysts. Macrocyclization is the most decisive step of a synthesis and can define the overall efficiency of any synthetic route. No biocatalyst has been developed to synthesize this key functional group. We will characterize and engineer thioesterases to macrocyclize a broad range of substrates, significantly impacting the synthetic chemistry and enzymology communities. 2) The chemoenzymatic total synthesis of polyketides. Natural product total synthesis is a rigorous testing ground for new chemical methodologies. Using polyketide synthases from multiple biosynthetic pathways, we will convert a complex synthetic substrate into the sponge derived marine natural product neopeltolide. This chemoenzymatic synthesis will be the first of its kind and demonstrate of the use of polyketide synthases in the late stages of complex molecule total synthesis, transforming complex polyketide synthesis. 3) New biocatalyst discovery. To provide greater access to chemical diversity, we will characterize enzymes from newly discovered biosynthetic pathways that catalyze formation of diverse functional groups. This work will expand our understanding of biosynthesis and increase the type of chemistry accessible from enzymatic reactions.