Harnessing Polyketide Natural Product Biosynthesis

点击翻译按钮获取中文摘要

Enzymatic chemistry is a powerful tool for the production of complex molecules however it has found use mainly in the generation of high purity strereogenic centers. A major limitation to the broad use of enzymes for research and manufacturing is the restricted chemical diversity currently accessible through enzymatic reactions. This is in stark contrast to synthetic organic chemistry. To expand the use of enzymes in synthesis, the limited toolbox of viable enzymatic reactions must be increased. The structures of natural products show that enzymatic reactions can access incredible chemical diversity. The enzymes that produce these natural products are ideally suited to meet the rigorous demands of high stereo-, regio-, and chemoselectivity that synthetic chemists require for use in the synthesis of polyfunctional complex molecules. My research program examines the biosynthetic pathways responsible for polyketide natural product production to identify and harness enzymes capable of expanding our enzymatic toolbox. While our long-term goal is to use these enzymes to enable rapid production of diverse molecules in vivo and in vitro, our immediate goals are focused on developing new catalysts that can be used in chemoenzymatic synthesis of natural products. Natural product total synthesis is a rigorous testing ground for new chemical methodology and 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) The development of thioesterases to catalyze macrocyclization. Macrocyclization is the most decisive step of a synthesis and can define the overall efficiency of any synthetic route. No enzymatic methodology has been developed to synthesize this key functional group. This objective allows us to rapidly impact the synthetic community with currently accessible enzymes from polyketide biosynthesis. 2) The chemoenzymatic total synthesis of neopeltolide. This objective will serve as a powerful and first of its kind demonstration of the use of enzymes in complex molecule total synthesis. This work has the potential to transform complex polyketide synthesis and will demonstrate the effectiveness of using enzymatic reactions in the late stages of a total synthesis. 3) The discovery of new polyketide biosynthetic pathways. This objective contributes to our long-term development of enzymes to access new chemical diversity. Within new biosynthetic pathways are enzymes that catalyze new chemistry. By discovering these pathways, we enable develop the new enzymes. In the short-term this objective will impact the pharmacology and drug discovery as polyketides have potent bioactivity that can be exploited to improve human health. These separate but interrelated approaches will expand the chemical diversity accessible through enzymatic reactions. The initial two projects focus on developing new catalysts based on known enzymes from polyketide biosynthesis to produce complex molecules. These enable the short-term introduction of enzymes for macrocyclization and aldol reactions into the synthetic chemist’s tool box. The last project describes our long-term plans for expanding the chemical diversity accessible through enzymatic chemistry by discovering new and unique polyketide biosynthetic pathways. In addition to finding new enzymes to harness, this project will have a major impact on approaches to natural product discovery and influence all the downstream discoveries directly related to natural products, including identification of new bioactive compounds, their mechanisms of action and targets, and the development of new drugs.