Harnessing Polyketide Natural Product Biosynthesis

利用聚酮化合物天然产物生物合成

• 批准号: RGPIN-2014-06167
• 负责人: Boddy, Christopher
• 金额: $ 7.18万
• 依托单位: University of Ottawa
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2016
• 资助国家: 加拿大
• 起止时间: 2016-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=612070
• 关键词: Harnessing; Polyketide; Natural; Product; Biosynthesis

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.

酶化学是生产复杂分子的有力工具，但它主要用于产生高纯度的产应力中心。酶广泛用于研究和制造的一个主要限制是目前通过酶反应可获得的有限的化学多样性。这与合成有机化学形成鲜明对比。为了扩大酶在合成中的应用，必须增加可行的酶促反应的有限工具箱。 天然产物的结构表明，酶促反应可以获得令人难以置信的化学多样性。生产这些天然产物的酶非常适合满足合成化学家在合成多官能复杂分子时对高立体选择性、区域选择性和化学选择性的严格要求。 我的研究项目研究负责聚酮化合物天然产物生产的生物合成途径，以识别和利用能够扩大我们的酶工具箱的酶。虽然我们的长期目标是利用这些酶在体内和体外快速生产不同的分子，但我们的近期目标是开发可用于天然产物化学酶合成的新催化剂。天然产物全合成是新化学方法学的严格试验场，在这一竞技场中成功地整合新酶将促进它们在研究和制造中的更广泛应用。 为了实现我们扩大可用酶反应工具箱的长期目标，我们提出了三个短期目标。 1)硫酯酶催化大环化反应的研究进展。大环化是合成中最具决定性的步骤，可以决定任何合成路线的总体效率。还没有开发出合成该关键官能团的酶促方法。这一目标使我们能够快速影响合成社区与目前可获得的酶从聚酮生物合成。 2)化学酶法全合成新倍妥内酯。这一目标将作为一个强大的和第一次的同类示范使用酶的复杂分子的全合成。这项工作有可能改变复杂的聚酮合成，并将证明在全合成的后期阶段使用酶促反应的有效性。 3)新的聚酮生物合成途径的发现。这一目标有助于我们长期开发酶，以获得新的化学多样性。在新的生物合成途径中，酶催化新的化学反应。通过发现这些途径，我们可以开发新的酶。在短期内，这一目标将影响药理学和药物发现，因为聚酮化合物具有潜在的生物活性，可以用于改善人类健康。 这些独立但相互关联的方法将扩大通过酶反应可获得的化学多样性。最初的两个项目侧重于开发基于聚酮生物合成中已知酶的新催化剂，以生产复杂分子。这使得短时间内将用于大环化和羟醛缩合反应的酶引入合成化学家的工具箱成为可能。最后一个项目描述了我们的长期计划，通过发现新的和独特的聚酮生物合成途径，通过酶化学扩大化学多样性。除了寻找新的酶来利用，该项目将对天然产物发现的方法产生重大影响，并影响与天然产物直接相关的所有下游发现，包括鉴定新的生物活性化合物，其作用机制和靶标，以及新药的开发。