Understanding the Formation and Utilization of Halogenated Metabolites in Natural Product Biosynthesis

有了这个奖项，化学部的生命过程化学计划正在资助哈佛大学的艾米丽巴尔斯库斯博士研究催化以前不受重视的化学转化的微生物酶。发现新的生物合成酶和策略扩展了我们对自然界化学能力的了解。 它还促进了新的合成方法和策略的发展，并且是在实际应用中使用酶的第一步。这项研究提供了对以前未知的酶的详细了解，这些酶最终可能通过实现更有效和环保的药物和工业化学品合成路线来影响社会。 此外，该研究产生了酶的知识，可以简化以前未表征和潜在生物活性的微生物天然产物的鉴定。 这些产品未来可能会应用于药物发现甚至农业。最后，这项研究的目标与正在进行的教育和推广活动，旨在教育和沟通的重要性，生命系统的化学给不同的学生群体协同作用。该项目的具体重点是表征新发现的参与生物合成的cylindrocyclophanes，一个家庭的结构不寻常的蓝藻代谢产物的酶。先前对该途径的研究揭示了一种新型的卤化酶，其能够使未活性碳原子官能化，以及一种先前未知的涉及酶促Friedel-Crafts烷基化的“隐蔽”卤化策略。拟议的研究阐明了这些新发现的产生和利用卤代烷的酶如何完成这些具有挑战性的反应，并开发了一种实验工作流程，可以快速发现使用类似生物合成逻辑构建的其他微生物天然产物。总而言之，这项研究有可能提高我们对酶催化的理解，并促进发现额外的，结构上不寻常的微生物代谢产物。该奖项反映了NSF的法定使命，并已被认为是值得通过使用基金会的智力价值和更广泛的影响审查标准进行评估的支持。

With this award, the Chemistry of Life Processes Program in the Chemistry Division is funding Dr. Emily Balskus from Harvard University to investigate microbial enzymes that catalyze previously unappreciated chemical transformations. Uncovering novel biosynthetic enzymes and strategies expands our knowledge of Nature’s chemical capabilities. It also motivates the development of new synthetic methods and strategies and is a first step toward employing enzymes in practical applications. This research is providing detailed understanding of previously unknown enzymes that could ultimately impact society by enabling more efficient and environmentally friendly routes for the synthesis of pharmaceuticals and industrial chemicals. Additionally, the research generates knowledge of enzymes that could streamline the identification of previously uncharacterized and potentially bioactive microbial natural products. Such products could have future applications in drug discovery and even agriculture. Finally, the goals of this research synergize with ongoing education and outreach activities aimed at educating and communicating the importance of the chemistry of living systems to a diverse group of students. The specific focus of this project is to characterize newly discovered enzymes involved in the biosynthesis of the cylindrocyclophanes, a family of structurally unusual cyanobacterial metabolites. Previous studies of this pathway revealed a new type of halogenating enzyme capable of functionalizing unactivated carbon atoms as well as a previously unknown ‘cryptic’ halogenation strategy that involves an enzymatic Friedel–Crafts alkylation. The proposed research elucidates how these newly discovered alkyl halide-generating and -utilizing enzymes accomplish these challenging reactions and develop an experimental workflow that could rapidly uncover additional microbial natural products constructed using analogous biosynthetic logic. Altogether, this research has the potential to enhance our understanding of enzymatic catalysis and facilitate the discovery of additional, structurally unusual microbial metabolites.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.