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

凭借这一奖项，化学部门的生命过程化学项目资助了哈佛大学的Emily Balskus博士研究微生物酶，这些酶催化了以前未被认识到的化学转化。发现新的生物合成酶和策略扩展了我们对自然化学能力的认识。它还激发了新的合成方法和策略的发展，是将酶用于实际应用的第一步。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为药物和工业化学品的合成提供更有效和更环保的途径来影响社会。此外，该研究产生的酶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，本研究的目标与正在进行的教育和推广活动协同，旨在向不同群体的学生教育和传达生命系统化学的重要性。这个项目的具体重点是表征新发现的酶参与生物合成的圆柱形环菌，一个家族的结构不寻常的蓝藻代谢产物。先前对这一途径的研究揭示了一种新型的卤化酶，能够功能化非活性碳原子，以及一种以前未知的“隐”卤化策略，涉及酶促Friedel-Crafts烷基化。提出的研究阐明了这些新发现的生成和利用烷基卤化物的酶如何完成这些具有挑战性的反应，并开发了一个实验工作流程，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。总之，这项研究有可能增强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物。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

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.