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

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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.