Evolving Hemoproteins for New-to-Nature Ring-Forming Reactions

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Molecules with ring structures are found in everything from drugs to plastics, where their special structures confer important functional properties. The bottleneck for discovering and developing such molecules and materials is often a limited ability to build complex rings from simple starting materials. This project establishes powerful and generalizable enzymatic routes to diverse ring structures, using chemistry not previously known in biological catalysis. The new-to-nature ring-forming enzymes are entirely genetically encoded, use earth-abundant iron, and function under mild conditions for sustainable production of a variety of materials, pharmaceuticals and chemicals. This interdisciplinary project trains highly talented graduate students and postdoctoral fellows for academic and industrial research in sustainable chemistry, biotechnology, and bioengineering. It is intended to inspire development of new catalyst technologies and methods for enzyme discovery and engineering.This research builds on the principal investigator’s successful engineering of hemeproteins for new-to-nature carbene and nitrene transfer reactions and extends it to discovery and optimization by directed evolution of new enzyme catalysts. These catalysts are used for preparing ring structures that are difficult to make using synthetic chemistry. Intramolecular carbene and nitrene C–H insertion reactions are optimized to access important ring-containing molecules such as lactams, lactones and cyclic amines. In many cases there are no equivalent small-molecule catalysts for these transformations, therefore they will be enabled catalytically for the first time. The utility of the evolved biocatalysts is evaluated in synthesis and late-stage modification of bioactive molecules and precursors to advanced materials. This research also includes kinetic, spectroscopic, structural and computational studies to elucidate the mechanisms of the enzymatic ring-forming reactions and support further enzyme engineering or development of small-molecule catalyst counterparts.This project is co-funded by the Systems and Synthetic Biology cluster in the Division of Molecular and Cellular Biosciences, the Cellular and Biochemical Engineering program in the Division of Chemical, Bioengineering, Environmental, and Transport Systems and the Chemistry of Life Processes program in the Division of Chemistry.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.