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Combining chemistry and protein engineering for new-to-nature biocatalysis

Abstract

Biocatalysis, the application of enzymes to solve synthetic problems of human import, has blossomed into a powerful technology for chemical innovation. In the past decade, a threefold partnership, where nature provides blueprints for enzymatic catalysis, chemists introduce innovative activity modes with abiological substrates, and protein engineers develop new tools and algorithms to tune and improve enzymatic function, has unveiled the frontier of new-to-nature enzyme catalysis. In this Perspective, we highlight examples of interdisciplinary studies, which have helped to expand the scope of biocatalysis, including concepts of enzymatic versatility explored through the lens of biomimicry, to achieve activities and selectivities beyond those currently possible with chemocatalysis. We indicate how modern tools, such as directed evolution, computational protein design and machine learning-based protein engineering methods, have already impacted and will continue to influence enzyme engineering for new abiological transformations. A sustained collaborative effort across disciplines is anticipated to spur further advances in biocatalysis in the coming years.

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Fig. 1: Biomimetic and enzymatic nitrene transfer for C–H insertion reactions.
Fig. 2: Representative examples of cofactor adaptation for abiological reactions with new-to-nature reactivity modes.
Fig. 3: Select examples of new-to-nature enzyme catalysis.

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Acknowledgements

This report was prepared as an account of work sponsored by an agency of the United States Government. Neither the United States Government nor any agency thereof, nor any of their employees, makes any warranty, express or implied, or assumes any legal liability or responsibility for the accuracy, completeness, or usefulness of any information, apparatus, product, or process disclosed, or represents that its use would not infringe on privately owned rights. Reference herein to any specific commercial product, process, or service by trade name, trademark, manufacturer, or otherwise does not necessarily constitute or imply its endorsement, recommendation, or favouring by the United States Government or any agency thereof. The views and opinions of the authors expressed herein do not necessarily state or reflect those of the United States Government or any agency thereof. D.C.M. was supported by a Ruth Kirschstein NIH Postdoctoral Fellowship (F32GM128247). This work was sponsored by the US Army Research Office and accomplished under cooperative agreement W911NF-19-2-0026 for the Institute of Collaborative Biotechnologies. This material is based on work sponsored by the US Department of Energy, Office of Basic Energy Sciences, under award number DE-SC0021141. We wish to thank E. Alfonzo, R. Mao and K. E. Johnston for helpful discussions. All protein structures were prepared using PyMOL (The PyMOL Molecular Graphics System, v.2.0 Schrödinger, LLC).

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Correspondence to Frances H. Arnold.

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Miller, D.C., Athavale, S.V. & Arnold, F.H. Combining chemistry and protein engineering for new-to-nature biocatalysis. Nat Synth 1, 18–23 (2022). https://doi.org/10.1038/s44160-021-00008-x

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