Engineering new catalytic activities in enzymes


The efficiency, selectivity and sustainability benefits offered by enzymes are enticing chemists to consider biocatalytic transformations to complement or even supplant more traditional synthetic routes. Increasing demands for efficient and versatile synthetic methods, combined with powerful new discovery and engineering tools, has prompted innovations in biocatalysis, especially the development of new enzymes for precise transformations or ‘molecular editing’. As a result, the past decade has witnessed an impressive expansion of the catalytic repertoire of enzymes to include new and useful transformations not known (or relevant) in the biological world. In this Review we illustrate various ways in which researchers have approached using the catalytic machineries of enzymes for new-to-nature transformations. These efforts have identified genetically encoded catalysts that can be tuned and diversified by engineering the protein sequence, particularly by directed evolution. Discovery and improvement of these new enzyme activities is opening a floodgate that connects the chemistry of the biological world to that invented by humans over the past 100 years.

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Fig. 1: Strategies for the discovery of new enzyme functions.
Fig. 2: Promiscuous functions enabled by versatile active sites.
Fig. 3: New chemistries with cofactor-dependent enzymes.
Fig. 4: Chemomimetic carbene- and nitrene-transfer chemistries with engineered haem proteins.
Fig. 5: Different strategies for artificial enzyme construction.


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We thank D. J. Wackelin and Y. Yang (Caltech) for helpful discussions and comments on the manuscript. This work was supported by NSF Division of Molecular and Cellular Biosciences grant no. MCB-1513007, the US Army Research Office Institute for Collaborative Biotechnologies (cooperative agreement no. W911NF-19-2-0026) and the US Army Research Office Institute for Collaborative Biotechnologies (contract no. W911NF-19-D-0001). K.C. thanks the Resnick Sustainability Institute at Caltech for fellowship support. The content of this paper does not necessarily reflect the position or the policy of the funding agencies, and no official endorsement should be inferred.

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Correspondence to Frances H. Arnold.

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Chen, K., Arnold, F.H. Engineering new catalytic activities in enzymes. Nat Catal 3, 203–213 (2020).

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