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Simultaneous machine-directed evolution of an imine reductase for activity and stereoselectivity

Moore, Charles, Siirola, Elina Maria, Ma, Eric, Kummer, Arkadij, Siegrist, Luca, Stoeckli, Markus, Bouquet, Caroline, Acker, Anne-Christine, Faller, Michael, Eggimann, Fabian, Ligibel, Mathieu, Freund, Ernst, Huynh, Dan, Cutler, Geoffrey, Lewis, Richard, Oakeley, Edward James and Snajdrova, Radka (2021) Simultaneous machine-directed evolution of an imine reductase for activity and stereoselectivity. ACS Catalysis, 11 (20). ISSN 2155-54352155-5435

Abstract

Biocatalysis is an effective tool to access small quantities of chiral molecules that are otherwise hard to synthesize or purify. A time-efficient process is needed to develop an enzyme that is adequate to perform desired chemistry. We evaluated machine-directed evolution as an enzyme engineering strategy, using a stereoselective imine reductase as the model system. Within one cycle, it was found that machine-directed evolution yielded a library of high activity mutants with a dramatically shifted activity distribution, compared to traditional directed evolution. Structure-guided analysis revealed that linear additivity may provide a simple explanation for the effectiveness of machine-directed evolution. The study concludes with a cost-benefit analysis showing that machine-directed evolution gives a good return on investment in high cost per measurement regimes.

Item Type: Article
Date Deposited: 09 Nov 2021 00:45
Last Modified: 09 Nov 2021 00:45
URI: https://oak.novartis.com/id/eprint/44562

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