Carbonic Anhydrase Variants Catalyze the Reduction of Dialkyl Ketones with High Enantioselectivity

Chen, Reichi; Kayrouz, Colby S.; McAmis, Eli; Clark, Douglas S.; Hartwig, John F.

doi:10.1002/ange.202407111

Carbonic Anhydrase Variants Catalyze the Reduction of Dialkyl Ketones with High Enantioselectivity

Journal Article · Fri Aug 30 00:00:00 EDT 2024 · Angewandte Chemie

DOI:https://doi.org/10.1002/ange.202407111· OSTI ID:2459376

Chen, Reichi ^[1]; ^[1]; McAmis, Eli ^[1]; Clark, Douglas S. ^[2]; ^[1]

Department of Chemistry University of California Berkeley California 94720 USA, Chemical Sciences Division Lawrence Berkeley National Laboratory 1 Cyclotron Road Berkeley CA 94720 USA
Department of Chemical and Biomolecular Engineering University of California Berkeley California 94720 United States

Abstract

Human carbonic anhydrase II (hCAII) naturally catalyzes the reaction between two achiral molecules—water and carbon dioxide—to yield the achiral product carbonic acid through a zinc hydroxide intermediate. We have previously shown that a zinc hydride, instead of a hydroxide, can be generated in this enzyme to create a catalyst for the reduction of aryl ketones. Dialkyl ketones are more challenging to reduce, and the enantioselective reduction of dialkyl ketones with two alkyl groups that are similar in size and electronic properties, is a particularly challenging transformation to achieve with high activity and selectivity. Here, we show that hCAII, as well as a double mutant of it, catalyzes the enantioselective reduction of dialkyl ketones with high yields and enantioselectivities, even when the two alkyl groups are similar in size. We also show that variants of hCAII catalyze the site‐selective reduction of one ketone over the other in an unsymmetrical aliphatic diketone. Computational docking of a dialkyl ketone to variants of hCAII containing the zinc hydride provides insights into the origins of the reactivity of various substrates and the high enantioselectivity of the transformations and show how a confined environment can control the enantioselectivity of an abiological intermediate.

View Accepted Manuscript (Publisher)

Sponsoring Organization:: USDOE

Grant/Contract Number:: AC02-05CH11231

OSTI ID:: 2459376

Journal Information:: Angewandte Chemie, Journal Name: Angewandte Chemie Journal Issue: 40 Vol. 136; ISSN 0044-8249

Publisher:: Wiley Blackwell (John Wiley & Sons)Copyright Statement

Country of Publication:: Germany

Language:: English

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