Turning Enzyme Models into Model Enzymes in a Substrate-Tailored, Desolvated Active Site
Date
2025-05-12
Authors
Lakavathu, Mohan
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American Chemical Society
Abstract
Once taken out of the active sites, the same functional groups used by enzymes for catalysis tend to lose their “magical” catalytic power in small-molecule enzyme models. We report a small-molecule enzyme model that activates a benzylic alcohol by a nearby amine for the nucleophilic attack of an activated ester. Only when the two groups are placed inside a substrate-tailored hydrophobic pocket can they display catalytic turnovers and even become reactive enough to hydrolyze amides catalytically near physiological conditions, a long-standing goal for synthetic protease mimics. These results suggest that the large gap between the innumerable catalytically incompetent small-molecule enzyme models made by chemists and true enzyme-like catalysts could be bridged by environmental engineering, which in this work enables a simple combination of a tertiary amine and an alcohol to replicate the catalytic properties of serine protease in hydrolyzing aryl amides with substrate specificity.
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This article is published as Lakavathu, Mohan, and Yan Zhao. "Turning Enzyme Models into Model Enzymes in a Substrate-Tailored, Desolvated Active Site." ACS Catalysis 15 (2025): 8925-8930.
doi: https://doi.org/10.1021/acscatal.5c01302.
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© 2025 The Authors. This is an open access publication is licensed under
CC-BY-NC-ND 4.0.