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Glycoside hydrolase stabilization of transition state charge: new directions for inhibitor design

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Abstract

Carbasugars are structural mimics of naturally occurring carbohydrates that can interact with and inhibit enzymes involved in carbohydrate processing. In particular, carbasugars have attracted attention as inhibitors of glycoside hydrolases (GHs) and as therapeutic leads in several disease areas. However, it is unclear how the carbasugars are recognized and processed by GHs. Here, we report the synthesis of three carbasugar isotopologues and provide a detailed transition state (TS) analysis for the formation of the initial GH-carbasugar covalent intermediate, as well as for hydrolysis of this intermediate, using a combination of experimentally measured kinetic isotope effects and hybrid QM/MM calculations. We find that the α-galactosidase from Thermotoga maritima effectively stabilizes TS charge development on a remote C5-allylic center acting in concert with the reacting carbasugar, and catalysis proceeds via an exploded, or loose, SN2 transition state with no discrete enzyme-bound cationic intermediate. We conclude that, in complement to what we know about the TS structures of enzyme-natural substrate complexes, knowledge of the TS structures of enzymes reacting with non-natural carbasugar substrates shows that GHs can stabilize a wider range of positively charged TS structures than previously thought. Furthermore, this enhanced understanding will enable the design of new carbasugar GH transition state analogues to be used as, for example, chemical biology tools and pharmaceutical lead compounds.

Graphical abstract: Glycoside hydrolase stabilization of transition state charge: new directions for inhibitor design

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Supplementary files

Article information


Submitted
10 Aug 2020
Accepted
16 Sep 2020
First published
16 Sep 2020

This article is Open Access
All publication charges for this article have been paid for by the Royal Society of Chemistry

Chem. Sci., 2020, Advance Article
Article type
Edge Article

Glycoside hydrolase stabilization of transition state charge: new directions for inhibitor design

W. Ren, M. Farren-Dai, N. Sannikova, K. Świderek, Y. Wang, O. Akintola, R. Britton, V. Moliner and A. J. Bennet, Chem. Sci., 2020, Advance Article , DOI: 10.1039/D0SC04401F

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