Structural Snapshots for Mechanism-Based Inactivation of a Glycoside Hydrolase by Cyclopropyl Carbasugars

Glycoside hydrolases (GHs) have attracted considerable attention as targets for therapeutic agents, and thus mechanism‐based inhibitors are of great interest. We report the first structural analysis of a carbocyclic mechanism‐based GH inactivator, the results of which show that the two Michaelis com...

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Bibliographic Details
Published in:Angewandte Chemie (International ed.) 2016-11, Vol.55 (48), p.14978-14982
Main Authors: Adamson, Christopher, Pengelly, Robert J., Shamsi Kazem Abadi, Saeideh, Chakladar, Saswati, Draper, Jason, Britton, Robert, Gloster, Tracey M., Bennet, Andrew J.
Format: Article
Language:English
Subjects:
carbocycles
Communication
Communications
enzyme mechanisms
glycoside hydrolases
inhibitors
X-ray crystallography
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Summary:Glycoside hydrolases (GHs) have attracted considerable attention as targets for therapeutic agents, and thus mechanism‐based inhibitors are of great interest. We report the first structural analysis of a carbocyclic mechanism‐based GH inactivator, the results of which show that the two Michaelis complexes are in 2H3 conformations. We also report the synthesis and reactivity of a fluorinated analogue and the structure of its covalently linked intermediate (flattened 2H3 half‐chair). We conclude that these inactivator reactions mainly involve motion of the pseudo‐anomeric carbon atom, knowledge that should stimulate the design of new transition‐state analogues for use as chemical biology tools. Cyclopropyl carbocycle inhibitors of a glycoside hydrolase act by covalently modifying the nucleophilic carboxylate while still retaining the strained cyclopropyl ring. A combined synthetic, kinetic, and structural study reveals the conformational itinerary for this family of carbocyclic inactivators through the incorporation of a fluorine atom into the inhibitor structure.
ISSN:1433-7851
1521-3773
DOI:10.1002/anie.201607431