Structural Snapshots for Mechanism‐Based Inactivation of a Glycoside Hydrolase by Cyclopropyl Carbasugars. Issue 48 (26th October 2016)

• Record Type: Journal Article
• Authors: Adamson, Christopher; Pengelly, Robert J.; Shamsi Kazem Abadi, Saeideh; Chakladar, Saswati; Draper, Jason; Britton, Robert; Gloster, Tracey M.; Bennet, Andrew J.
• Is Part Of: Angewandte Chemie international edition. Volume 55:Issue 48(2016)
• Page Start: 14978
• Page End: 14982
• Publication Date: 2016-10-26
• Subjects: carbocycles -- enzyme mechanisms -- glycoside hydrolases -- inhibitors -- X-ray crystallography; Chemistry -- Periodicals; 540
• DOI: 10.1002/anie.201607431
• Languages: English
• ISSNs: 1433-7851

Abstract

Abstract: 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 2 H3 conformations. We also report the synthesis and reactivity of a fluorinated analogue and the structure of its covalently linked intermediate (flattened 2 H3 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. Abstract : 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.