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Structural snapshots for mechanism-based inactivation of a glycoside hydrolase by cyclopropyl-carbasugars

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Author(s)

Christopher Adamson, Robert J. Pengelly, Saeideh Shamsi Kazem Abadi, Saswati Chakladar, Jason Draper, Robert Britton, Tracey M. Gloster, Andrew J. Bennet

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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 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.
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Original languageEnglish
Pages (from-to)14978-14982
JournalAngewandte Chemie International Edition
Volume55
Issue number48
Early online date26 Oct 2016
DOIs
StatePublished - 21 Nov 2016

    Research areas

  • Carbocycles, Enzyme mechanisms, Glycoside hydrolase, Inhibitors, X-ray crystallography

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