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

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

Research output: Contribution to journalArticlepeer-review

23 Citations (Scopus)
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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.
Original languageEnglish
Pages (from-to)14978-14982
JournalAngewandte Chemie International Edition
Volume55
Issue number48
Early online date26 Oct 2016
DOIs
Publication statusPublished - 18 Nov 2016

Keywords

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

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