Structural snapshots for mechanism-based inactivation of a glycoside hydrolase by cyclopropyl-carbasugars
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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.
Adamson , C , Pengelly , R J , Kazem Abadi , S S , Chakladar , S , Draper , J , Britton , R , Gloster , T M & Bennet , A J 2016 , ' Structural snapshots for mechanism-based inactivation of a glycoside hydrolase by cyclopropyl-carbasugars ' Angewandte Chemie International Edition , vol 55 , no. 48 , pp. 14978-14982 . DOI: 10.1002/anie.201607431
Angewandte Chemie International Edition
Copyright 2016 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
This work was supported by an NSERC Discovery Grant (AJB: #121348-2012), a Wellcome Trust Career Development Fellowship (TMG: grant 095828), a Wellcome Trust Institutional Strategic Support award (TMG and RJP), a MSFHR Career Investigator Award (RB), a NSERC Discovery Grant (RB), and an NSERC PGSM Scholarship (CA).
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