Structural snapshots for mechanism-based inactivation of a glycoside hydrolase by cyclopropyl carbasugars
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.
Citation
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 . https://doi.org/10.1002/anie.201607431
Publication
Angewandte Chemie International Edition
Status
Peer reviewed
ISSN
1433-7851Type
Journal article
Description
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).Collections
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