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Structural Snapshots for Mechanism‐Based Inactivation of a Glycoside Hydrolase by Cyclopropyl Carbasugars
Author(s) -
Adamson Christopher,
Pengelly Robert J.,
Shamsi Kazem Abadi Saeideh,
Chakladar Saswati,
Draper Jason,
Britton Robert,
Gloster Tracey M.,
Bennet Andrew J.
Publication year - 2016
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201607431
Subject(s) - chemistry , stereochemistry , glycoside hydrolase , reactivity (psychology) , anomer , mechanism (biology) , covalent bond , glycoside , combinatorial chemistry , enzyme , biochemistry , organic chemistry , philosophy , medicine , alternative medicine , epistemology , pathology
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 H 3 conformations. We also report the synthesis and reactivity of a fluorinated analogue and the structure of its covalently linked intermediate (flattened 2 H 3 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.