|
|||||
|
|
Structural Snapshots for Mechanism‐Based Inactivation of a Glycoside Hydrolase by Cyclopropyl Carbasugars |
|
| Authors: | Christopher Adamson Robert J Pengelly Saeideh Shamsi?Kazem?Abadi Dr Saswati Chakladar Jason Draper Prof Robert Britton Dr Tracey M Gloster Prof Andrew J Bennet |
| Affiliation: | 1. Department of Chemistry, Simon Fraser University, Burnaby, British Columbia, Canada;2. Biomedical Sciences Research Complex, University of St Andrews, St Andrews, Fife, UK;3. Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, Canada |
| 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. |
| Keywords: | carbocycles enzyme mechanisms glycoside hydrolases inhibitors X-ray crystallography |
