Structural Snapshots for Mechanism-Based Inactivation of a Glycoside Hydrolase by Cyclopropyl Carbasugars

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• 作者：Christopher Adamson ; Robert J. Pengelly ; Saeideh Shamsi Kazem Abadi ; Dr. Saswati Chakladar ; Jason Draper ; Prof. Robert Britton ; Dr. Tracey M. Gloster and Prof. Andrew J. Bennet
• 刊名：Angewandte Chemie
• 出版年：2016
• 出版时间：November 21, 2016
• 年：2016
• 卷：128
• 期：48
• 页码：15202-15206
• 全文大小：2229K
• ISSN：1521-3757

文摘

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 ²Hb>3b> conformations. We also report the synthesis and reactivity of a fluorinated analogue and the structure of its covalently linked intermediate (flattened ²Hb>3b> 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.