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Evidence for a Boat Conformation at the Transition State of GH76 α-1,6-Mannanases-Key Enzymes in Bacterial and Fungal Mannoprotein Metabolism

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JournalAngewandte Chemie International Edition
DateE-pub ahead of print - 13 Mar 2015
DatePublished (current) - 27 Apr 2015
Issue number18
Volume54
Number of pages5
Pages (from-to)5378-5382
Early online date13/03/15
Original languageEnglish

Abstract

α-Mannosidases and α-mannanases have attracted attention for the insight they provide into nucleophilic substitution at the hindered anomeric center of α-mannosides, and the potential of mannosidase inhibitors as cellular probes and therapeutic agents. We report the conformational itinerary of the family GH76 α-mannanases studied through structural analysis of the Michaelis complex and synthesis and evaluation of novel aza/imino sugar inhibitors. A Michaelis complex in an OS2 conformation, coupled with distortion of an azasugar in an inhibitor complex to a high energy B2,5 conformation are rationalized through ab initio QM/MM metadynamics that show how the enzyme surface restricts the conformational landscape of the substrate, rendering the B2,5 conformation the most energetically stable on-enzyme. We conclude that GH76 enzymes perform catalysis using an itinerary that passes through OS2 and B2,5 conformations, information that should inspire the development of new antifungal agents.

Bibliographical note

© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

    Research areas

  • Carbohydrates, Computational chemistry, Conformational analysis, Enzymatic mechanisms, Glycosidase inhibitors

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