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

Andrew J. Thompson, Gaetano Speciale, Javier Iglesias-Fernández, Zalihe Hakki, Tyson Belz, Alan Cartmell, Richard J. Spears, Emily Chandler, Max J. Temple, Judith Stepper, Harry J. Gilbert, Carme Rovira*, Spencer J. Williams, Gideon J. Davies

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)5378-5382
Number of pages5
JournalAngewandte Chemie International Edition
Issue number18
Early online date13 Mar 2015
Publication statusPublished - 27 Apr 2015

Bibliographical note

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


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

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