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Evidence for a Boat Conformation at the Transition State of GH76 α Normal 0 false false false EN-GB X-NONE X-NONE -1,6-Mannanases-Key Enzymes in Bacterial and Fungal Mannoprotein Metabolism

Lookup NU author(s): Dr Max Temple, Emeritus Professor Harry Gilbert

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Abstract

alpha-Mannosidases and alpha-mannanases have attracted attention for the insight they provide into nucleophilic substitution at the hindered anomeric center of alpha-mannosides, and the potential of mannosidase inhibitors as cellular probes and therapeutic agents. We report the conformational itinerary of the family GH76 alpha-mannanases studied through structural analysis of the Michaelis complex and synthesis and evaluation of novel aza/imino sugar inhibitors. A Michaelis complex in an S-O(2) conformation, coupled with distortion of an azasugar in an inhibitor complex to a high energy B-2,5(not equal) conformation are rationalized through ab initio QM/MM metadynamics that show how the enzyme surface restricts the conformational landscape of the substrate, rendering the B-2,B-5 conformation the most energetically stable on-enzyme. We conclude that GH76 enzymes perform catalysis using an itinerary that passes through OS2 and B-2,5(not equal) conformations, information that should inspire the development of new antifungal agents.

Publication metadata

Author(s): Thompson AJ, Speciale G, Iglesias-Fernandez J, Hakki Z, Belz T, Cartmell A, Spears RJ, Chandler E, Temple MJ, Stepper J, Gilbert HJ, Rovira C, Williams SJ, Davies GJ

Publication type: Article

Publication status: Published

Journal: Angewandte Chemie

Year: 2015

Volume: 54

Issue: 18

Pages: 5378-5382

Print publication date: 27/04/2015

Online publication date: 13/03/2015

ISSN (print): 1433-7851

ISSN (electronic): 1521-3773

Publisher: Wiley - V C H Verlag GmbH & Co. KGaA

URL: http://dx.doi.org/10.1002/anie.201410502

DOI: 10.1002/anie.201410502

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