Browse by author
Lookup NU author(s): Dr Max Temple, Emeritus Professor Harry Gilbert
Full text for this publication is not currently held within this repository. Alternative links are provided below where available.
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.
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
Altmetrics provided by Altmetric
