Lookup NU author(s): Dr Adam Jackson,
Dr Elisabeth Lowe,
Professor Harry Gilbert
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
Mannosidases catalyze the hydrolysis of a diverse range of polysaccharides and glycoconjugates, and the various sequence-based mannosidase families have evolved ingenious strategies to overcome the stereoelectronic challenges of mannoside chemistry. Using a combination of computational chemistry, inhibitor design and synthesis, and X-ray crystallography of inhibitor/enzyme complexes, it is demonstrated that mannoimidazole-type inhibitors are energetically poised to report faithfully on mannosidase transition-state conformation, and provide direct evidence for the conformational itinerary used by diverse mannosidases, including -mannanases from families GH26 and GH113. Isofagomine-type inhibitors are poor mimics of transition-state conformation, owing to the high energy barriers that must be crossed to attain mechanistically relevant conformations, however, these sugar-shaped heterocycles allow the acquisition of ternary complexes that span the active site, thus providing valuable insight into active-site residues involved in substrate recognition.
Author(s): Williams RJ, Iglesias-Fernandez J, Stepper J, Jackson A, Thompson AJ, Lowe EC, White JM, Gilbert HJ, Rovira C, Davies GJ, Williams SJ
Publication type: Article
Publication status: Published
Journal: Angewandte Chemie International Edition
Print publication date: 20/01/2014
Online publication date: 11/12/2013
Date deposited: 15/04/2014
ISSN (print): 1433-7851
ISSN (electronic): 1521-3773
Publisher: Wiley-VCH Verlag GmbH
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