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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
Authors:
Andrew J.
Thompson
(University of York)
,
Gaetano
Speciale
(University of Melbourne)
,
Javier
Iglesias-fernández
(University of Melbourne)
,
Zalihe
Hakki
(University of York; University of Melbourne)
,
Tyson
Belz
(University of Melbourne)
,
Alan
Cartmell
(University of Melbourne)
,
Richard J.
Spears
(University of York)
,
Emily
Chandler
(University of York)
,
Max J.
Temple
(Newcastle University)
,
Judith
Stepper
(University of York)
,
Harry J.
Gilbert
(Newcastle University)
,
Carme
Rovira
(Universitat de Barcelona)
,
Spencer J.
Williams
(University of Melbourne)
,
Gideon J.
Davies
(University of York)
Co-authored by industrial partner:
No
Type:
Journal Paper
Journal:
Angewandte Chemie
, VOL 127 (18)
, PAGES 5468 - 5472
State:
Published (Approved)
Published:
April 2015
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.
Journal Keywords: Computerchemie;Enzymatische Mechanismen;Glycosidaseinhibitoren;Kohlenhydrate;Konformationsanalyse
Subject Areas:
Chemistry
Instruments:
I03-Macromolecular Crystallography
,
I04-1-Macromolecular Crystallography (fixed wavelength)
,
I04-Macromolecular Crystallography