Evidence for a boat conformation at the transition state of GH76 α-1,6-mannanases--key enzymes in bacterial and fungal mannoprotein metabolism

Angewandte Chemie
Andrew J ThompsonG J Davies

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 (O) S2 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 (O) S2 and B2,5 (≠) conformations, information that should inspire the development of new antifungal agents.

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Citations

Aug 21, 2015·Expert Opinion on Drug Discovery·Florent Barbault, François Maurel
Dec 28, 2016·Journal of the American Chemical Society·Santiago Alonso-GilCarme Rovira
Dec 13, 2016·Current Opinion in Structural Biology·Jon AgirreKevin D Cowtan
Feb 9, 2017·Acta Crystallographica. Section D, Structural Biology·Jon Agirre
May 25, 2016·Physical Chemistry Chemical Physics : PCCP·Nathan J DeYonkerWilliam A Alexander
May 1, 2016·Carbohydrate Research·Tyson Belz, Spencer J Williams
Aug 3, 2017·Chemical Communications : Chem Comm·Tyson BelzSpencer J Williams
Apr 8, 2020·Chemistry : a European Journal·Emilio LenceConcepción González-Bello
Feb 11, 2016·Biochemical Society Transactions·Gideon J Davies, Spencer J Williams
Aug 26, 2020·Proceedings of the National Academy of Sciences of the United States of America·Marian Samuel VogtLars-Oliver Essen
Jan 17, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Alejandro PuetJavier Pérez-Castells
Jan 1, 2020·Current Opinion in Structural Biology·Carme RoviraSpencer J Williams
Jul 8, 2020·Carbohydrate Research·Lenka Kerényiová, Štefan Janeček
May 14, 2021·Journal of Computational Chemistry·Santiago Alonso-Gil

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