Exploration of Strategies for Mechanism-Based Inhibitor Design for Family GH99 endo--1,2-Mannanases
Pearl Z Fernandes, Marija Petricevic, Lukasz Sobala, Gideon J Davies, Spencer J Williams
CHEMISTRY-A EUROPEAN JOURNAL | WILEY-V C H VERLAG GMBH | Published : 2018
endo-α-1,2-Mannosidases and -mannanases, members of glycoside hydrolase family 99 (GH99), cleave α-Glc/Man-1,3-α-Man-OR structures within mammalian N-linked glycans and fungal α-mannan, respectively. They are proposed to act through a two-step mechanism involving a 1,2-anhydrosugar "epoxide" intermediate incorporating two conserved catalytic carboxylates. In the first step, one carboxylate acts as a general base to deprotonate the 2-hydroxy group adjacent to the fissile glycosidic bond, and the other provides general acid assistance to the departure of the aglycon. We report herein the synthesis of two inhibitors designed to interact with either the general base (α-mannosyl-1,3-(2-aminodeoxy..View full abstract
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Awarded by Australian Research Council
Awarded by European Research Council
The Australian Research Council is thanked for financial support (DP120101396, FT130100103). We thank Diamond Light Source for access to beamline i04 (proposal mx13587) that contributed to the results presented here. G.J.D. and L.F.S. were supported by the European Research Council (ERC-2012-AdG-32294 'Glycopoise'). G.J.D. thanks the Royal Society for the Ken Murray Research Professorship.