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Publication Abstract from PubMed

Endo-alpha-1,2-mannosidases and -mannanases, members of glycoside hydrolase family 99 (GH99), cleave alpha-Glc/Man-1,3-alpha-Man-OR structures within mammalian N-linked glycans and fungal alpha-mannan, respectively. They are proposed to act through a two-step mechanism involving a 1,2-anhydrosugar 'epoxide' intermediate, involving two conserved catalytic residues. In the first step Glu333 acts as general base to deprotonate the 2-hydroxyl group adjacent to the fissile glycosidic bond, while Glu336 provides general acid assistance to departure of the aglycon. We report the synthesis of two inhibitors designed to interact with either the general base (alpha-mannosyl-1,3-(2-aminodeoxymannojirimycin); Man2NH2DMJ) or the general acid (alpha-mannosyl-1,3-mannoimidazole; ManManIm). Modest affinities were observed for an endo-alpha-1,2-mannanase from Bacteroides thetaiotaomicron. Structural studies reveal that Man2NH2DMJ binds like other iminosugar inhibitors, suggesting that the poor inhibition by this compound is not a result of a failure to achieve the expected interaction with the general base, but rather the reduction in basicity of the endocyclic nitrogen caused by introduction of a vicinal, protonated amine at C2. ManManIm binds with the imidazole headgroup distorted downwards, a result of an unfavourable interaction with a conserved active site tyrosine. This study identifies important limitations associated with mechanism-inspired inhibitor design for GH99 enzymes.

Exploration of strategies for mechanism-based inhibitor design for family GH99 endo-alpha-1,2-mannanases.,Fernandes PZ, Petricevic M, Sobala L, Davies GJ, Williams SJ Chemistry. 2018 Mar 5. doi: 10.1002/chem.201800435. PMID:29508463^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.