O-GlcNAcase Catalyzes Cleavage of Thioglycosides without General Acid Catalysis

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O-GlcNAcase catalyzes the removal of N-acetylglucosamine residues from serine and threonine residues of post-translationally modified proteins using a catalytic mechanism involving substrate-assisted catalysis and general acid/base catalysis. Since thioglycosides are widely perceived as resistant to hydrolysis by glycosidases, it was surprising to find that O-GlcNAcase also catalyzes the efficient hydrolysis of S-glycosides. Brønsted analyses and pH-activity studies of the O-GlcNAcase-catalyzed hydrolysis of a series of aryl S- and O-glycosides reveal that O-GlcNAcase effects hydrolysis of thioglycosides without the assistance of general acid catalysis. α-Deuterium kinetic isotope effects for O- and S-glycosides, as well as Taft-like analyses using N-fluoroacetyl-β-glycosides, suggest that O-GlcNAcase accomplishes hydrolysis of thioglycosides by stabilizing late transition states. For S-glycosides this transition state shows greater nucleophilic participation from the 2-acetamido group than for O-glycosides. The rate constants governing the O-GlcNAcase-catalyzed hydrolysis of O- and S-glycosides as compared to those previously determined for the spontaneous hydrolysis of structurally similar O,O- and O,S-acetals show a similar ratio. O-GlcNAcase therefore demonstrates similar catalytic proficiency toward both O- and S-glycosides. We conclude that O-GlcNAcase is a bifunctional catalyst capable of efficiently cleaving thioglycosides without general acid catalysis, an observation that may have biological implications.
DOI: 10.1021/ja0567687
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Macauley, M. S., Stubbs, K. A., & Vocadlo, D. J. (2005). O-GlcNAcase Catalyzes Cleavage of Thioglycosides without General Acid Catalysis. Journal of the American Chemical Society, 127(49), 17202–17203. https://doi.org/10.1021/ja0567687.
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Journal of the American Chemical Society
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O-GlcNAcase Catalyzes Cleavage of Thioglycosides without General Acid Catalysis
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