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Issue 8, 2014
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Recognition of diazirine-modified O-GlcNAc by human O-GlcNAcase

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Abstract

The mammalian O-GlcNAc hydrolase (OGA) removes O-GlcNAc from serine and threonine residues on intracellular glycoproteins. OGA activity is sensitive to N-acyl substitutions to O-GlcNAc, with alkyl diazirine-modified O-GlcNAc (O-GlcNDAz) being completely resistant to removal by OGA. Using homology modeling, we identified OGA residues proximal to the N-acyl position of O-GlcNAc substrate. Mutation of one of these residues, C215, results in mutant enzymes that are able to hydrolytically remove O-GlcNDAz from a model compound. Further, the C215A mutant is capable of removing O-GlcNDAz from a peptide substrate. These results can be used to improve metabolism of O-GlcNAc analogs in cells. In addition, the enzyme specificity studies reported here provide new insight into the active site of OGA, an important drug target.

Graphical abstract: Recognition of diazirine-modified O-GlcNAc by human O-GlcNAcase

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Supplementary files

Article information


Submitted
10 Apr 2014
Accepted
30 May 2014
First published
02 Jun 2014

Med. Chem. Commun., 2014,5, 1227-1234
Article type
Concise Article

Recognition of diazirine-modified O-GlcNAc by human O-GlcNAcase

A. C. Rodriguez and J. J. Kohler, Med. Chem. Commun., 2014, 5, 1227
DOI: 10.1039/C4MD00164H

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