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. This journal is
Original language | English (US) |
---|---|
Pages (from-to) | 1227-1234 |
Number of pages | 8 |
Journal | MedChemComm |
Volume | 5 |
Issue number | 8 |
DOIs | |
State | Published - Aug 2014 |
ASJC Scopus subject areas
- Biochemistry
- Molecular Medicine
- Pharmacology
- Pharmaceutical Science
- Drug Discovery
- Organic Chemistry