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

Andrea C. Rodriguez, Jennifer J. Kohler

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

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 languageEnglish (US)
Pages (from-to)1227-1234
Number of pages8
JournalMedChemComm
Volume5
Issue number8
DOIs
StatePublished - Aug 2014

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Pharmacology
  • Pharmaceutical Science
  • Drug Discovery
  • Organic Chemistry

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