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O-GlcNAc transferase invokes nucleotide sugar pyrophosphate participation in catalysis

O-GlcNAc transferase invokes nucleotide sugar pyrophosphate participation in catalysis

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Authors

  • Marianne Schimpl
  • Xiaowei Zheng
  • Vladimir S. Borodkin
  • David E. Blair
  • Andrew T. Ferenbach
  • Alexander W. Schüttelkopf
  • Iva Navratilova
  • Tonia Aristotelous
  • Osama Albarbarawi
  • David A. Robinson
  • Daan M.F. van Aalten
  • Megan A. Macnaughtan

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Info

Original languageEnglish
JournalNature Chemical Biology
Journal publication date2012
Early online date28/10/12
DOIs
StatePublished

Abstract

Protein O-GlcNAcylation is an essential post-translational modification on hundreds of intracellular proteins in metazoa, catalyzed by O-linked ß-N-acetylglucosamine (O-GlcNAc) transferase (OGT) using unknown mechanisms of transfer and substrate recognition. Through crystallographic snapshots and mechanism-inspired chemical probes, we define how human OGT recognizes the sugar donor and acceptor peptide and uses a new catalytic mechanism of glycosyl transfer, involving the sugar donor a-phosphate as the catalytic base as well as an essential lysine. This mechanism seems to be a unique evolutionary solution to the spatial constraints imposed by a bulky protein acceptor substrate and explains the unexpected specificity of a recently reported metabolic OGT inhibitor.

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