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Nat Chem Biol. 2012 Dec;8(12):969-74. doi: 10.1038/nchembio.1108. Epub 2012 Oct 28.

O-GlcNAc transferase invokes nucleotide sugar pyrophosphate participation in catalysis.

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1
College of Life Sciences, University of Dundee, Dundee, UK.

Abstract

Protein O-GlcNAcylation is an essential post-translational modification on hundreds of intracellular proteins in metazoa, catalyzed by O-linked β-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 α-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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PMID:
23103942
PMCID:
PMC3509171
DOI:
10.1038/nchembio.1108
[Indexed for MEDLINE]
Free PMC Article

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