Published in
Nature Research, Nature Chemical Biology, 12(8), p. 969-974, 2012
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- [www.researchgate.net] | PDF
- [www.ncbi.nlm.nih.gov] | PDF
- [www.ncbi.nlm.nih.gov] | PDF
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O-GlcNAc transferase invokes nucleotide sugar pyrophosphate participation in catalysis
,
Xiaowei Zheng,
Vladimir S. Borodkin,
David E. Blair,
Andrew T. Ferenbach,
Alexander W. Schüttelkopf,
Iva Navratilova,
Tonia Aristotelous,
Osama Albarbarawi,
David A. Robinson,
Megan A. Macnaughtan,
Daan M. F. van Aalten
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Abstract
Protein O-GlcNAcylation is an essential post-translational modification on hundreds of intracellular proteins in metazoa, catalyzed by O-GlcNAc transferase using unknown mechanisms of transfer and substrate recognition. Through crystallographic snapshots and mechanism-inspired chemical probes, we define how human O-GlcNAc transferase recognizes the sugar donor and acceptor peptide and employs a novel catalytic mechanism of glycosyl transfer, involving the sugar donor α-phosphate as the catalytic base, as well as an essential lysine. This mechanism appears 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 O-GlcNAc transferase inhibitor.