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O-GlcNAc transferase invokes nucleotide sugar pyrophosphate participation in catalysis

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 de...

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Detalles Bibliográficos
Autores principales: Schimpl, Marianne, Zheng, Xiaowei, Borodkin, Vladimir S., Blair, David E., Ferenbach, Andrew T., Schüttelkopf, Alexander W., Navratilova, Iva, Aristotelous, Tonia, Albarbarawi, Osama, Robinson, David A., Macnaughtan, Megan A., van Aalten, Daan M.F.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3509171/
https://www.ncbi.nlm.nih.gov/pubmed/23103942
http://dx.doi.org/10.1038/nchembio.1108
Descripción
Sumario: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.