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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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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
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author 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.
author_facet 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.
author_sort Schimpl, Marianne
collection PubMed
description 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.
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spelling pubmed-35091712013-06-01 O-GlcNAc transferase invokes nucleotide sugar pyrophosphate participation in catalysis 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. Nat Chem Biol Article 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. 2012-10-28 2012-12 /pmc/articles/PMC3509171/ /pubmed/23103942 http://dx.doi.org/10.1038/nchembio.1108 Text en Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
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.
O-GlcNAc transferase invokes nucleotide sugar pyrophosphate participation in catalysis
title O-GlcNAc transferase invokes nucleotide sugar pyrophosphate participation in catalysis
title_full O-GlcNAc transferase invokes nucleotide sugar pyrophosphate participation in catalysis
title_fullStr O-GlcNAc transferase invokes nucleotide sugar pyrophosphate participation in catalysis
title_full_unstemmed O-GlcNAc transferase invokes nucleotide sugar pyrophosphate participation in catalysis
title_short O-GlcNAc transferase invokes nucleotide sugar pyrophosphate participation in catalysis
title_sort o-glcnac transferase invokes nucleotide sugar pyrophosphate participation in catalysis
topic Article
url 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
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