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Chemical approaches to understanding O-GlcNAc glycosylation in the brain

Nature Chemical Biology volume 4, pages 97–106 (2008)Cite this article

Abstract

O-GlcNAc glycosylation is a unique, dynamic form of glycosylation found on intracellular proteins of all multicellular organisms. Studies suggest that O-GlcNAc represents a key regulatory modification in the brain, contributing to transcriptional regulation, neuronal communication and neurodegenerative disease. Recently, several new chemical tools have been developed to detect and study the modification, including chemoenzymatic tagging methods, quantitative proteomics strategies and small-molecule inhibitors of O-GlcNAc enzymes. Here we highlight some of the emerging roles for O-GlcNAc in the nervous system and describe how chemical tools have significantly advanced our understanding of the scope, functional significance and cellular dynamics of this modification.

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Figure 1: O-GlcNAc glycosylation is the addition of β-N-acetylglucosamine to serine or threonine residues of proteins.
Figure 2: O-GlcNAc proteome from rodent brain tissue.
Figure 3: Strategy for chemically tagging O-GlcNAc proteins.
Figure 4: The BEMAD strategy for mapping glycosylation sites.
Figure 5: Small-molecule inhibitors of O-GlcNAc transferase (OGT) and β-N-acetylglucosaminidase (OGA).
Figure 6: Chemical tools for monitoring O-GlcNAc dynamics.

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Acknowledgements

We thank C.J. Rogers and H.E. Murrey for critical reading of the manuscript. This work was supported in part by grants from the US National Institutes of Health (RO1 GM084724 and F31 NS056525-02 to J.E.R.) and the US National Science Foundation (CHE-0239861).

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  1. Jessica E Rexach and Peter M Clark: These authors contributed equally to this work.

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  1. Division of Chemistry and Chemical Engineering, and Howard Hughes Medical Institute, California Institute of Technology, Pasadena, 91125, California, USA

    Jessica E Rexach, Peter M Clark & Linda C Hsieh-Wilson

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  1. Jessica E Rexach
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Correspondence to Linda C Hsieh-Wilson.

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Rexach, J., Clark, P. & Hsieh-Wilson, L. Chemical approaches to understanding O-GlcNAc glycosylation in the brain. Nat Chem Biol 4, 97–106 (2008). https://doi.org/10.1038/nchembio.68

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