O-GlcNac

J. E. O-GlcNAc modification is an endogenous inhibitor of the proteasome. Ceil 2003, 335, 715-725. 

G. J. Davies and C. Martinez-Fleites, The O-GlcNAc modification Three-dimentional structure, enzymology and the development of selective inhibitors to probe disease, Biochem. Soc. Trans., 38 (2010) 1179-1188. 

The discovery of -linked p-N-acetylglucosamine (O-GlcNAc) more than 28 years ago disproved the long-held dogma that protein glycosylation is restricted to the luminal compartments of the secretory machinery and to the cell surface and extracellular matrix (Hart et ah, 1989). Early studies of... 

O-GlcNAc s subcellular localization in rat hepatocytes established that it is highly concentrated at the nuclear envelope, particularly at the nuclear pore complex, but is also abundant and widespread within chromatin (Holt and Hart, 1986). Aside from the biosynthetic intermediates,... 

Guinez, C., Morelle, W., Michalski, J. C., and Lefebvre, T. (2005). O-GlcNAc glycosylation A signal for the nuclear transport of cytosolic proteins Int. ]. Biochem. Cell Biol. 37, 765-774. 

Yang, X., Zhang, F., and Kudlow, J. E. (2002). Recruitment of O-GlcNAc transferase to promoters by corepressor mSin3A Coupling protein O-GlcNAcylation to transcriptional repression. Cell 110, 69-80. 

Lefebvre, T., Ferreira, S., Dupont-Wallois, L., Bussiere, T., Dupire, M. J., Delacourte, A., et al. (2003) Evidence of a balance between phosphorylation and O-GlcNAc glycosylation of Tau proteins—a role in nuclear localization. Biochim. Biophys. Acta 1619, 167-176. 

G. W. Hart Dynamic cycling of O-GlcNAc on nucleocytoplasmic proteins a nutrient/stress sensor globally regulating cellular mechanism... 

Zachara NE, Hart GW (2002) The emerging significance of O-GlcNAc in cellular regulation. Chem Rev 102 431-438... 

Meinjohanns, E., Meldal, M and Bock, K. (1995) Efficient synthesis of 0-(2-acetamido-2-deoxy-(3-D-glucopyranosyl)-Ser/Thr building blocks for SPPS of O-GlcNAc glycopeptides. Tetrahedron Lett. 36, 9205-9208. 

Meinjohanns, E., Vargas-Berenguel, A., Meldal, M., Paulsen, H., and Bock, K. (1995) Comparision of Al-Dts and N-Aloe in the solid-phase synthesis of O-GlcNAc glycopeptide fragments of RNA-polymerase II and mammalian neurofilaments. /. Am. Chem. Soc. Perkin Trans I., 2165-2175. 

Vocadlo DJ, Hang HC, Kim EJ et al (2003) A chemical approach for identifying O-GlcNAc-modified proteins in cells. Proc Natl Acad Sci USA 100 9116-9121... 

Akimoto, Y., Comer, F.I., Cole, R.N., Kudo, A., Kawakami, H., Hirano, H. and Hart, G.W. (2003) Localization of the O-GlcNAc transferase and 0-GlcNAc-modified proteins in rat cerebellar cortex. Brain Res. 966, 194-205. 

Khidekel, N., Ficarro, S.B., Peters, E.C. and Hsieh-Wilson, L.C. (2004) Exploring the O-GlcNAc pro-teome direct identification of 0-GlcNAc-modified proteins from the brain. Proc. Nad Acad. Sci. U.S.A. 101, 13132-13137. 

Finally, because this modification occurs on serine and threonine residues, it can also compete directly with an O-phosphory lation event at an identical or nearby site to provide an additional level of regulation on a specific protein. To date, all described O-GlcNAc-modified proteins have been found to be phospho-proteins (28, 29, 30). Such competition between O-GlcNAc and O-phosphate binding occurs with many examples listed above as well as with others. 

Traditional methods to map posttranslational modification sites, like those of phosphorylation, have been anchored by protein digest and mass spectroscopic (MS) approaches (for a review on the classic evaluation and for MS analyses of O-glycans, see Reference (56)). Unfortunately, like many posttranslational modifications, O-GlcNAcylation occurs routinely on a protein population with substoichiometric frequency, which results in a very small detectable population of a O-GlcNAc-modified product. Also, much like O-phosphate additions, the protein-O-GlcNAc bond is labile and is detached by collision-induced dissociation (CID) during MS analysis. Often, the bond is lost before it can be detected on the peptides analyzed (57, 58). Phosphate modifications, however, can overcome this limitation by emiching the peptide mixtures... 

Vosseller K, Wells L, Lane MD, Hart GW. Elevated nucleocyto-plasmic glycosylation by O-GlcNAc results in insulin resistance associated with defects in Akt activation in 3T3-L1 adipocytes. Proc. Natl. Acad. Sci. U.S.A. 2002 99 5313-5318. 

Wells L, Vosseller K, Cole RN, Cronshaw JM, Matunis MJ, Hart GW. Mapping sites of O-GlcNAc modification using affinity tags for serine and threonine post-translational modifications. Mol. Cell. Proteomics 2002 1 791-804. 

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