O-Linked N-Acetylglucosamine (GlcNAc) Transferase (UDP-N-Acetylglucosamine: Polypeptide-N-Acetylglucosaminyl Transferase) (OGT)

  • Partha Banerjee
  • Gerald W. Hart
Reference work entry


UDP-N-acetylglucosamine/polypeptide-N-acetylglucosaminyltransferase or O-GlcNAc transferase catalyzes the transfer of an N-acetylglucosamine moiety from the donor substrate UDP-GlcNAc onto serine/threonine residues of nuclear and cytoplasmic proteins (Torres and Hart 1984). Discovered in the early 1980’s, this O-linked sugar modification better known as O-GlcNAcylation is different from other saccharide modification in that it does not get elongated to long oligosaccharide chains; is nuclear/cytosolic in nature; is sub-stoichiometric at individual sites, with rapid cycling dynamics; and functions as an important signaling moiety akin to protein phosphorylation. The cellular concentration of UDP-GlcNAc, the donor substrate for cellular O-GlcNAcylation, is highly responsive to glucose flux, amino acid and fatty acid metabolism, nucleotide biosynthesis, as well as flux through glycolysis and Kreb’s cycle (Marshall et al. 1991). Overall about 2–5 % of cellular glucose gets diverted towards the hexosamine biosynthetic pathway to produce UDP-GlcNAc. Since UDP-GlcNAc production is impacted by a number of metabolic pathways and the binding of UDP-GlcNAc to O-GlcNAc transferase varies over a wide range of substrate concentrations, O-GlcNAcylation functions as an excellent nutrient and stress sensor (Wells et al. 2001; Hart et al. 2007). O-GlcNAcylation also serves as an important regulatory PTM for a wide variety of biological pathways. Cell cycle progression, transcription, intracellular signaling, nutrient sensing, and neuronal plasticity are all affected by protein O-GlcNAcylation. Abnormalities in levels of O-GlcNAc have been shown to be an underlying cause of insulin resistance and glucose toxicity in diabetes, neurodegenerative disorders, and dysregulation of tumor suppressors and oncogenic proteins in cancer.


Substrate Peptide Glycosyl Transferase Trimeric Complex Hydroxyl Amino Hexosamine Biosynthetic Pathway 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. Akimoto Y, Kreppel LK, Hirano H, Hart GW (2000) Increased O-GlcNAc transferase in pancreas of rats with streptozotocin-induced diabetes. Diabetologia 43:1239–1247PubMedCrossRefGoogle Scholar
  2. Andrali SS, Qian Q, Özcan S (2007) Glucose mediates the translocation of NeuroD1 by O-Linked glycosylation. J Biol Chem 282:15589–15596PubMedCentralPubMedCrossRefGoogle Scholar
  3. Arnold CS, Johnson GV, Cole RN, Dong DL, Lee M, Hart GW (1996) The microtubule-associated protein tau is extensively modified with O-linked N-acetylglucosamine. J Biol Chem 271:28741–28744PubMedCrossRefGoogle Scholar
  4. Cheung WD, Hart GW (2008) AMP-activated protein kinase and p38 MAPK activate O-GlcNAcylation of neuronal proteins during glucose deprivation. J Biol Chem 283:13009–13020PubMedCrossRefGoogle Scholar
  5. Cheung WD, Sakabe K, Housley MP, Dias WB, Hart GW (2008) O-linked β-N-acetylglucosaminyltransferase substrate specificity is regulated by myosin phosphatase targeting and other interacting proteins. J Biol Chem 283:33935–33941PubMedCrossRefGoogle Scholar
  6. Clarke AJ, Hurtado-Guerrero R, Pathak S, Schuttelkopf AW, Borodkin V, Shepherd SM, Ibrahim AFM, van Aalten DMF (2008) Structural insights into mechanism and specificity of O-GlcNAc transferase. EMBO J 27:2780–2788PubMedCrossRefGoogle Scholar
  7. Comer FI, Hart GW (2001) Reciprocity between O-GlcNAc and O-phosphate on the carboxyl terminal domain of RNA polymerase II. Biochemistry 40:7845–7852PubMedCrossRefGoogle Scholar
  8. Dias WB, Hart GW (2007) O-GlcNAc modification in diabetes and Alzheimer’s disease. Mol Biosyst 3:766–772PubMedCrossRefGoogle Scholar
  9. Du X-L, Edelstein D, Rossetti L, Fantus IG, Goldberg H, Ziyadeh F, Wu J, Brownlee M (2000) Hyperglycemia-induced mitochondrial superoxide overproduction activates the hexosamine pathway and induces plasminogen activator inhibitor-1 expression by increasing Sp1 glycosylation. Proc Natl Acad Sci 97:12222–12226PubMedCrossRefGoogle Scholar
  10. Gao Y, Wells L, Comer FI, Parker GJ, Hart GW (2001) Dynamic O-glycosylation of nuclear and cytosolic proteins: cloning and characterization of a neutral, cytosolic β-N-acetylglucosaminidase from human brain. J Biol Chem 276:9838–9845PubMedCrossRefGoogle Scholar
  11. Gao Y, Miyazaki J-I, Hart GW (2003) The transcription factor PDX-1 is post-translationally modified by O-linked N-acetylglucosamine and this modification is correlated with its DNA binding activity and insulin secretion in min6 β-cells. Arch Biochem Biophys 415:155–163PubMedCrossRefGoogle Scholar
  12. Gloster TM, Zandberg WF, Heinonen JE, Shen DL, Deng L, Vocadlo DJ (2011) Hijacking a biosynthetic pathway yields a glycosyltransferase inhibitor within cells. Nat Chem Biol 7:174–181PubMedCentralPubMedCrossRefGoogle Scholar
  13. Gross BJ, Kraybill BC, Walker S (2005) Discovery of O-GlcNAc transferase inhibitors. J Am Chem Soc 127:14588–14589PubMedCrossRefGoogle Scholar
  14. Gross BJ, Swoboda JG, Walker S (2008) A strategy to discover inhibitors of O-Linked glycosylation. J Am Chem Soc 130:440–441PubMedCrossRefGoogle Scholar
  15. Haltiwanger RS, Holt GD, Hart GW (1990) Enzymatic addition of O-GlcNAc to nuclear and cytoplasmic proteins. Identification of a uridine diphospho-N-acetylglucosamine:peptide beta-N-acetylglucosaminyltransferase. J Biol Chem 265:2563–2568PubMedGoogle Scholar
  16. Haltiwanger RS, Blomberg MA, Hart GW (1992) Glycosylation of nuclear and cytoplasmic proteins. Purification and characterization of a uridine diphospho-N-acetylglucosamine:polypeptide beta-N-acetylglucosaminyltransferase. J Biol Chem 267:9005–9013PubMedGoogle Scholar
  17. Hanover JA, Yu S, Lubas WB, Shin S-H, Ragano-Caracciola M, Kochran J, Love DC (2003) Mitochondrial and nucleocytoplasmic isoforms of O-linked GlcNAc transferase encoded by a single mammalian gene. Arch Biochem Biophys 409:287–297PubMedCrossRefGoogle Scholar
  18. Hanover JA, Forsythe ME, Hennessey PT, Brodigan TM, Love DC, Ashwell G, Krause M (2005) A Caenorhabiditis elegans model of insulin resistance: altered macronutrient storage and dauer formation in an OGT-1 knockout. Proc Natl Acad Sci USA 102:11266–11271PubMedCrossRefGoogle Scholar
  19. Hart GW, Copeland RJ (2010) Glycomics hits the big time. Cell 143:672–676PubMedCentralPubMedCrossRefGoogle Scholar
  20. Hart GW, Housley MP, Slawson C (2007) Cycling of O-linked [beta]-N-acetylglucosamine on nucleocytoplasmic proteins. Nature 446:1017–1022PubMedCrossRefGoogle Scholar
  21. Hart GW, Slawson C, Ramirez-Correa G, Lagerlof O (2011) Cross talk between O-GlcNAcylation and phosphorylation: roles in signaling, transcription, and chronic disease. Annu Rev Biochem 80:825–858PubMedCentralPubMedCrossRefGoogle Scholar
  22. Hartweck LM, Scott CL, Olszewski NE (2002) Two O-Linked N-Acetylglucosamine transferase genes of Arabidopsis thaliana L. Heynh. Have overlapping functions necessary for gamete and seed development. Genetics 161:1279–1291PubMedGoogle Scholar
  23. Housley MP, Rodgers JT, Udeshi ND, Kelly TJ, Shabanowitz J, Hunt DF, Puigserver P, Hart GW (2008) O-GlcNAc regulates FoxO activation in response to glucose. J Biol Chem 283:16283–16292PubMedCrossRefGoogle Scholar
  24. Housley MP, Udeshi ND, Rodgers JT, Shabanowitz J, Puigserver P, Hunt DF, Hart GW (2009) A PGC-1α-O-GlcNAc transferase complex regulates FoxO transcription factor activity in response to glucose. J Biol Chem 284:5148–5157PubMedCrossRefGoogle Scholar
  25. Iyer SPN, Hart GW (2003a) Dynamic nuclear and cytoplasmic glycosylation: enzymes of O-GlcNAc cycling†. Biochemistry 42:2493–2499PubMedCrossRefGoogle Scholar
  26. Iyer SPN, Hart GW (2003b) Roles of the tetratricopeptide repeat domain in O-GlcNAc transferase targeting and protein substrate specificity. J Biol Chem 278:24608–24616PubMedCrossRefGoogle Scholar
  27. Iyer SPN, Akimoto Y, Hart GW (2003a) Identification and cloning of a novel family of coiled-coil domain proteins that interact with O-GlcNAc transferase. J Biol Chem 278:5399–5409PubMedCrossRefGoogle Scholar
  28. Iyer SP, Akimoto Y, Hart GW (2003b) Identification and cloning of a novel family of coiled-coil domain proteins that interact with O-GlcNAc transferase. J Biol Chem 278:5399–5409PubMedCrossRefGoogle Scholar
  29. Jackson SP, Tjian R (1988) O-glycosylation of eukaryotic transcription factors: implications for mechanisms of transcriptional regulation. Cell 55:125–133PubMedCrossRefGoogle Scholar
  30. Kreppel LK, Hart GW (1999) Regulation of a cytosolic and nuclear O-GlcNAc transferase: role of the tetratricopeptide repeats. J Biol Chem 274:32015–32022PubMedCrossRefGoogle Scholar
  31. Kreppel LK, Blomberg MA, Hart GW (1997) Dynamic glycosylation of nuclear and cytosolic proteins: cloning and characterization of a unique O-GlcNAc transferase with multiple tetratricopeptide repeats. J Biol Chem 272:9308–9315PubMedCrossRefGoogle Scholar
  32. Lazarus BD, Love DC, Hanover JA (2006) Recombinant O-GlcNAc transferase isoforms: identification of O-GlcNAcase, yes tyrosine kinase, and tau as isoform-specific substrates. Glycobiology 16:415–421PubMedCrossRefGoogle Scholar
  33. Lazarus MB, Nam Y, Jiang J, Sliz P, Walker S (2011) Structure of human O-GlcNAc transferase and its complex with a peptide substrate. Nature 469:564–567PubMedCentralPubMedCrossRefGoogle Scholar
  34. Lazarus MB, Jiang J, Gloster TM, Zandberg WF, Whitworth GE, Vocadlo DJ, Walker S (2012) Structural snapshots of the reaction coordinate for O-GlcNAc transferase. Nat Chem Biol 8(12):966–968PubMedCentralPubMedCrossRefGoogle Scholar
  35. Leavy TM, Bertozzi CR (2007) A high-throughput assay for O-GlcNAc transferase detects primary sequence preferences in peptide substrates. Bioorg Med Chem Lett 17:3851–3854PubMedCentralPubMedCrossRefGoogle Scholar
  36. Liu F, Iqbal K, Grundke-Iqbal I, Hart GW, Gong CX (2004) O-GlcNAcylation regulates phosphorylation of tau: a mechanism involved in Alzheimer’s disease. Proc Natl Acad Sci USA 101:10804–10809PubMedCrossRefGoogle Scholar
  37. Love DC, Kochran J, Cathey RL, Shin S-H, Hanover JA (2003) Mitochondrial and nucleocytoplasmic targeting of O-linked GlcNAc transferase. J Cell Sci 116:647–654PubMedCrossRefGoogle Scholar
  38. Lubas WA, Frank DW, Krause M, Hanover JA (1997) O-Linked GlcNAc transferase is a conserved nucleocytoplasmic protein containing tetratricopeptide repeats. J Biol Chem 272:9316–9324PubMedCrossRefGoogle Scholar
  39. Lynch TP, Reginato MJ (2011) GlcNAc transferase: a sweet new cancer target. Cell Cycle 10:1712–1713PubMedCrossRefGoogle Scholar
  40. Lynch TP, Ferrer CM, Jackson SR, Shahriari KS, Vosseller K, Reginato MJ (2012) Critical cole of O-Linked β-N-Acetylglucosamine transferase in prostate cancer invasion, angiogenesis, and metastasis. J Biol Chem 287:11070–11081PubMedCrossRefGoogle Scholar
  41. Marshall S, Bacote V, Traxinger RR (1991) Discovery of a metabolic pathway mediating glucose-induced desensitization of the glucose transport system. Role of hexosamine biosynthesis in the induction of insulin resistance. J Biol Chem 266:4706–4712PubMedGoogle Scholar
  42. Martinez-Fleites C, Macauley MS, He Y, Shen DL, Vocadlo DJ, Davies GJ (2008) Structure of an O-GlcNAc transferase homolog provides insight into intracellular glycosylation. Nat Struct Mol Biol 15:764–765PubMedCrossRefGoogle Scholar
  43. Martinez-Fleites C, He Y, Davies GJ (2010) Structural analyses of enzymes involved in the O-GlcNAc modification. Biochim Biophys Acta Gen Subj 1800:122–133CrossRefGoogle Scholar
  44. Marz P, Stetefeld J, Bendfeldt K, Nitsch C, Reinstein J et al (2006) Ataxin-10 interacts with O-linked beta-N-acetylglucosamine transferase in the brain. J Biol Chem 281:20263–20270PubMedCrossRefGoogle Scholar
  45. Mazars R, Gonzalez-de-Peredo A, Cayrol C, Lavigne AC, Vogel JL et al (2010) The THAP-zinc finger protein THAP1 associates with coactivator HCF-1 and O-GlcNAc transferase: a link between DYT6 and DYT3 dystonias. J Biol Chem 285:13364–13371PubMedCrossRefGoogle Scholar
  46. O’Donnell N, Zachara NE, Hart GW, Marth JD (2004) Ogt-Dependent X-Chromosome-linked protein glycosylation is a requisite modification in somatic cell function and embryo viability. Mol Cell Biol 24:1680–1690PubMedCentralPubMedCrossRefGoogle Scholar
  47. Ranuncolo SM, Ghosh S, Hanover JA, Hart GW, Lewis BA (2012) Evidence of the involvement of O-GlcNAc-modified human RNA polymerase II CTD in transcription in vitro and in vivo. J Biol Chem 287(28):23549–23561PubMedCrossRefGoogle Scholar
  48. Schimpl M, Zheng X, Borodkin VS, Blair DE, Ferenbach AT, Schüttelkopf AW, Navratilova I, Aristotelous T, Albarbarawi O, Robinson DA, Macnaughtan MA, van Aalten DMF (2012) O-GlcNAc transferase invokes nucleotide sugar pyrophosphate participation in catalysis. Nat Chem Biol 8(12):969–974PubMedCentralPubMedCrossRefGoogle Scholar
  49. Shafi R, Iyer SPN, Ellies LG, O’Donnell N, Marek KW, Chui D, Hart GW, Marth JD (2000) The O-GlcNAc transferase gene resides on the X chromosome and is essential for embryonic stem cell viability and mouse ontogeny. Proc Natl Acad Sci 97:5735–5739PubMedCrossRefGoogle Scholar
  50. Shen DL, Gloster TM, Yuzwa SA, Vocadlo DJ (2012) Insights into O-linked N-acetylglucosamine ([0-9]O-GlcNAc) processing and dynamics through kinetic analysis of O-GlcNAc transferase and O-GlcNAcase activity on protein substrates. J Biol Chem 287:15395–15408PubMedCrossRefGoogle Scholar
  51. Slawson C, Hart GW (2011) O-GlcNAc signalling: implications for cancer cell biology. Nat Rev Cancer 11:678–684PubMedCentralPubMedCrossRefGoogle Scholar
  52. Slawson C, Zachara NE, Vosseller K, Cheung WD, Lane MD, Hart GW (2005) Perturbations in O-linked β-N-Acetylglucosamine protein modification cause severe defects in mitotic progression and cytokinesis. J Biol Chem 280:32944–32956PubMedCrossRefGoogle Scholar
  53. Tanahashi E, Kiso M, Hasegawa A (1983) A facile synthesis of 2-acetamido-2-deoxy-5-thio-d-glucopyranose. Carbohydr Res 117:304–308CrossRefGoogle Scholar
  54. Torres CR, Hart GW (1984) Topography and polypeptide distribution of terminal N-acetylglucosamine residues on the surfaces of intact lymphocytes. Evidence for O-linked GlcNAc. J Biol Chem 259:3308–3317PubMedGoogle Scholar
  55. Tvaroška I, Kozmon S, Wimmerová M, Koča J (2012) Substrate-assisted catalytic mechanism of O-GlcNAc transferase discovered by quantum mechanics/molecular mechanics investigation. J Am Chem Soc 134:15563–15571PubMedCrossRefGoogle Scholar
  56. Wang Z, Gucek M, Hart GW (2008) Cross-talk between GlcNAcylation and phosphorylation: site-specific phosphorylation dynamics in response to globally elevated O-GlcNAc. Proc Natl Acad Sci 105:13793–13798PubMedCrossRefGoogle Scholar
  57. Wang Z, Udeshi ND, Slawson C, Compton PD, Sakabe K, Cheung WD, Shabanowitz J, Hunt DF, Hart GW (2010) Extensive crosstalk between O-GlcNAcylation and phosphorylation regulates cytokinesis. Sci Signal 3:ra2PubMedCentralPubMedGoogle Scholar
  58. Webster DM, Teo CF, Sun Y, Wloga D, Gay S et al (2009) O-GlcNAc modifications regulate cell survival and epiboly during zebrafish development. BMC Dev Biol 9:28PubMedCentralPubMedCrossRefGoogle Scholar
  59. Wells L, Vosseller K, Hart GW (2001) Glycosylation of nucleocytoplasmic proteins: signal transduction and O-GlcNAc. Science 291:2376–2378PubMedCrossRefGoogle Scholar
  60. Wells L, Kreppel LK, Comer FI, Wadzinski BE, Hart GW (2004) O-GlcNAc transferase is in a functional complex with protein phosphatase 1 catalytic subunits. J Biol Chem 279:38466–38470PubMedCrossRefGoogle Scholar
  61. Whelan SA, Lane MD, Hart GW (2008) Regulation of the O-linked β-N-acetylglucosamine transferase by insulin signaling. J Biol Chem 283:21411–21417PubMedCrossRefGoogle Scholar
  62. Whelan SA, Dias WB, Thiruneelakantapillai L, Lane MD, Hart GW (2010) Regulation of insulin receptor substrate 1 (IRS-1)/AKT kinase-mediated insulin signaling by O-Linked β-N-Acetylglucosamine in 3 T3-L1 adipocytes. J Biol Chem 285:5204–5211PubMedCrossRefGoogle Scholar
  63. Wrabl JO, Grishin NV (2001) Homology between O-linked GlcNAc transferases and proteins of the glycogen phosphorylase superfamily. J Mol Biol 314:365–374PubMedCrossRefGoogle Scholar
  64. Yang X, Ongusaha PP, Miles PD, Havstad JC, Zhang F, So WV, Kudlow JE, Michell RH, Olefsky JM, Field SJ, Evans RM (2008) Phosphoinositide signalling links O-GlcNAc transferase to insulin resistance. Nature 451:964–969PubMedCrossRefGoogle Scholar
  65. Yonghong Shi J, Tomic FW, Bahlo A, Harrison R, James Dennis R, Williams BJ, Gross SW, Zuccolo J, Deans JP, Hart GW, Spaner DE (2010) Aberrant O-GlcNAcylation characterizes chronic lymphocytic leukemia. Leukemia 24(9):1588–1598CrossRefGoogle Scholar
  66. Zeidan Q, Wang Z, De Maio A, Hart GW (2010) O-GlcNAc cycling enzymes associate with the translational machinery and modify core ribosomal proteins. Mol Biol Cell 21:1922–1936PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Springer Japan 2014

Authors and Affiliations

  1. 1.Department of Biological ChemistryJohns Hopkins School of MedicineBaltimoreUSA

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