Protein O-GlcNAcylation in diabetes and diabetic complications

Expert Review of Proteomics

Volumn 10, Issue 4, 2013, Pages 365-380

  M a , Junfeng ^a   Hart, Gerald W ^a  

^a JOHNS HOPKINS UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

diabetes; diabetic complications; hyperglycemia; insulin resistance; O GlcNAc; O GlcNAcomics; proteomics

Indexed keywords

ACETYLATION; ACETYLGLUCOSAMINE; DIABETES MELLITUS; HUMANS; PROTEOME;

EID: 84894029904     PISSN: 14789450     EISSN: 17448387     Source Type: Journal    
DOI: 10.1586/14789450.2013.820536     Document Type: Review

References (153)

1. IDF Diabetes Atlas (5th Edition). International Diabetes Federation, Brussels, Belgium (2012).
2. Whiting DR, Guariguata L, Weil C, Shaw, J. IDF diabetes atlas: global estimates of the prevalence of diabetes for and 2030. Diabetes Res. Clin. Pract. 94, 311-321 (2011).
3. Daneman D. Type 1 diabetes. Lancet 367, 847-858 (2006).
4. Stumvoll M, Goldstein BJ, Haeften TW van, Type 2 diabetes: principles of pathogenesis and therapy. Lancet 365, 1333-1346 (2005).
5. DeFronzo RA. The triumvirate: (-cell muscle, liver: a collusion) responsible for NIDDM. Diabetes 37, 677-687 (1988).
6. Rossetti L, Giaccari A, DeFronzo RA. Glucose toxicity. Diabetes Care 13, 610-630 (1990).
7. Robertson RP, Harmon J, Tran PO et al. Glucose toxicity in beta-cells: Type 2 diabetes, good radicals gone bad, and the glutathione connection. Diabetes 52, 581-587 (2003).
8. Rossetti L, Smith D, Shulman GI et al. Correction of hyperglycemia with phlorizin normalizes tissue sensitivity to insulin in diabetic rats. J. Clin. Invest. 79, 1510-1515 (1987).
9. Garvey WT, Olefsky JM, Matthaei S et al. Glucose and insulin co-regulate the glucose transport system in primary cultured adipocytes. J. Biol. Chem. 262, 189-197 (1987).
10. Brownlee M. Biochemistry and molecular cell biology of diabetic complications. Nature 414, 813-820 (2001).
11. Brownlee M. The pathobiology of diabetic complications: a unifying mechanism. Diabetes 54, 1615-1625 (2005).
12. Torres CR, Hart GW. Topography and polypeptide distribution of terminal N-acetylglucosamine residues on the surfaces of intact lymphocytes. Evidence for O-linked GlcNAc. J. Biol. Chem. 259, 3308-3317 (1984).
13. Holt GD, Hart GW. The subcellular distribution of terminal N-acetylglucosamine moieties. Localization of a novel proteinsaccharide linkage, O-linked GlcNAc. J. Biol. Chem. 261, 8049-8057 (1986).
14. Hart GW, Slawson C, Ramirez Correa GA et al. Cross talk between GlcNAcylation and phosphorylation: Roles in signaling, transcription, and chronic disease. Annu. Rev. Biochem. 80, 825-858 (2011).
15. Bond MB, Hanover JA. O-GlcNAc Cycling: A link between metabolism and chronic disease. Annu. Rev. Nutr. 33, 13.1-13.25 (2013).
16. Marshall S, Bacote V, Traxinger RR. 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, 4706-4712 (1991).
17. Haltiwanger RS, Holt, GD, Hart GW. 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, 2563-2568 (1990).
18. Buse MG. Hexosamines, insulin resistance, and the complications of diabetes: current status. Am. J. Physiol. Endocrinol. Metab. 290, E1-E8 (2006).
19. Dias WB, Hart GW. O-GlcNAc modification in diabetes and Alzheimer's disease. Mol. Biosyst. 3, 766-772 (2007).
20. Copeland RJ, Bullen JW, Hart GW. Cross-talk between GlcNAcylation and phosphorylation: roles in insulin resistance and glucose toxicity. Am. J. Physiol. Endocrinol. Metab. 295, E17-E28 (2008).
21. Slawson C, Copeland RJ, Hart GW. O-GlcNAc signaling: a metabolic link between diabetes and cancer? Trends Biochem. Sci. 35, 547-555 (2010).
22. Konrad RJ, Zhang FX, Hale JE et al. Alloxan is an inhibitor of the enzyme O-linked N-acetylglucosamine transferase. Biochem. Biophys. Res. Commun. 293, 207-212 (2002).
23. Kang E-S, Han D, Park J et al. O-GlcNAc modulation at Akt1 Ser473 correlates with apoptosis of murine pancreatic beta cells. Exp. Cell Res. 314, 2238-2248 (2008).
24. Dorfmueller HC, Borodkin VS, Blair DE et al. Substrate and product analogues as human O-GlcNAc transferase inhibitors. Amino Acids. 40, 781-792 (2011).
25. Gloster TM, Zandberg WF, Heinonen JE et al. Hijacking a biosynthetic pathway yields a glycosyltransferase inhibitor within cells. Nat. Chem. Biol. 7, 174-181 (2011).
26. Haltiwanger RS, Grove K, Philipsberg GA. Modulation of O-linked N-acetylglucosamine levels on nuclear and cytoplasmic proteins in vivo using the peptide O-GlcNAc-beta-N-acetylglucosaminidase inhibitor O-(2-acetamido-2-deoxy- dgluco-pyranosylidene)amino-N-phenylcarbamate. J. Biol. Chem. 273, 3611-3617 (1998).
27. Macauley MS, Bubb AK, Martinez-Fleites C et al. Elevation of global O-GlcNAc levels in 3T3-L1 adipocytes by selective inhibition of O-GlcNAcase does not induce insulin resistance. J. Biol. Chem. 283, 34687-34695 (2008).
28. Yuzwa SA, Macauley MS, Heinonen JE et al. A potent mechanism-inspired O-GlcNAcase inhibitor that blocks phos-phorylation of tau in vivo. Nat. Chem. Biol. 4, 483-490 (2008).
29. Andres-Bergos J, Tardio L, Larranaga-Vera A et al. The increase in O-linked N-acetylglucosamine protein modification stimulates chondrogenic differentiation both in vitro and in vivo. J. Biol. Chem. 287, 33615-33628 (2012).
30. Macauley MS, He Y, Gloster TM et al. Inhibition of O-GlcNAcase using a potent and cell-permeable inhibitor does not induce insulin resistance in 3T3-L1 adipocytes. Chem. Biol. 17, 937-948 (2010).
31. Macauley MS, Shan X, Yuzwa SA et al. Elevation of global O-GlcNAc in rodents using a selective O-GlcNAcase inhibitor does not cause insulin resistance or perturb glucohomeostasis. Chem. Biol. 17, 949-958 (2010).
32. Dorfmueller HC, Borodkin VS, Schimpl M et al. Cell-penetrant, nanomolar O-GlcNAcase inhibitors selective against lysosomal hexosaminidases. Chem. Biol. 17, 1250-1255 (2010).
33. Reed MJ, Meszaros K, Entes LJ et al. A new rat model of Type 2 diabetes: The fat-fed, streptozotocin-treated rat. Metabolism 49, 1390-1394 (2000).
34. Roos MD, Xie W, Su K et al. Streptozotocin, an analog of N-acetylglucosamine, blocks the removal of O-GlcNAc from intracellular proteins. Proc. Assoc. Am. Physicians. 110, 422-432 (1998).
35. O'Donnell N, Zachara NE, Hart GW et al. Ogt-dependent X-chromosome-linked protein glycosylation is a requisite modifi-cation in somatic cell function and embryo viability. Mol. Cell Biol. 24, 1680-1690 (2004).
36. Watson LJ, Facundo HT, Ngoh GA et al. O-linked -N-acetyl-glucosamine transferase is indispensable in the failing heart. Proc. Natl Acad. Sci. USA 107, 17797-17802 (2010).
37. Hanover JA, Forsythe ME, Hennessey PT et al. A Caenorhabditis elegans model of insulin resistance: altered macronutrient storage and dauer formation in an OGT-1 knockout. Proc. Natl Acad. Sci . USA 102, 11266-11271 (2005).
38. Mondoux MA, Love DC, Ghosh SK et al. O-Linked-N-Acetylglucosamine cycling and insulin signaling are required for the glucose stress response in Caenorhabditis elegans. Genetics 188, 369-382 (2011).
39. Sinclair DAR, Syrzycka M, Macauley MS et al. Drosophila O-GlcNAc transferase (OGT) is encoded by the Polycomb group (PcG) gene, super sex combs (sxc). Proc. Natl Acad. Sci. USA 106, 13427-13432 (2009).
40. Sekine O, Love DC, Rubenstein DS et al. Blocking O-linked GlcNAc cycling in Drosophila insulin-producing cells perturbs glucose-insulin homeostasis. J. Biol. Chem. 285, 38684-38691 (2010).
41. Oki T, Yamazaki K, Kuromitsu J et al. cDNA cloning and mapping of a novel subtype of glutamine:fructose-6-phosphate amido-transferase (GFAT2) in human and mouse. Genomics 57, 227-234 (1999).
42. DeHaven JE, Robinson KA, Nelson BA et al. A novel variant of glutamine: fructose-6-phosphate amidotransferase-1 (GFAT1) mRNA is selectively expressed in striated muscle. Diabetes 50, 2419-2424 (2001).
43. Zhou J, Huynh QK, Hoffman RT et al. Regulation of glutamine:fructose-6- phosphate amidotransferase by cAMP-dependent protein kinase. Diabetes 47, 1836-1840 (1998).
44. Chang Q, Su K, Baker JR et al. Phosphorylation of human glutamine:fructose-6-phosphate amidotransferase by cAMPdependent protein kinase at serine 205 blocks the enzyme activity. J. Biol. Chem. 275, 21981-21987 (2000).
45. Li Y, Roux C, Lazereg S et al. Identification of a novel serine phosphorylation site in human glutamine:fructose-6-phosphate amidotransferase isoform 1. Biochemistry 46, 13163-13169 (2007).
46. Broschat KO, Gorka C, Page JD et al. Kinetic characterization of human glutamine-fructose-6-phosphate amidotransferase I: potent feedback inhibition by glucosamine 6-phosphate. J. Biol. Chem. 277, 14764-14770 (2002).
47. Kornfeld R. Studies on L-glutamine D-fructose 6-phosphate amidotransferase. I. Feedback inhibition by uridine diphosphate-N- acetylglucosamine. J. Biol. Chem. 242, 3135-3141 (1967).
48. Henry RR, Wallace P, Olefsky JM. Effects of weight loss on mechanisms of hyperglycemia in obese non-insulin dependent diabetes mellitus. Diabetes 35, 990-998 (1986).
49. Yki-Jarvinen H, Helve E, Koivisto VA. Hyperglycemia decreases glucose uptake in Type 1 diabetes. Diabetes 36, 892-896 (1987).
50. Kahn B, Schulman GI, DeFronzo RA et al. Normalization of blood glucose in diabetic rats with phlorizin treatment reverses insulin-resistant glucose transport in adipose cells without restoring glucose transporter gene expression. J. Clin. Invest. 87, 561-570 (1991).
51. McClain DA, Lubas WA, Cooksey RC et al. Altered glycan-dependent signaling induces insulin resistance and hyper-leptinemia. Proc. Natl Acad. Sci. USA 99, 10695-10699 (2002).
52. Herbert L, Daniels M, Zhou J et al. Over-expression of glutamine:fructose-6-phosphate amidotransferase in transgenic mice leads to insulin resistance. J. Clin. Invest. 98, 930-936 (1996).
53. Yki-Jarvinen H, Virkamaki A, Daniels MD et al. Insulin and glucosamine infusions increase O-linked N-acetylglucosamine in skeletal muscle proteins in vivo. Metabolism 47, 449-455 (1998).
54. Manning G, Whyte DB, Martinez R et al. The protein kinase complement of the human genome. Science 298, 1912-1934 (2002).
55. Muller U, Steinberger D, Nemeth AH. Clinical and molecular genetics of primary dystonias. Neurogenetics 1, 165-177 (1998).
56. Lubas WA, Frank DW, Krause M et al. O-linked GlcNAc transferase is a conserved nucleocytoplasmic protein containing tetratricopeptide repeats. J. Biol. Chem. 272, 9316-9324 (1997).
57. Jacobsen SE, Binkowski KA, Olszewski NE. SPINDLY, a tetratricopeptide repeat protein involved in gibberellin signal transduction in Arabidopsis. Proc. Natl Acad. Sci. USA 93, 9292-9296 (1996).
58. Hanover JA, Yu S, Lubas WB et al. Mitochondrial and nucleocytoplasmic isoforms of O-linked GlcNAc transferase encoded by a single mammalian gene. Arch. Biochem. Biophys 409, 287-297 (2003).
59. Lazarus MB, Yunsun Nam, Jiang J et al. Structure of human O-GlcNAc transferase and its complex with a peptide substrate. Nature 469, 564-568 (2011).
60. Jinek M, Rehwinkel J, Lazarus BD et al. The superhelical TPR-repeat domain of O-linked GlcNAc transferase exhibits structural similarities to importin alpha. Nat. Struct. Mol. Biol. 11, 1001-1007 (2004).
61. Kreppel LK, Hart GW. Regulation of a cytosolic and nuclear O-GlcNAc transferase. Role of the tetratricopeptide repeats. J. Biol. Chem. 274, 32015-32022 (1999).
62. Haltiwanger RS, Blomberg MA, Hart GW. Glycosylation of nuclear and cytoplasmic proteins. Purification and characterization of a uridine diphospho-Nacetylglucosamine: polypeptide beta-Nacetylglucosaminyltransferase. J. Biol. Chem. 267, 9005-9013 (1992).
63. Lazarus MB, Jiang J, Gloster TM, et al. Structural snapshots of the reaction coordinate for O-GlcNAc transferase. Nat. Chem. Biol. 8, 966-968 (2012).
64. Schimpl M, Zheng X, Borodkin VS et al. O-GlcNAc transferase invokes nucleotide sugar pyrophosphate participation in catalysis. Nat. Chem. Biol. 8, 969-974 (2012).
65. Hart GW, Akimoto Y. The O-GlcNAc modification. In: Essentials of Glycobiology (2nd Edition). Varki ACR, Esko JD, Freeze HH, Stanley P, Bertozzi CR, Hart GW, Etzler ME (Eds). Cold Spring Harbor Laboratory Press, Cold Spring, Harbor NY, USA (2009).
66. Kreppel LK, Blomberg MA, Hart GW. Dynamic glycosylation of nuclear and cytosolic proteins. Cloning and characterization of a unique O-GlcNAc transferase with multiple tetratricopeptide repeats. J. Biol. Chem. 272, 9308-9315 (1997).
67. Whelan SA, Lane DM, Hart GW. Regulation of the O-GlcNAc transferase by insulin signaling. J. Biol. Chem. 283, 21411-21417 (2008).
68. Akimoto Y, Hart GW, Wells L et al. Elevation of the post-translational modification of proteins by O-linked N-acetylglucosamine leads to deterioration of the glucose-stimulated insulin secretion in the pancreas of diabetic Goto-Kakizaki rats. Glycobiology 17, 127-140 (2007).
69. Yang X, Ongusaha P, Miles P et al. Phosphoinositide signaling links O-GlcNAc transferase to insulin resistance. Nature 451, 964-970 (2008).
70. Clark RJ, McDonough PM, Swanson E et al. Diabetes and the accompanying hyperglycemia impairs cardiomyocyte calcium cycling through increased nuclear GlcNAcylation. J. Biol. Chem. 278, 44230-44237 (2003).
71. Lenzen S, Munday R. Thiol-group reactivity, hydrophilicity and stability of alloxan, its reduction products and its N-methyl derivatives and a comparison with ninhydrin. Biochem. Pharmacol. 42, 1385-1391 (1991).
72. Robinson KA, Ball LE, Buse MG. Reduction of O-GlcNAc protein modification does not prevent insulin resistance in 3T3-L1 adipocytes. Am. J. Physiol. Endocrinol. Metab. 292, E884-E890 (2007).
73. Shafi R, Lyer SP, Ellies LG et al. 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. USA 97, 5735-5739 (2000).
74. Kazemi Z, Chang H, Haserodt S et al. O-Linked Beta-N-acetylglucosamine (O-GlcNAc) regulates stress-induced heat shock protein expression in a GSK-3-dependent manner. J. Biol. Chem. 285, 39096-39107 (2010).
75. de la Monte SM, Tong M, Lester-Coll N et al. Therapeutic rescue of neurodegeneration in experimental Type 3 diabetes: relevance to Alzheimer's disease. J. Alzheimers Dis. 10, 89-109 (2006).
76. Butkinaree C, Cheung WD, Park S et al. Characterization of beta-N-acetylglucosaminidase cleavage by caspase-3 during apoptosis. J. Biol. Chem. 283, 23557-23566 (2008).
77. Comtesse N, Maldener E, Meese E. Identification of a nuclear variant of MGEA5, a cytoplasmic hyaluronidase and a beta-N-acetylglucosaminidase. Biochem. Biophys. Res. Commun. 283, 634-640 (2001).
78. Soesant Y, Luo B, Parker G et al. Pleiotropic and age-dependent effects of decreased protein modification by O-Linked N-acetylglucosamine on pancreatic beta-cell function and vascularization. J. Biol. Chem. 286, 26118-26126 (2011).
79. Dentin R, Hedrick S, Xie J et al. Hepatic glucose sensing via the CREB coactivator CRTC2. Science 319, 1402-1405 (2008).
80. Soesanto YA, Luo B, Jones D et al. Regulation of Akt signaling by O-GlcNAc in euglycemia. Am. J. Physiol. Endocrinol. Metab. 295, E974-E980 (2008).
81. Hu Y, Belke D, Suarez J et al. Adenovirusmediated over-expression of O-GlcNAcase improves contractile function in the diabetic heart. Circ. Res. 96, 1006-1013 (2005).
82. Forsythe ME, Love DC, Lazarus BD et al. Caenorhabditis elegans ortholog of a diabetes susceptibility locus: oga-1 (O-GlcNAcase) knockout impacts O-GlcNAc cycling, metabolism, and dauer. Proc. Natl Acad. Sci. USA 103, 11952-11957 (2006).
83. Vosseller K, Wells L, Lane MD et al. Elevated nucleocytoplasmic glycosylation by O-GlcNAc results in insulin resistance associated with defects in Akt activation in 3T3-L1 adipocytes. Proc. Natl Acad. Sci. USA 99, 5313-5318 (2002).
84. Arias EB, Kim J, Cartee GD. Prolonged incubation in PUGNAc results in increased protein O-Linked glycosylation and insulin resistance in rat skeletal muscle. Diabetes 53, 921-930 (2004).
85. Issad T, Kuo M. O-GlcNAc modification of transcription factors, glucose sensing and glucotoxicity. Trends Endocrinol Metab. 19, 380-389 (2008).
86. Ozcan S, Andrali SS, Cantrell, J.E. Modulation of transcription factor function by O-GlcNAc modification. Biochim. Biophys. Acta 1799, 353-364 (2010).
87. Slawson C, Hart GW. O-GlcNAc signalling: implications for cancer cell biology. Nat. Rev. Cancer 11, 678-684 (2011).
88. Liu K, Paterson AJ, Chin E et al. Glucose stimulates protein modification by O-linked GlcNAc in pancreatic b cells: Linkage of O-linked GlcNAc to beta cell death. Proc. Natl Acad. Sci. USA 97, 2820-2825 (2000).
89. Andrali SS, Qian Q, Ozcan S. Glucose mediates the translocation of NeuroD1 by O-linked glycosylation. J. Biol. Chem. 282, 15589-15596 (2007).
90. Gao Y, Miyazaki J, Hart GW. The transcription factor PDX-1 is posttranslationally modified by O-linked N-acetylglucosamine and this modification is correlated with its DNA binding activity and insulin secretion in min6 beta-cells. Arch. Biochem. Biophys. 415,155-163 (2003).
91. Kebede M, Ferdaoussi M, Mancini A et al. Glucose activates free fatty acid receptor 1 gene transcription via phosphatidylinositol-3-kinase-dependent O-GlcNAcylation of pancreas-duodenum homeobox-1. Proc. Natl Acad. Sci. USA 109, 2376-2381 (2012).
92. Whelan SA, Dias WB, Lakshmanan T et al. Regulation of insulin receptor substrate 1 (IRS-1)/AKT kinase-mediated insulin signaling by O-linked beta-Nacetylglucosamine in 3T3-L1 adipocytes. J. Biol. Chem. 285, 5204-5211 (2010).
93. Parker GJ, Lund KP, Taylor RP et al. Insulin resistance of glycogen synthase mediated by O-linked N-acetylglucosamine. J. Biol. Chem. 278, 10022-10027 (2003).
94. Teo CF, Wollaston-Hayden EE, Wells L. Hexosamine flux, the O-GlcNAc modification, and the development of insulin resistance in adipocytes. Mol. Cell. Endocrinol. 318, 44-53 (2010).
95. Housley MP, Rodgers JT, Udeshi ND et al. O-GlcNAc regulates FoxO activation in response to glucose. J. Biol. Chem. 283, 16283-16292 (2008).
96. Housley MP, Udeshi ND, Rodgers JT et al. A PGC-1alpha-O-GlcNAc transferase complex regulates FoxO transcription factor activity in response to glucose. J. Biol. Chem. 284, 5148-5157 (2009).
97. Ruan H, Han X, Li M et al. O-GlcNAc Transferase/host cell factor C1 complex regulates gluconeogenesis by modulating PGC-1a stability. Cell Metab. 16, 226-237 (2012).
98. Guinez C, Filhoulaud G, Rayah-Benhamed F et al. O-GlcNAcylation increases ChREBP protein content and trans-criptional activity in the liver. Diabetes 60, 1399-1413 (2011).
99. Anthonisen EH, Berven L, Holm S et al. Nuclear receptor liver X receptor is O-GlcNAc-modified in response to glucose. J. Biol. Chem. 285, 1607-1615 (2010).
100. Arias EB, Cartee GD. Relationship between protein O-linked glycosylation and insulin-stimulated glucose transport in rat skeletal muscle following calorie restriction or exposure to O-(2-acetamido-2-deoxy-d-glucopyranosylidene) amino-Nphenylcarba-mate. Acta Physiol. Scand. 183, 281-289 (2005).
101. Walgren JL, Vincent TS, Schey KL et al. High glucose and insulin promote O-GlcNAc modification of proteins, including alpha-tubulin. Am. J. Physiol. Endocrinol. Metab. 284, E424-E434 (2003).
102. Hedou J, Cieniewski-Bernard C, Leroy Y et al. O-linked N-acetylglucosaminylation is involved in the Ca2+ activation properties of rat skeletal muscle. J. Biol. Chem. 282, 10360-10369 (2007).
103. Hedou J, Bastide B, Page A et al. Mapping of O-linked beta-N-acetylglucosamine modification sites in key contractile proteins of rat skeletal muscle. Proteomics 9, 2139-2148 (2009.)
104. Fulop N, Marchase RB, Chatham JC. Role of protein O-linked N-acetyl-glucosamine in mediating cell function and survival in the cardiovascular system. Cardiovasc. Res. 73, 288-297 (2007).
105. Laczy B, Hill BG, Wang K et al. Protein O-GlcNAcylation: a new signaling paradigm for the cardiovascular system. Am. J. Physiol. Heart Circ. Physiol. 296, H13-H28 (2009).
106. Ngoh GA, Facundo HT, Zafir A et al. O-GlcNAc Signaling in the Cardiovascular System. Circ. Res. 107, 171-185 (2010).
107. Zachara NE. The roles of O-linked -N-acetylglucosamine in cardiovascular physiology and disease. Am. J. Physiol. Heart Circ. Physiol. 302, H1905-H1918 (2012).
108. Jones SP, Zachara NE, Ngoh GA et al. Cardioprotection by N-acetylglucosamine linkage to cellular proteins. Circulation 117, 1172-1182 (2008).
109. Ngoh GA, Watson LJ, Facundo HT et al. Noncanonical glycosyltransferase modulates post-hypoxic cardiac myocyte death and mitochondrial permeability transition. J. Mol. Cell. Cardiol. 45, 313-325 (2008).
110. Hu Y, Suarez J, Fricovsky E et al. Increased enzymatic O-GlcNAcylation of mitochondrial proteins impairs mitochondrial function in cardiac myocytes exposed to high glucose. J. Biol. Chem. 284, 547-555 (2009).
111. Johnsen VL, Belke DD, Hughey CC, et al. Enhanced cardiac protein glycosylation (O-GlcNAc) of selected mitochondrial proteins in rats artificially selected for low running capacity. Physiol. Genomics 45, 17-25 (2013).
112. Ramirez-Correa GA, Jin W, Wang Z et al. O-linked GlcNAc modification of cardiac myofilament proteins: a novel regulator of myocardial contractile function. Circ. Res. 103, 1354-1358 (2008).
113. Goldberg H, Whiteside C, Fantus I. O-linked beta-N-acetylgluco-samine supports p38 MAPK activation by high glucose in glomerular mesangial cells. Am. J. Physiol. Endocrinol. Metab. 301, E713-E726 (2011).
114. Yao D, Taguchi T, Matsumura T et al. High glucose increases angiopoietin-2 transcription in microvascular endothelial cells through methylglyoxal modification of mSin3A. J. Biol. Chem. 282, 31038-31045 (2007).
115. James LR, Tang D, Ingram A et al. Flux through the hexosamine pathway is a determinant of nuclear factor kappaBdependent promoter activation. Diabetes 51, 1146-1156 (2002).
116. Yang WH, Park SY, Nam HW et al. NF-kappaB activation is associated with its O-GlcNAcylation state under hyperglycemic conditions. Proc. Natl Acad. Sci. USA 105, 17345-17350 (2008).
117. Allison DF, Wamsley JJ, Kumar M et al. Modification of RelA by O-linked N-acetylglucosamine links glucose metabolism to NF-B acetylation and transcription. Proc. Natl Acad. Sci. USA 94, 2927-2932 (2012).
118. Du XL, Edelstein D, Rossetti L et al. Hyperglycemia-induced mitochondrial superoxide overproduction activates the hexosamine pathway and induces plasminogen activator inhibitor-1 expression by increasing Sp1 glycosylation. Proc. Natl Acad. Sci. USA 97, 12222-12226 (2000).
119. Du XL, Edelstein D, Dimmeler S et al. Hyperglycemia inhibits endothelial nitric oxide synthase activity by posttranslational modification at the Akt site. J. Clin. Invest. 108, 1341-1348 (2001).
120. Musicki B, Kramer MF, Becker RE et al. Inactivation of phosphorylated endothelial nitric oxide synthase (Ser-1177) by O-GlcNAc in diabetes-associated erectile dysfunction. Proc. Natl Acad. Sci. USA 102, 11870-11875 (2005).
121. Wang Z, Park K, Comer F et al. Site-specific GlcNAcylation of human erythrocyte proteins: potential biomarker(s) for diabetes. Diabetes 58, 309-317 (2009).
122. Hu P, Shimoji S, Hart GW. Site-specific interplay between O-GlcNAcylation and phosphorylation in cellular regulation. FEBS Lett. 584, 2526-2538 (2010).
123. Butkinaree C, Park K, Hart GW. O-linked N-acetylglucosamine (O-GlcNAc): Extensive crosstalk with phosphorylation to regulate signaling and transcription in response to nutrients and stress. Biochem. Biophys. Acta 1800, 96-106 (2010).
124. Zeidan Q, Hart GW. The intersections between O-GlcNAcylation and phosphorylation: implications for multiple signaling pathways. J. Cell Sci. 123:13-22 (2010).
125. Ande SR, Moulik S, Mishra S. Interaction between O-GlcNAc modification and tyrosine phosphorylation of prohibitin: Implication for a novel binary switch. PLoS One 4, e4586 (2009).
126. Sakabe K, Hart GW. O-GlcNAc transferase regulates mitotic chromatin dynamics. J. Biol. Chem. 285, 34460-34468 (2010).
127. Sakabe K, Wang Z, Hart GW. ?-Nacetylglucosamine (O-GlcNAc) is part of the histone code. Proc. Natl Acad. Sci. USA 107, 19915-19920 (2010).
128. Fujiki R, Hashiba W, Sekine H et al. GlcNAcylation of histone H2B facilitates its monoubiquitination. Nature 480, 557-560 (2011).
129. Comer FI, Vosseller K, Wells L et al. Characterization of a mouse monoclonal antibody specific for O-linked N-acetylglucosamine. Anal. Biochem. 293, 169-177 (2001).
130. Snow CM, Senior A, Gerace L. Monoclonal antibodies identify a group of nuclear pore complex glycoproteins. J. Cell Biol. 104, 1143-1156 (1987).
131. Wang J, Torij M, Liu H et al. dbOGAP-an integrated bio-informatics resource for protein O-GlcNAcylation. BMC Bioinformatics. 12, 91 (2011).
132. Syka JE, Coon JJ, Schroeder MJ et al. Peptide and protein sequence analysis by electron transfer dissociation mass spectrometry. Proc. Natl Acad. Sci. USA 101, 9528-9533 (2004).
133. Wells L, Vosseller K, Cole RN et al. Mapping sites of O-GlcNAc modification using affinity tags for serine and threonine post-translational modifications. Mol. Cell Proteomics 1, 791-804 (2002).
134. Vosseller K, Hansen KC, Chalkley RJ et al. Quantitative analysis of both protein expression and serine/threonine post-translational modifications through stable isotope labeling with dithiothreitol. Proteomics 5, 388-398 (2005).
135. Overath T, Kuckelkorn U, Henklein P et al. Mapping of O-GlcNAc sites of 20S proteasome subunits and Hsp90 by a novel biotin-cystamine tag. Mol. Cell Proteomics 11, 467-477 (2012).
136. Hahne H, Moghaddas-Gholami A, Kuster B. Discovery of O-GlcNAc-modified proteins in published large-scale proteome data. Mol. Cell Proteomics 11, 843-850 (2012).
137. Teo CF, Ingale S, Wolfert M et al. Glycopeptide-specific mono-clonal antibodies suggest new roles for O-GlcNAc. Nat. Chem. Biol. 6, 338-343 (2010).
138. Zhao P, Viner R, Teo CF et al. Combining high-energy C-trap dissociation and electron transfer dissociation for protein O-GlcNAc modification site assignment. J. Proteome Res. 10, 4088-4104 (2011).
139. Kelly WG, Hart GW. Glycosylation of chromosomal proteins: localization of O-linked N-acetylglucosamine in Drosophila chromatin. Cell 57, 243-251 (1989).
140. Chalkley RJ, Thalhammer A, Schoepfer R et al. Identification of protein O-GlcNAcylation sites using electron transfer dissociation mass spectrometry on native peptides. Proc. Natl Acad. Sci. USA 106, 8894-8899 (2009).
141. Trinidad JC, Barkan DT, Gulledge BF et al. Global identification and characterization of both O-GlcNAcylation and phosphory-lation at the murine synapse. Mol. Cell Proteomics 11, 215-229 (2012).
142. Khidekel N, Ficarro SB, Clark MC et al. Probing the dynamics of O-GlcNAc glycosylation in the brain using quantitative proteomics. Nat. Chem. Biol. 3, 339-348 (2007).
143. Wang Z, Udeshi ND, O'Malley M et al. Enrichment and sitemapping of O-linked N-acetylglucosamine by a combination of chemical/enzymatic tagging, photochemical cleavage, and electron transfer dissociation mass spectrometry. Mol. Cell Proteomics 9, 153-160 (2010).
144. Alfaro JF, Gong CX, Monroe ME et al. Tandem mass spectrometry identifies many mouse brain O-GlcNAcylated proteins including EGF domain-specific O-GlcNAc transferase targets. Proc. Natl Acad. Sci. USA 109, 7280-7285 (2012).
145. Wang Z, Udeshi ND, Slawson C et al. Extensive crosstalk between O-GlcNAcylation and phosphorylation regulates cytokinesis. Sci. Signal. 3, ra2 (2010).
146. Vocadlo DJ, Hang HC, Kim EJ et al. A chemical approach for identifying O-GlcNAc-modified proteins in cells. Proc. Natl Acad. Sci. USA 100, 9116-9121 (2003).
147. Nandi A, Sprung R, Barma DK et al. Global identification of O-GlcNAc-modified proteins. Anal. Chem. 78, 452-458 (2006).
148. Zaro BW, Yang YY, Hang HC et al. Chemical reporters for fluorescent detection and identification of O-GlcNAc-modified proteins reveal glycosylation of the ubiquitin ligase NEDD4-1. Proc. Natl Acad. Sci. USA 108, 8146-8151 (2011).
149. Hahne H, Sobotzki N, Tamara N et al. Proteome wide purification and identification of O-GlcNAc-modified proteins using click chemistry and mass spectrometry. J. Proteome Res. 12 (2), 927-936 (2013).
150. Choudhary C, Mann M. Decoding signaling networks by mass spectrometrybased proteomics. Nat. Rev. Mol. Cell Bio. 11, 427-439 (2010).
151. Topf F, Schvartz D, Gaudet P et al. The Human Diabetes Proteome Project (HDPP): from network biology to targets for therapies and prevention. Transl. Proteomics 1, 3-11 (2013).
152. Park K, Saudek CD, Hart GW et al. Increased expression of beta-N-acetylglucosaminidase in erythrocytes from individuals with pre-diabetes and diabetes. Diabetes 59, 1845-1850 (2010).
153. Springhorn C, Matsha TE, Erasmus RT et al. Exploring leukocyte O-GlcNAcylation as a novel diagnostic tool for the earlier detection of Type 2 diabetes mellitus. J. Clin. Endocrinol. Metab. 97, 4640-4649 (2012).