The O-GlcNAc modification: Three-dimensional structure, enzymology and the development of selective inhibitors to probe disease

Biochemical Society Transactions

Volumn 38, Issue 5, 2010, Pages 1179-1188

  Davies, Gideon J ^a   Martinez Fleites, Carlos ^a  

^a UNIVERSITY OF YORK   (United Kingdom)

Author keywords

Carbohydrate active enzyme; Diabetes; Neurodegeneration; O linked N acetylglucosamine (O GlcNac); X ray structure

Indexed keywords

BETA N ACETYLGLUCOSAMINE; ENZYME; HYDROLASE; N ACETYLGLUCOSAMINE; STREPTOZOCIN; UNCLASSIFIED DRUG; ENZYME INHIBITOR; N ACETYLGLUCOSAMINYLTRANSFERASE;

DISEASE COURSE; ENZYME STRUCTURE; ENZYMOLOGY; GLYCOSYLATION; HUMAN; MOLECULAR PROBE; NERVE DEGENERATION; NON INSULIN DEPENDENT DIABETES MELLITUS; PRIORITY JOURNAL; PROTEIN MODIFICATION; REVIEW; THREE DIMENSIONAL IMAGING; ANIMAL; DEGENERATIVE DISEASE; DRUG ANTAGONISM; GENETICS; METABOLISM;

ACETYLGLUCOSAMINE; ANIMALS; DIABETES MELLITUS, TYPE 2; ENZYME INHIBITORS; HUMANS; N-ACETYLGLUCOSAMINYLTRANSFERASES; NEURODEGENERATIVE DISEASES;

EID: 77957269724     PISSN: 03005127     EISSN: 14708752     Source Type: Journal    
DOI: 10.1042/BST0381179     Document Type: Review

References (75)

1. Davies, G.J., Gloster, T.M. and Henrissat, B. (2005) Recent structural insights into the expanding world of carbohydrate-active enzymes. Curr. Opin. Struct. Biol. 15, 637-645
2. Sulzenbacher, G., Driguez, H., Henrissat, B., Schulein, M. and Davies, G.J. (1996) Structure of the Fusarium oxysporum endoglucanase I with a nonhydrolyzable substrate analogue: substrate distortion gives rise to the preferred axial orientation for the leaving group. Biochemistry 35, 15280-15287
3. Davies, G.J., Mackenzie, L., Varrot, A., Dauter, M., Brzozowski, A.M., Schulein, M. and Withers, S.G. (1998) Snapshots along an enzymatic reaction coordinate: analysis of a retaining β-glycoside hydrolase. Biochemistry 37, 11707-11713
4. Ducros, V., Zechel, D.L., Murshudov, G.N., Gilbert, H.J., Szabo, L., Stoll, D., Withers, S.G. and Davies, G.J. (2002) Substrate distortion by a β-mannanase: snapshots of the Michaelis and covalent intermediate complexes suggest a B2,5 conformation for the transition-state. Angew. Chem. Int. Ed. Engl. 41, 2824-2827
5. Varrot, A., Leydier, S., Pell, G., Macdonald, J.M., Stick, R.V., Gilbert, H.J. and Davies, G.J. (2005) Mycobacterium tuberculosis strains possess functional cellulases. J. Biol. Chem. 280, 20181-20184
6. Money, V.A., Smith, N.L., Scaffidi, A., Stick, R.V., Gilbert, H.J. and Davies, G.J. (2006) Substrate distortion by a lichenase highlights the different conformational itineraries harnessed by related glycoside hydrolases. Angew. Chem. Int. Ed. Engl. 45, 5136-5140
7. Cartmell, A., Topakas, E., Ducros, V.M.-A., Suits, M.D., Davies, G.J. and Gilbert, H.J. (2008) The Cellvibrio japonicus mannanase CjMan26c displays a unique exo-mode of action that is conferred by subtle changes to the distal region of the active site. J. Biol. Chem. 283, 34403-34413
8. Offen, W.A., Zechel, D.L., Withers, S.G., Gilbert, H.J. and Davies, G.J. (2009) Structure of the Michaelis complex of β-mannosidase, Man2A, provides insight into the conformational itinerary of mannoside hydrolysis. Chem. Commun., 2484-2486
9. Davies, G.J., Ducros, V.M.-A., Varrot, A. and Zechel, D.L. (2003) Mapping the conformational itinerary of β-glycosidases by X-ray crystallography. Biochem. Soc. Trans. 31, 523-527
10. Vocadlo, D. and Davies, G.J. (2008) Mechanistic insights into glycosidase chemistry. Curr. Opin. Chem. Biol. 12, 539-555
11. Gloster, T.M., Meloncelli, P., Stick, R., Zechel, D., Vasella, A. and Davies, G.J. (2007) Glycosidase inhibition: an assessment of the binding of eighteen putative transition-state mimics. J. Am. Chem. Soc. 129, 2345-2354
12. Tailford, L.N., Offen, W.A., Smith, N.L., Dumon, C., Morland, C., Gratien, J., Heck, M.-P., Stick, R.V., Blériot, Y., Vasella, A. et al. (2008) Structural and biochemical evidence for a boat-like transition state in β-mannosidases. Nat. Chem. Biol. 4, 306-312
13. Zhu, Y., Suits, M.D., Thompson, A.J., Chavan, S., Dinev, Z., Dumon, C., Smith, N., Moremen, K., Xiang, Y., Siriwardena, A. et al. (2010) Mechanistic insights into a calcium-dependent family of α-mannosidases in a human gut symbiont. Nat. Chem. Biol. 6, 125-132
14. Gloster, T.M. and Davies, G.J. (2010) Glycosidase inhibition: assessing mimicry of the transition state. Org. Biomol. Chem. 8, 305-320
15. Torres, C.R. and Hart, G.W. (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, 3308-3317
16. Hart, G.W., Housley, M.P. and Slawson, C. (2007) Cycling of O-linked β-N-acetylglucosamine on nucleocytoplasmic proteins. Nature 446, 1017-1022
17. Wells, L., Vosseller, K. and Hart, G.W. (2001) Glycosylation of nucleocytoplasmic proteins: signal transduction and O-GlcNAc. Science 291, 2376-2378
18. Butkinaree, C., Park, K. and Hart, G.W. (2010) O-linked β-N-acetylglucosamine (O-GlcNAc): extensive crosstalk with phosphorylation to regulate signaling and transcription in response to nutrients and stress. Biochim. Biophys. Acta 1800, 96-106
19. Manning, G., Whyte, D.B., Martinez, R., Hunter, T. and Sudarsanam, S. (2002) The protein kinase complement of the human genome. Science 298, 1912-1934
20. Hanover, J.A., Yu, S., Lubas, W.B., Shin, S.H., Ragano-Caracciola, M., Kochran, J. and Love, D.C. (2003) Mitochondrial and nucleocytoplasmic isoforms of O-linked GlcNAc transferase encoded by a single mammalian gene. Arch. Biochem. Biophys. 409, 287-297
21. Love, D.C., Kochan, J., Cathey, R.L., Shin, S.H. and Hanover, J.A. (2003) Mitochondrial and nucleocytoplasmic targeting of O-linked GlcNAc transferase. J. Cell Sci. 116, 647-654
22. Kreppel, L.K. and Hart, G.W. (1999) Regulation of a cytosolic and nuclear O-GlcNAc transferase: role of the tetratricopeptide repeats. J. Biol. Chem. 274, 32015-32022
23. Marshall, S., Bacote, V. and Traxinger, R.R. (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, 4706-4712
24. Hanover, J.A. (2001) Glycan-dependent signaling: O-linked N-acetylglucosamine. FASEB J. 15, 1865-1876
25. Akimoto, Y., Hart, G.W., Wells, L., Vosseller, K., Yamamoto, K., Munetomo, E., Ohara-Imaizumi, M., Nishiwaki, C., Nagamatsu, S., Hirano, H. and Kawakami, H. (2007) 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
26. Vosseller, K., Wells, L., Lane, M.D. and Hart, G.W. (2002) Elevated nucleocytoplasmic 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. 99, 5313-5318
27. Dentin, R., Hedrick, S., Xie, J.X., Yates, J. and Montminy, M. (2008) Hepatic glucose sensing via the CREB coactivator CRTC2. Science 319, 1402-1405
28. Yang, X.Y., Ongusaha, P.P., Miles, P.D., Havstad, J.C., Zhang, F.X., So, W.V., Kudlow, J.E., Michell, R.H., Olefsky, J.M., Field, S.J. and Evans, R.M. (2008) Phosphoinositide signalling links O-GlcNAc transferase to insulin resistance. Nature 451, 964-969
29. Knight, Z.A. and Shokat, K.M. (2005) Features of selective kinase inhibitors. Chem. Biol. 12, 621-637
30. Lubas, W.A. and Hanover, J.A. (2000) Functional expression of O-linked GlcNAc transferase: domain structure and substrate specificity. J. Biol. Chem. 275, 10983-10988
31. Iyer, S.P. and Hart, G.W. (2003) Roles of the tetratricopeptide repeat domain in O-GlcNAc transferase targeting and protein substrate specificity. J. Biol. Chem. 278, 24608-24616
32. Clarke, A.J., Hurtado-Guerrero, R., Pathak, S., Schuttelkopf, A.W., Borodkin, V., Shepherd, S.M., Ibrahim, A.F. and van Aalten, D.M. (2008) Structural insights into mechanism and specificity of O-GlcNAc transferase. EMBO J. 27, 2780-2788
33. Jinek, M., Rehwinkel, J., Lazarus, B.D., Izaurralde, E., Hanover, J.A. and Conti, E. (2004) The superhelical TPR-repeat domain of O-linked GlcNAc transferase exhibits structural similarities to importin α. Nat. Struct. Mol. Biol. 11, 1001-1007 (Pubitemid 39315305)
34. Conti, E., Uy, M., Leighton, L., Blobel, G. and Kuriyan, J. (1998) Crystallographic analysis of the recognition of a nuclear localization signal by the nuclear import factor karyopherin α. Cell 94, 193-204
35. Huber, A.H. and Weis, W.I. (2001) The structure of the β-catenin/E-cadherin complex and the molecular basis of diverse ligand recognition by β-catenin. Cell 105, 391-402
36. Martinez-Fleites, C., Macauley, M.S., He, Y., Shen, D.L., Vocadlo, D.J. and Davies, G.J. (2008) Structure of an O-GlcNAc transferase homolog provides insight into intracellular glycosylation. Nat. Struct. Mol. Biol. 15, 764-765
37. D'Andrea, L.D. and Regan, L. (2003) TPR proteins: the versatile helix. Trends Biochem. Sci. 28, 655-662
38. Lairson, L.L., Henrissat, B., Davies, G.J. and Withers, S.G. (2008) Glycosyltransferases: structures, functions, and mechanisms. Annu. Rev. Biochem. 77, 521-555
39. Coutinho, P.M., Deleury, E., Davies, G.J. and Henrissat, B. (2003) An evolving hierarchical family classification for glycosyltransferases. J. Mol. Biol. 328, 307-317
40. Gross, B.J., Kraybill, B.C. and Walker, S. (2005) Discovery of O-GlcNAc transferase inhibitors. J. Am. Chem. Soc. 127, 14588-14589
41. Toleman, C., Paterson, A.J., Whisenhunt, T.R. and Kudlow, J.E. (2004) Characterization of the histone acetyltransferase (HAT) domain of a bifunctional protein with activable O-GlcNAcase and HAT activities. J. Biol. Chem. 279, 53665-53673
42. Butkinaree, C., Cheung, W.D., Park, S., Park, K., Barber, M. and Hart, G.W. (2008) Characterization of β-N-acetylglucosaminidase cleavage by caspase-3 during apoptosis. J. Biol. Chem. 283, 23557-23566
43. Davies, G.J. and Sinnott, M.L. (2008) Sorting the diverse: the sequence-based classifications of carbohydrate-active enzymes. Biochem. J., doi:10.1042/BJ20080382
44. Cantarel, B.L., Coutinho, P.M., Rancurel, C., Bernard, T., Lombard, V. and Henrissat, B. (2009) The Carbohydrate-Active EnZymes database (CAZy): an expert resource for glycogenomics. Nucleic Acids Res. 37, D233-D238
45. Rao, F.V., Dorfmueller, H.C., Villa, F., Allwood, M., Eggleston, I.M. and van Aalten, D.M. (2006) Structural insights into the mechanism and inhibition of eukaryotic O-GlcNAc hydrolysis. EMBO J. 25, 1569-1578
46. Dennis, R.J., Taylor, E.J., Macauley, M.S., Stubbs, K.A., Turkenburg, J.P., Hart, S.J., Black, G.N., Vocadlo, D.J. and Davies, G.J. (2006) Structure and mechanism of a bacterial β-glucosaminidase having O-GlcNAcase activity. Nat. Struct. Mol. Biol. 13, 365-371
47. Martinez-Fleites, C., He, Y. and Davies, G.J. (2010) Structural analyses of enzymes involved in the O-GlcNAc modification. Biochim. Biophys. Acta 1800, 122-133
48. Pauling, L. (1946) Molecular architecture and biological reactions. Chem. Eng. News 24, 1375-1377
49. Macauley, M.S., Whitworth, G.E., Debowski, A.W., Chin, D. and Vocadlo, D.J. (2005) O-GlcNAcase uses substrate-assisted catalysis: kinetic analysis and development of highly selective mechanism-inspired inhibitors. J. Biol. Chem. 280, 25313-25322
50. 175 as the key catalytic residues of human O-GlcNAcase by functional analysis of site-directed mutants. Biochemistry 45, 3835-3844
51. Greig, I.R., Macauley, M.S., Williams, I.H. and Vocadlo, D.J. (2009) Probing synergy between two catalytic strategies in the glycoside hydrolase O-GlcNAcase using multiple linear free energy relationships. J. Am. Chem. Soc. 131, 13415-13422
52. He, Y., Macauley, M.S., Stubbs, K.A., Vocadlo, D.J. and Davies, G.J. (2010) Visualizing the reaction coordinate of an O-GlcNAc hydrolase. J. Am. Chem. Soc. 132, 1807-1809
53. Rempel, B.P. and Withers, S.G. (2008) Covalent inhibitors of glycosidases and their applications in biochemistry and biology. Glycobiology 18, 570-586
54. Whitworth, G.E., Macauley, M.S., Stubbs, K.A., Dennis, R.J., Taylor, E.J., Davies, G.J., Greig, I.R. and Vocadlo, D.J. (2007) Analysis of PUGNAc and NAG-thiazoline as transition state analogues for human O-GlcNAcase: structural and mechanistic insights into inhibitor selectivity and transition state poise. J. Am. Chem. Soc. 129, 635-644
55. Beer, D., Maloisel, J.L., Rast, D.M. and Vasella, A. (1990) Synthesis of 2-acetamido-2-deoxy-d-gluconhydroximolactone-derived and chitobionhydroximolactone-derived N-phenylcarbamates, potential inhibitors of β-N-acetylglucosaminidase. Helv. Chim. Acta 73, 1918-1922 (Pubitemid 20353197)
56. Macauley, M.S. and Vocadlo, D.J. (2010) Increasing O-GlcNAc levels: an overview of small-molecule inhibitors of O-GlcNAcase. Biochim. Biophys. Acta 1800, 107-121
57. Abbott, D.W., Macauley, M.S., Vocadlo, D.J. and Boraston, A.B. (2009) Streptococcus pneumoniae endohexosaminidase D: structural and mechanistic insight into substrate-assisted catalysis in family 85 glycoside hydrolases. J. Biol. Chem. 284, 11676-11689
58. Knapp, S., Vocadlo, D., Gao, Z.N., Kirk, B., Lou, J.P. and Withers, S.G. (1996) NAG-thiazoline, an N-acetyl-β-hexosaminidase inhibitor that implicates acetamido participation. J. Am. Chem. Soc. 118, 6804-6805
59. Mark, B.L., Mahuran, D.J., Cherney, M.M., Zhao, D., Knapp, S. and James, M.N. (2003) Crystal structure of human β-hexosaminidase B: understanding the molecular basis of Sandhoff and Tay-Sachs disease. J. Mol. Biol. 327, 1093-1109
60. M2 ganglioside hydrolysis. J. Mol. Biol. 359, 913-929
61. Dorfmueller, H.C., Borodkin, V.S., Schimpl, M., Shepherd, S.M., Shpiro, N.A. and van Aalten, D.M. (2006) GlcNAcstatin: a picomolar, selective O-GlcNAcase inhibitor that modulates intracellular O-GlcNAcylation levels. J. Am. Chem. Soc. 128, 16484-16485
62. Dorfmueller, H.C., Borodkin, V.S., Schimpl, M. and van Aalten, D.M. (2009) GlcNAcstatins are nanomolar inhibitors of human O-GlcNAcase inducing cellular hyper-O-GlcNAcylation. Biochem. J. 420, 221-227
63. Macauley, M.S., Bubb, A.K., Martinez-Fleites, C., Davies, G.J. and Vocadlo, D.J. (2008) 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
64. Wang, Z., Gucek, M. and Hart, G.W. (2008) Cross-talk between GlcNAcylation and phosphorylation: site-specific phosphorylation dynamics in response to globally elevated O-GlcNAc. Proc. Natl. Acad. Sci. U.S.A. 105, 13793-13798
65. Yuzwa, S.A., Macauley, M.S., Heinonen, J.E., Shan, X., Dennis, R.J., He, Y., Whitworth, G.E., Stubbs, K.A., McEachern, E.J., Davies, G.J. and Vocadlo, D.J. (2008) A potent mechanism-inspired O-GlcNAcase inhibitor that blocks phosphorylation of tau in vivo. Nat. Chem. Biol. 4, 483-490
66. Lee, V.M. Y., Goedert, M. and Trojanowski, J.Q. (2001) Neurodegenerative tauopathies. Annu. Rev. Neurosci. 24, 1121-1159
67. Liu, F., Shi, J.H., Tanimukai, H., Gu, J.H., Gu, J.L., Grundke-Iqbal, I., Iqbal, K. and Gong, C.X. (2009) Reduced O-GlcNAcylation links lower brain glucose metabolism and tau pathology in Alzheimer's disease. Brain 132, 1820-1832
68. Lefebvre, T., Dehennaut, V., Guinez, C., Olivier, S., Drougat, L., Mir, A.-M., Mortuaire, M., Vercoutter-Edouart, A.-S. and Michalski, J.-C. (2010) Dysregulation of the nutrient/stress sensor O-GlcNAcylation is involved in the etiology of cardiovascular disorders, type-2 diabetes and Alzheimer's disease. Biochim. Biophys. Acta 1800, 67-79
69. Liu, F., Iqbal, K., Grundke-Iqbal, I., Hart, G.W. and Gong, C.X. (2004) O-GlcNAcylation regulates phosphorylation of tau: a mechanism involved in Alzheimer's disease. Proc. Natl. Acad. Sci. U.S.A. 101, 10804-10809
70. Shafi, R., Lyer, S.P. N., Ellies, L.G., O'Donnell, N., Marek, K.W., Chui, D., Hart, G.W. and Marth, J.D. (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. U.S.A. 97, 5735-5739
71. Olszewski, N.E., West, C.M., Sassi, S.O. and Hartweck, L.M. (2010) O-GlcNAc protein modification in plants: evolution and function. Biochim. Biophys. Acta 1800, 49-56
72. Golks, A. and Guerini, D. (2008) The O-linked N-acetylglucosamine modification in cellular signalling and the immune system. EMBO Rep. 9, 748-753
73. Fujiki, R., Chikanishi, T., Hashiba, W., Ito, H., Takada, I., Roeder, R.G., Kitagawa, H. and Kato, S. (2009) GlcNAcylation of a histone methyltransferase in retinoic-acid-induced granulopoiesis. Nature 459, 455-459
74. Gambetta, M.C., Oktaba, K. and Muller, J. (2009) Essential role of the glycosyltransferase Sxc/Ogt in polycomb repression. Science 325, 93-96
75. Sinclair, D.A.R., Syrzycka, M., Macauley, M.S., Rastgardani, T., Komljenovic, I., Vocadlo, D.J., Brock, H.W. and Honda, B.M. (2009) Drosophila O-GlcNAc transferase (OGT) is encoded by the Polycomb group (PcG) gene, super sex combs (sxc). Proc. Natl. Acad. Sci. U.S.A. 106, 13427-13432