Abstract
In animals, cellular and physiological responses to oxygen level variations are regulated via the post-translational modification of the heterodimeric hypoxia-inducible transcription factor (HIF). Hydroxylation of the HIF-α subunit at either of two conserved prolyl residues enables binding to the von Hippel-Lindau protein (pVHL) elongin C/B complex (VCB) which targets HIF-α for degradation via the ubiquitin proteasome pathway. Hydroxylation of an asparaginyl residue in the C-terminal transcriptional activation domain of HIF-α reduces its interaction with the transcriptional coactivator p300. Thus, post-translational hydroxylation is used both to "make" (HIF-VCB) and "break" (HIF-p300) protein-protein interactions in the hypoxic response. The requirement for oxygen of the HIF prolyl and asparaginyl hydroxylases in catalysis links changes in oxygen concentration and transcription of the gene array that enables cells to adapt to hypoxia. All four identified human HIF hydroxylases are members of the Fe(II) and 2-oxoglutarate (2OG)-dependent family of oxygenases. Inhibition of HIF hydroxylases mimics the hypoxic response resulting in the upregulation of erythropoietin (EPO), vascular endothelial growth factor (VEGF), and other proteins of biomedicinal importance. We briefly review biochemical analyses on the HIF hydroxylases and discuss how their structural and mechanistic characteristics may make them suited to their oxygen-sensing role.
Conference
CHEM-BIO-TECH-2007, a joint meeting of the IUPAC 1st Symposium on Chemical Biotechnology (ISCB-1) and the 8th Symposium on Bioorganic Chemistry (ISBOC-8), International Symposium on Bioorganic Chemistry, ISBOC, Bioorganic Chemistry, Turin, Italy, 2007-08-08–2007-08-11
References
1. doi:10.1073/pnas.92.12.5510, G. L. Wang, B. H. Jiang, E. A. Rue, G. L. Semenza. Proc. Natl. Acad. Sci. USA 92, 5510 (1995).Search in Google Scholar
2. doi:10.1073/pnas.88.13.5680, G. L. Semenza, M. K. Nejfelt, S. M. Chi, S. E. Antonarakis. Proc. Natl. Acad. Sci. USA 88, 5680 (1991).Search in Google Scholar
3. doi:10.1124/mol.106.027029, Q. Ke, M. Costa. Mol. Pharmacol. 70, 1469 (2006).Search in Google Scholar
4. doi:10.1016/j.bbrc.2005.08.165, W. G. Kaelin Jr. Biochem. Biophys. Res. Commun. 338, 627 (2005).Search in Google Scholar
5. doi:10.1038/nrm1366, C. J. Schofield, P. J. Ratcliffe. Nat. Rev. Mol. Cell. Biol. 5, 343 (2004).Search in Google Scholar
6. doi:10.1152/physiol.00001.2004, G. L. Semenza. Physiology (Bethesda) 19, 176 (2004).Search in Google Scholar
7. doi:10.1126/science.1059817, M. Ivan, K. Kondo, H. F. Yang, W. Kim, J. Valiando, M. Ohh, A. Salic, J. M. Asara, W. S. Lane, W. G. Kaelin. Science 292, 464 (2001).Search in Google Scholar
8. doi:10.1126/science.1059796, P. Jaakkola, D. R. Mole, Y. M. Tian, M. I. Wilson, J. Gielbert, S. J. Gaskell, A. von Kriegsheim, H. F. Hebestreit, M. Mukherji, C. J. Schofield, P. H. Maxwell, C. W. Pugh, P. J. Ratcliffe. Science 292, 468 (2001).Search in Google Scholar
9. doi:10.1126/science.1068592, D. Lando, D. J. Peet, D. A. Whelan, J. J. Gorman and M. L. Whitelaw. Science 295, 858 (2002).Search in Google Scholar
10. doi:10.1016/S1359-6446(04)03202-7, K. S. Hewitson, C. J. Schofield. Drug Discov. Today 9, 704 (2004).Search in Google Scholar
11. doi:10.1016/j.bcp.2006.10.013, M. C. Brahimi-Horn, J. Pouyssegur. Biochem. Pharmacol. 73, 450 (2007).Search in Google Scholar
12. doi:10.1517/14728222.10.2.267, G. L. Semenza. Expert Opin. Ther. Targets 10, 267 (2006).Search in Google Scholar
13. doi:10.1042/BSE0430001, M. L. Coleman, P. J. Ratcliffe. Essays Biochem. 43, 1 (2007).Search in Google Scholar
14. doi:10.1515/BC.2004.016, E. Metzen, P. J. Ratcliffe. Biol. Chem. 385, 223 (2004).Search in Google Scholar
15. doi:10.1038/nchembio863, A. Ozer, R. K. Bruick. Nat. Chem. Biol. 3, 144 (2007).Search in Google Scholar
16. doi:10.1073/pnas.94.9.4273, M. Ema, S. Taya, N. Yokotani, K. Sogawa, Y. Matsuda, Y. Fujii-Kuriyama. Proc. Natl. Acad. Sci. USA 94, 4273 (1997).Search in Google Scholar
17. Y. Z. Gu, S. M. Moran, J. B. Hogenesch, L. Wartman, C. A. Bradfield. Gene Expr. 7, 205 (1998).Search in Google Scholar
18. doi:10.1038/35107085, Y. Makino, R. H. Cao, K. Svensson, G. R. Bertilsson, M. Asman, H. Tanaka, Y. H. Cao, A. Berkenstam, L. Poellinger. Nature 414, 550 (2001).Search in Google Scholar
19. doi:10.1093/emboj/20.18.5197, N. Masson, C. Willam, P. H. Maxwell, C. W. Pugh, P. J. Ratcliffe. EMBO J. 20, 5197 (2001).Search in Google Scholar
20. P. H. Maxwell, C. W. Pugh, P. J. Ratcliffe. Adv. Exp. Med. Biol. 502, 365 (2001).Search in Google Scholar
21. doi:10.1593/neo.06442, M. Ohh. Neoplasia 8, 623 (2006).Search in Google Scholar
22. doi:10.1016/S0959-437X(02)00010-2, W. Kim, W. G. Kaelin Jr. Curr. Opin. Genet. Dev. 13, 55 (2003).Search in Google Scholar
23. doi:10.1128/MCB.22.9.2984-2992.2002, N. Sang, J. Fang, V. Srinivas, I. Leshchinsky, J. Caro. Mol. Cell. Biol. 22, 2984 (2002).Search in Google Scholar
24. doi:10.1016/S1357-2725(03)00211-5, R. J. Kewley, M. L. Whitelaw, A. Chapman-Smith. Int. J. Biochem. Cell. Biol. 36, 189 (2004).Search in Google Scholar
25. doi:10.1126/stke.4072007cm8, G. L. Semenza. Sci. STKE 407, cm8 (2007).Search in Google Scholar
26. D. Peet, S. Linke. Novartis Found. Symp. 272, 37 (2006). See also discussion on pp. 49-53, 131-140.Search in Google Scholar
27. I. P. Stolze, D. R. Mole, P. J. Ratcliffe. Novartis Found. Symp. 272, 15 (2006). See also discussion on pp. 25-36.Search in Google Scholar
28. doi:10.1038/nature00767, W. C. Hon, M. I. Wilson, K. Harlos, T. D. W. Claridge, C. J. Schofield, C. W. Pugh, P. H. Maxwell, P. J. Ratcliffe, D. I. Stuart, E. Y. Jones. Nature 417, 975 (2002).Search in Google Scholar
29. doi:10.1126/science.1073440, J. H. Min, H. F. Yang, M. Ivan, F. Gertler, W. G. Kaelin, N. P. Pavletich. Science 296, 1886 (2002).Search in Google Scholar
30. doi:10.1039/a903001h, C. L. Jenkins, R. T. Raines. Nat. Prod. Rep. 19, 49 (2002).Search in Google Scholar
31. doi:10.1073/pnas.082117899, S. J. Freedman, Z.-Y. J. Sun, F. Poy, A. L. Kung, D. M. Livingston, G. Wagner, M. J. Eck. Proc. Natl. Acad. Sci. USA 99, 5367 (2002).Search in Google Scholar
32. doi:10.1073/pnas.082121399, S. A. Dames, M. Martinez-Yamout, R. N. De Guzman, H. J. Dyson, P. E. Wright. Proc. Natl. Acad. Sci. USA 99, 5271 (2002).Search in Google Scholar
33. doi:10.1042/BJ20021162, L. A. McNeill, K. S. Hewitson, T. D. W. Claridge, J. F. Seibel, L. E. Horsfall, C. J. Schofield. Biochem. J. 367, 571 (2002).Search in Google Scholar
34. doi:10.1126/science.1066373, R. K. Bruick, S. L. McKnight. Science 294, 1337 (2001).Search in Google Scholar
35. doi:10.1016/S0092-8674(01)00507-4, A. C. R. Epstein, J. M. Gleadle, L. A. McNeill, K. S. Hewitson, J. O'Rourke, D. R. Mole, M. Mukherji, E. Metzen, M. I. Wilson, A. Dhanda, Y. M. Tian, N. Masson, D. L. Hamilton, P. Jaakkola, R. Barstead, J. Hodgkin, P. H. Maxwell, C. W. Pugh, C. J. Schofield, P. J. Ratcliffe. Cell 107, 43 (2001).Search in Google Scholar
36. doi:10.1128/MCB.25.15.6415-6426.2005, D. A. Chan, P. D. Sutphin, S. E. Yen, A. J. Giaccia. Mol. Cell. Biol. 25, 6415 (2005).Search in Google Scholar
37. doi:10.1074/jbc.M304982200, M. Hirsila, P. Koivunen, V. Gunzler, K. I. Kivirikko, J. Myllyharju. J. Biol. Chem. 278, 30772 (2003).Search in Google Scholar
38. doi:10.1016/j.bbrc.2006.09.170, M. O. Landazuri, A. Vara-Vega, M. Viton, Y. Cuevas, L. del Peso. Biochem. Biophys. Res. Commun. 351, 313 (2006).Search in Google Scholar
39. doi:10.1016/j.febslet.2005.08.033, R. W. Welford, J. M. Kirkpatrick, L. A. McNeill, M. Puri, N. J. Oldham, C. J. Schofield. FEBS Lett. 579, 5170 (2005).Search in Google Scholar
40. doi:10.1080/10409230490440541, R. P. Hausinger. Crit. Rev. Biochem. Mol. 39, 21 (2004).Search in Google Scholar
41. doi:10.1021/ar700066p, C. Krebs, D. Galonic Fujimori, C. T. Walsh, J. M. Bollinger Jr. Acc. Chem. Res. 40, 484 (2007).Search in Google Scholar
42. doi:10.1016/S0959-440X(99)00036-6, C. J. Schofield, Z. H. Zhang. Curr. Opin. Struct. Biol. 9, 722 (1999).Search in Google Scholar
43. doi:10.1073/pnas.0601283103, M. A. McDonough, V. Li, E. Flashman, R. Chowdhury, C. Mohr, B. M. Lienard, J. Zondlo, N. J. Oldham, I. J. Clifton, J. Lewis, L. A. McNeill, R. J. Kurzeja, K. S. Hewitson, E. Yang, S. Jordan, R. S. Syed, C. J. Schofield. Proc. Natl. Acad. Sci. USA 103, 9814 (2006).Search in Google Scholar
44. doi:10.1039/b511249b, L. A. McNeill, E. Flashman, M. R. Buck, K. S. Hewitson, I. J. Clifton, G. Jeschke, T. D. Claridge, D. Ehrismann, N. J. Oldham, C. J. Schofield. Mol. Biosyst. 1, 321 (2005).Search in Google Scholar
45. doi:10.1042/BJ20061151, D. Ehrismann, E. Flashman, D. N. Genn, N. Mathioudakis, K. S. Hewitson, P. J. Ratcliffe, C. J. Schofield. Biochem. J. 401, 227 (2007).Search in Google Scholar
46. doi:10.1074/jbc.M312254200, P. Koivunen, M. Hirsila, V. Gunzler, K. I. Kivirikko, J. Myllyharju. J. Biol. Chem. 279, 9899 (2004).Search in Google Scholar
47. doi:10.1074/jbc.M604628200, P. Koivunen, M. Hirsila, K. I. Kivirikko, J. Myllyharju. J. Biol. Chem. 281, 28712 (2006).Search in Google Scholar
48. doi:10.1042/BJ20071052, D. Villar, A. Vara-Vega, M. O. Landazuri, L. Del Peso. Biochem. J. 408, 231 (2007).Search in Google Scholar
49. doi:10.1074/jbc.M707411200, E. Flashman, E. A. L. Bagg, R. Chowdhury, J. Mecinovic, C. Loenarz, M. A. McDonough, K. S. Hewitson, C. J. Schofield. J. Biol. Chem. 283, 3808 (2007).Search in Google Scholar
50. doi:10.1182/blood-2007-04-084434, M. J. Percy, P. W. Furlow, P. A. Beer, T. R. Lappin, M. F. McMullin, F. S. Lee. Blood 110, 2193 (2007).Search in Google Scholar
51. doi:10.1073/pnas.0508423103, M. J. Percy, Q. Zhao, A. Flores, C. Harrison, T. R. Lappin, P. H. Maxwell, M. F. McMullin, F. S. Lee. Proc. Natl. Acad. Sci. USA 103, 654 (2006).Search in Google Scholar
52. doi:10.1074/jbc.C200273200, K. S. Hewitson, L. A. McNeill, M. V. Riordan, Y. M. Tian, A. N. Bullock, R. W. D. Welford, J. M. Elkins, N. J. Oldham, S. Battacharya, J. Gleadle, P. J. Ratcliffe, C. W. Pugh, C. J. Schofield. J. Biol. Chem. 277, 26351 (2002).Search in Google Scholar
53. doi:10.1101/gad.991402, D. Lando, D. J. Peet, J. J. Gorman, D. A. Whelan, M. L. Whitelaw, R. K. Bruick. Genes Dev. 16, 1466 (2002).Search in Google Scholar
54. doi:10.1101/gad.924501, P. C. Mahon, K. Hirota, G. L. Semenza. Genes Dev. 15, 2675 (2001).Search in Google Scholar
55. doi:10.1073/pnas.202614999, C. E. Dann III, R. K. Bruick, J. Deisenhofer. Proc. Natl. Acad. Sci. USA 99, 15351 (2002).Search in Google Scholar
56. doi:10.1074/jbc.C200644200, J. M. Elkins, K. S. Hewitson, L. A. McNeill, J. F. Seibel, I. Schlemminger, C. W. Pugh, P. J. Ratcliffe, C. J. Schofield. J. Biol. Chem. 278, 1802 (2003).Search in Google Scholar
57. doi:10.1074/jbc.M210385200, C. Lee, S. J. Kim, D. G. Jeong, S. M. Lee, S. E. Ryu. J. Biol. Chem. 278, 7558 (2003).Search in Google Scholar
58. doi:10.1016/0076-6879(82)82067-3, K. I. Kivirikko, R. Myllyla. Methods Enzymol. 82, 245 (1982).Search in Google Scholar
59. doi:10.1042/0264-6021:3610417, F. M. Vaz, R. J. Wanders. Biochem. J. 361, 417 (2002).Search in Google Scholar
60. doi:10.1002/humu.10315, G. A. Jansen, H. R. Waterham, R. J. Wanders. Hum. Mutat. 23, 209 (2004).Search in Google Scholar
61. doi:10.1074/jbc.M507528200, M. A. McDonough, K. L. Kavanagh, D. Butler, T. Searls, U. Oppermann, C. J. Schofield. J. Biol. Chem. 280, 41101 (2005).Search in Google Scholar
62. doi:10.1073/pnas.86.2.444, J. Stenflo, E. Holme, S. Lindstedt, N. Chandramouli, L. H. T. Huang, J. P. Tam, R. B. Merrifield. Proc. Natl. Acad. Sci. USA 86, 444 (1989).Search in Google Scholar
63. doi:10.1073/pnas.84.2.368, J. Stenflo, A. Lundwall, B. Dahlback. Proc. Natl. Acad. Sci. USA 84, 368 (1987).Search in Google Scholar
64. doi:10.1074/jbc.M110389200, J. E. Dinchuk, R. J. Focht, J. A. Kelley, N. L. Henderson, N. I. Zolotarjova, R. Wynn, N. T. Neff, J. Link, R. M. Huber, T. C. Burn, M. J. Rupar, M. R. Cunningham, B. H. Selling, J. Ma, A. A. Stern, G. F. Hollis, R. B. Stein, P. A. Friedman. J. Biol. Chem. 277, 12970 (2002).Search in Google Scholar
65. doi:10.1016/j.jinorgbio.2005.12.018, Y. Mishina, C. He. J. Inorg. Biochem. 100, 670 (2006).Search in Google Scholar
66. doi:10.1016/j.dnarep.2006.10.005, B. Sedgwick, P. A. Bates, J. Paik, S. C. Jacobs, T. Lindahl. DNA Repair (Amst). 6, 429 (2007).Search in Google Scholar
67. doi:10.1073/pnas.0602235103, E. P. Cummins, E. Berra, K. M. Comerford, A. Ginouves, K. T. Fitzgerald, F. Seeballuck, C. Godson, J. E. Nielsen, P. Moynagh, J. Pouyssegur, C. T. Taylor. Proc. Natl. Acad. Sci. USA 103, 18154 (2006).Search in Google Scholar
68. doi:10.1073/pnas.0436037100, A. V. Kuznetsova, J. Meller, P. O. Schnell, J. A. Nash, M. L. Ignacak, Y. Sanchez, J. W. Conaway, R. C. Conaway, M. F. Czyzyk-Krzeska. Proc. Natl. Acad. Sci. USA 100, 2706 (2003).Search in Google Scholar
69. doi:10.1073/pnas.0606877103, M. E. Cockman, D. E. Lancaster, I. P. Stolze, K. S. Hewitson, M. A. McDonough, M. L. Coleman, C. H. Coles, X. Yu, R. T. Hay, S. C. Ley, C. W. Pugh, N. J. Oldham, N. Masson, C. J. Schofield, P. J. Ratcliffe. Proc. Natl. Acad. Sci. USA 103, 14767 (2006).Search in Google Scholar
70. C. T. Walsh. Posttranslational Modification of Proteins. Expanding Nature's Inventory, Roberts, Englewood, CO (2005).Search in Google Scholar
71. doi:10.1074/jbc.M704102200, M. L. Coleman, M. A. McDonough, K. S. Hewitson, C. Coles, J. Mecinovic, M. Edelmann, K. M. Cook, M. E. Cockman, D. E. Lancaster, B. M. Kessler, N. J. Oldham, P. J. Ratcliffe, C. J. Schofield. J. Biol. Chem. 282, 24027 (2007).Search in Google Scholar
72. K. S. Hewitson, N. Granatino, R. W. Welford, M. A. McDonough, C. J. Schofield. Philos. Transact. A, Math. Phys. Eng. Sci. 363, 807 (2005). See also discussion on pp. 1035-1040.Search in Google Scholar
73. doi:10.1038/nrm2143, R. J. Klose, Y. Zhang. Nat. Rev. Mol. Cell. Biol. 8, 307 (2007).Search in Google Scholar
74. doi:10.1016/S0968-0004(00)01700-X, P. M. Clissold, C. P. Ponting. Trends Biochem. Sci. 26, 7 (2001).Search in Google Scholar
75. doi:10.1038/nature04433, Y. Tsukada, J. Fang, H. Erdjument-Bromage, M. E. Warren, C. H. Borchers, P. Tempst, Y. Zhang. Nature 439, 811 (2006).Search in Google Scholar
76. doi:10.1016/j.cell.2006.03.028, J. R. Whetstine, A. Nottke, F. Lan, M. Huarte, S. Smolikov, Z. Chen, E. Spooner, E. Li, G. Zhang, M. Colaiacovo, Y. Shi. Cell 125, 467 (2006).Search in Google Scholar
77. doi:10.1016/j.cell.2004.12.012, Y. Shi, F. Lan, C. Matson, P. Mulligan, J. R. Whetstine, P. A. Cole, R. A. Casero, Y. Shi. Cell 119, 941 (2004).Search in Google Scholar
78. doi:10.1126/science.1141634, T. M. Frayling, N. J. Timpson, M. N. Weedon, E. Zeggini, R. M. Freathy, C. M. Lindgren, J. R. Perry, K. S. Elliott, H. Lango, N. W. Rayner, B. Shields, L. W. Harries, J. C. Barrett, S. Ellard, C. J. Groves, B. Knight, A. M. Patch, A. R. Ness, S. Ebrahim, D. A. Lawlor, S. M. Ring, Y. BenShlomo, M. R. Jarvelin, U. Sovio, A. J. Bennett, D. Melzer, L. Ferrucci, R. J. Loos, I. Barroso, N. J. Wareham, F. Karpe, K. R. Owen, L. R. Cardon, M. Walker, G. A. Hitman, C. N. Palmer, A. S. Doney, A. D. Morris, G. D. Smith, A. T. Hattersley, M. I. McCarthy. Science 316, 889 (2007).Search in Google Scholar
79. doi:10.1126/science.1151710, T. Gerken, C. A. Girard, Y. C. Tung, C. J. Webby, V. Saudek, K. S. Hewitson, G. S. Yeo, M. A. McDonough, S. Cunliffe, L. A. McNeill, J. Galvanovskis, P. Rorsman, P. Robins, X. Prieur, A. P. Coll, M. Ma, Z. Jovanovic, I. S. Farooqi, B. Sedgwick, I. Barroso, T. Lindahl, C. P. Ponting, F. M. Ashcroft, S. O'Rahilly, C. J. Schofield. Science 318, 1469 (2007).Search in Google Scholar
© 2013 Walter de Gruyter GmbH, Berlin/Boston
