Hypoxia-inducible factor-proline dioxygenase
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EC no.1.14.11.29
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Hypoxia-inducible factor-proline dioxygenase (EC 1.14.11.29, HIF hydroxylase) is an enzyme with systematic name hypoxia-inducible factor-L-proline, 2-oxoglutarate:oxygen oxidoreductase (4-hydroxylating).[1][2][3][4][5][6] This enzyme catalyses the following chemical reaction

hypoxia-inducible factor-L-proline + 2-oxoglutarate + O2 hypoxia-inducible factor-trans-4-hydroxy-L-proline + succinate + CO2

Hypoxia-inducible factor-proline dioxygenase contains iron, and requires ascorbate.

Hypoxia-inducible factor (HIF) is an evolutionarily conserved transcription factor[7] that allows the cell to respond physiologically to low concentrations of oxygen.[8] A class of prolyl hydroxylases which act specifically on HIF has been identified;[9] hydroxylation of HIF allows the protein to be targeted for degradation.[9] HIF prolyl-hydroxylase has been targeted by a variety of inhibitors that aim to treat stroke,[10] kidney disease,[11] ischemia,[12] anemia,[13] and other important diseases. Clinically observed prolyl hydroxylase domain mutations, as in the case of erythrocytosis- and breast cancer-associated PHD2 mutations, affect its selectivity for its HIF substrate, which has important implication for drug design.[14]

In humans, there are three isoforms of hypoxia-inducible factor-proline dioxygenase. These are PHD1, PHD2 and PHD3. PHD2, in particular, was identified as the most important human oxygen sensors due to its slow reaction with oxygen.[15]

References

  1. ↑ Jaakkola, P.; Mole, D.R.; Tian, Y.M.; Wilson, M.I.; Gielbert, J.; Gaskell, S.J.; Kriegsheim Av; Hebestreit, H.F.; Mukherji, M.; Schofield, C.J.; Maxwell, P.H.; Pugh, C.W.; Ratcliffe, P.J. (2001). "Targeting of HIF-α to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation". Science. 292 (5516): 468–472. Bibcode:2001Sci...292..468J. doi:10.1126/science.1059796. PMID 11292861.
  2. ↑ Ivan, M.; Kondo, K.; Yang, H.; Kim, W.; Valiando, J.; Ohh, M.; Salic, A.; Asara, J.M.; Lane, W.S.; Kaelin, W.G. (2001). "HIFα targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing". Science. 292 (5516): 464–468. Bibcode:2001Sci...292..464I. doi:10.1126/science.1059817. PMID 11292862.
  3. ↑ Bruick, R.K.; McKnight, S.L. (2001). "A conserved family of prolyl-4-hydroxylases that modify HIF". Science. 294 (5545): 1337–1340. Bibcode:2001Sci...294.1337B. doi:10.1126/science.1066373. PMID 11598268.
  4. ↑ Epstein, A.C.; Gleadle, J.M.; McNeill, L.A.; Hewitson, K.S.; O'Rourke, J.; Mole, D.R.; Mukherji, M.; Metzen, E.; Wilson, M.I.; Dhanda, A.; Tian, Y.M.; Masson, N.; Hamilton, D.L.; Jaakkola, P.; Barstead, R.; Hodgkin, J.; Maxwell, P.H.; Pugh, C.W.; Schofield, C.J.; Ratcliffe, P.J. (2001). "C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation". Cell. 107 (1): 43–54. doi:10.1016/S0092-8674(01)00507-4. PMID 11595184.
  5. ↑ Oehme, F.; Ellinghaus, P.; Kolkhof, P.; Smith, T.J.; Ramakrishnan, S.; Hutter, J.; Schramm, M.; Flamme, I. (2002). "Overexpression of PH-4, a novel putative proline 4-hydroxylase, modulates activity of hypoxia-inducible transcription factors". Biochem. Biophys. Res. Commun. 296 (2): 343–349. doi:10.1016/S0006-291X(02)00862-8. PMID 12163023.
  6. ↑ McNeill, L.A.; Hewitson, K.S.; Gleadle, J.M.; Horsfall, L.E.; Oldham, N.J.; Maxwell, P.H.; Pugh, C.W.; Ratcliffe, P.J.; Schofield, C.J. (2002). "The use of dioxygen by HIF prolyl hydroxylase (PHD1)". Bioorg. Med. Chem. Lett. 12 (12): 1547–1550. doi:10.1016/S0960-894X(02)00219-6. PMID 12039559.
  7. ↑ Bacon, N. C.; Wappner, P; O'Rourke, J. F.; Bartlett, S. M.; Shilo, B; Pugh, C. W.; Ratcliffe, P. J. (1998). "Regulation of the Drosophila bHLH-PAS protein Sima by hypoxia: Functional evidence for homology with mammalian HIF-1 alpha". Biochemical and Biophysical Research Communications. 249 (3): 811–6. doi:10.1006/bbrc.1998.9234. PMID 9731218.
  8. ↑ Smith, T. G.; Robbins, P. A.; Ratcliffe, P. J. (2008). "The human side of hypoxia-inducible factor". British Journal of Haematology. 141 (3): 325–34. doi:10.1111/j.1365-2141.2008.07029.x. PMC 2408651. PMID 18410568.
  9. 1 2 Bruick, R. K. (2001). "A Conserved Family of Prolyl-4-Hydroxylases That Modify HIF". Science. 294 (5545): 1337–40. doi:10.1126/science.1066373. PMID 11598268.
  10. ↑ Karuppagounder, S. S.; Ratan, R. R. (2012). "Hypoxia-inducible factor prolyl hydroxylase inhibition: Robust new target or another big bust for stroke therapeutics?". Journal of Cerebral Blood Flow & Metabolism. 32 (7): 1347–1361. doi:10.1038/jcbfm.2012.28. PMC 3390817. PMID 22415525.
  11. ↑ Warnecke, C.; Griethe, W.; Weidemann, A.; Jurgensen, J. S.; Willam, C.; Bachmann, S.; Ivashchenko, Y.; Wagner, I.; Frei, U.; Wiesener, M.; Eckardt, K. -U. (2003). "Activation of the hypoxia-inducible factor pathway and stimulation of angiogenesis by application of prolyl hydroxylase inhibitors". The FASEB Journal. 17 (9): 1186–8. doi:10.1096/fj.02-1062fje. PMID 12709400.
  12. ↑ Selvaraju, V; Parinandi, N. L.; Adluri, R. S.; Goldman, J. W.; Hussain, N; Sanchez, J. A.; Maulik, N (2013). "Molecular Mechanisms of Action and Therapeutic Uses of Pharmacological Inhibitors of HIF-Prolyl 4-Hydroxylases for Treatment of Ischemic Diseases". Antioxidants & Redox Signaling. 20 (16): 2631–2665. doi:10.1089/ars.2013.5186. PMC 4026215. PMID 23992027.
  13. ↑ Muchnik, E; Kaplan, J (2011). "HIF prolyl hydroxylase inhibitors for anemia". Expert Opinion on Investigational Drugs. 20 (5): 645–56. doi:10.1517/13543784.2011.566861. PMID 21406036.
  14. ↑ Chowdhury, Rasheduzzaman; Leung, Ivanhoe K. H.; Tian, Ya-Min; Abboud, Martine I.; Ge, Wei; Domene, Carmen; Cantrelle, François-Xavier; Landrieu, Isabelle; Hardy, Adam P. (2016-08-26). "Structural basis for oxygen degradation domain selectivity of the HIF prolyl hydroxylases". Nature Communications. 7: 12673. doi:10.1038/ncomms12673. PMC 5007464. PMID 27561929.
  15. ↑ Berra E, Benizri E, Ginouvès A, Volmat V, Roux D, Pouysségur J (Aug 2003). "HIF prolylhydroxylase 2 is the key oxygen sensor setting low steady-state levels of HIF-1α in normoxia". EMBO J. 22 (16): 4082–4090. doi:10.1093/emboj/cdg392. PMC 175782. PMID 12912907.
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