Hypoxia-inducible factor-proline dioxygenase explained

Hypoxia-inducible factor-proline dioxygenase
Ec Number:1.14.11.29

Hypoxia-inducible factor-proline dioxygenase (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

\rightleftharpoons

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]

Notes and References

  1. Targeting of HIF-α to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation . 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. . Christopher J. Schofield . Maxwell, P.H. . Pugh, C.W. . Ratcliffe, P.J. . Science . 2001 . 292 . 468–472 . 11292861 . 10.1126/science.1059796 . 5516. 2001Sci...292..468J . free .
  2. HIFα targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing . Ivan, M. . Kondo, K. . Yang, H. . Kim, W. . Valiando, J. . Ohh, M. . Salic, A. . Asara, J.M. . Lane, W.S. . Kaelin, W.G. . Science . 2001 . 292 . 464–468 . 11292862 . 10.1126/science.1059817 . 5516. 2001Sci...292..464I . free .
  3. A conserved family of prolyl-4-hydroxylases that modify HIF . Bruick, R.K. . McKnight, S.L. . Science . 2001 . 294 . 1337–1340 . 11598268 . 2001Sci...294.1337B . 10.1126/science.1066373 . 5545.
  4. C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation . 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. . Cell . 2001 . 107 . 43–54 . 11595184 . 10.1016/S0092-8674(01)00507-4 . 1. free .
  5. Overexpression of PH-4, a novel putative proline 4-hydroxylase, modulates activity of hypoxia-inducible transcription factors . Oehme, F. . Ellinghaus, P. . Kolkhof, P. . Smith, T.J. . Ramakrishnan, S. . Hutter, J. . Schramm, M. . Flamme, I. . Biochem. Biophys. Res. Commun. . 2002 . 296 . 343–349 . 12163023 . 10.1016/S0006-291X(02)00862-8 . 2.
  6. The use of dioxygen by HIF prolyl hydroxylase (PHD1) . 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. . Bioorg. Med. Chem. Lett. . 2002 . 12 . 1547–1550 . 12039559 . 10.1016/S0960-894X(02)00219-6 . 12.
  7. 9731218 . 1998 . Bacon . N. C. . 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 . Wappner . P . O'Rourke . J. F. . Bartlett . S. M. . Shilo . B . Pugh . C. W. . Ratcliffe . P. J. . 10.1006/bbrc.1998.9234.
  8. 18410568 . 2008 . Smith . T. G. . The human side of hypoxia-inducible factor . British Journal of Haematology . 141 . 3 . 325–34 . Robbins . P. A. . Ratcliffe . P. J. . 10.1111/j.1365-2141.2008.07029.x . 2408651.
  9. 10.1126/science.1066373 . A Conserved Family of Prolyl-4-Hydroxylases That Modify HIF . Science . 294 . 5545 . 1337–40 . 2001 . Bruick . R. K. . 11598268. 2001Sci...294.1337B .
  10. 10.1038/jcbfm.2012.28. 22415525. 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. 2012. Karuppagounder . S. S. . Ratan . R. R. . 3390817.
  11. 10.1096/fj.02-1062fje . Activation of the hypoxia-inducible factor pathway and stimulation of angiogenesis by application of prolyl hydroxylase inhibitors . The FASEB Journal . 2003 . Warnecke . C. . Griethe . W. . Weidemann . A. . Jurgensen . J. S. . Willam . C. . Bachmann . S. . Ivashchenko . Y. . Wagner . I. . Frei . U. . Wiesener . M. . Eckardt . K. -U. . 12709400 . 17 . 9 . 1186–8. free .
  12. 23992027 . 2013 . Selvaraju . V . Molecular Mechanisms of Action and Therapeutic Uses of Pharmacological Inhibitors of HIF-Prolyl 4-Hydroxylases for Treatment of Ischemic Diseases . Antioxidants & Redox Signaling . 2631–2665 . Parinandi . N. L. . Adluri . R. S. . Goldman . J. W. . Hussain . N . Sanchez . J. A. . Maulik . N . 10.1089/ars.2013.5186 . 20 . 16. 4026215 .
  13. 21406036 . 2011 . Muchnik . E . HIF prolyl hydroxylase inhibitors for anemia . Expert Opinion on Investigational Drugs . 20 . 5 . 645–56 . Kaplan . J . 10.1517/13543784.2011.566861.
  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. en. 7. 12673. 10.1038/ncomms12673. 27561929. 5007464. 2016NatCo...712673C .
  15. Berra E, Benizri E, Ginouvès A, Volmat V, Roux D, Pouysségur J . HIF prolylhydroxylase 2 is the key oxygen sensor setting low steady-state levels of HIF-1α in normoxia . EMBO J . 22 . 16 . 4082–4090 . Aug 2003 . 12912907 . 175782 . 10.1093/emboj/cdg392 .

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