Hypoxia-inducible factor-proline dioxygenase

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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]

Related Research Articles

<span class="mw-page-title-main">Hydroxyproline</span> Chemical compound

(2S,4R)-4-Hydroxyproline, or L-hydroxyproline (C5H9O3N), is an amino acid, abbreviated as Hyp or O, e.g., in Protein Data Bank.

In chemistry, hydroxylation can refer to:

Hypoxia-inducible factors (HIFs) are transcription factors that respond to decreases in available oxygen in the cellular environment, or hypoxia. They are only present in parahoxozoan animals.

<span class="mw-page-title-main">Von Hippel–Lindau tumor suppressor</span> Mammalian protein found in Homo sapiens

The Von Hippel–Lindau tumor suppressor also known as pVHL is a protein that, in humans, is encoded by the VHL gene. Mutations of the VHL gene are associated with Von Hippel–Lindau disease, which is characterized by hemangioblastomas of the brain, spinal cord and retina. It is also associated with kidney and pancreatic lesions.

<span class="mw-page-title-main">HIF1A</span> Protein-coding gene in the species Homo sapiens

Hypoxia-inducible factor 1-alpha, also known as HIF-1-alpha, is a subunit of a heterodimeric transcription factor hypoxia-inducible factor 1 (HIF-1) that is encoded by the HIF1A gene. The Nobel Prize in Physiology or Medicine 2019 was awarded for the discovery of HIF.

<span class="mw-page-title-main">Procollagen-proline dioxygenase</span>

Procollagen-proline dioxygenase, commonly known as prolyl hydroxylase, is a member of the class of enzymes known as alpha-ketoglutarate-dependent hydroxylases. These enzymes catalyze the incorporation of oxygen into organic substrates through a mechanism that requires alpha-Ketoglutaric acid, Fe2+, and ascorbate. This particular enzyme catalyzes the formation of (2S, 4R)-4-hydroxyproline, a compound that represents the most prevalent post-translational modification in the human proteome.

<span class="mw-page-title-main">EPAS1</span> Protein-coding gene in the species Homo sapiens

Endothelial PAS domain-containing protein 1 is a protein that is encoded by the EPAS1 gene in mammals. It is a type of hypoxia-inducible factor, a group of transcription factors involved in the physiological response to oxygen concentration. The gene is active under hypoxic conditions. It is also important in the development of the heart, and for maintaining the catecholamine balance required for protection of the heart. Mutation often leads to neuroendocrine tumors.

<span class="mw-page-title-main">EGLN2</span> Protein-coding gene in the species Homo sapiens

Egl nine homolog 2 is a protein that in humans is encoded by the EGLN2 gene. ELGN2 is an alpha-ketoglutarate-dependent hydroxylase, a superfamily of non-haem iron-containing proteins.

<span class="mw-page-title-main">EGLN1</span> Protein-coding gene in the species Homo sapiens

Hypoxia-inducible factor prolyl hydroxylase 2 (HIF-PH2), or prolyl hydroxylase domain-containing protein 2 (PHD2), is an enzyme encoded by the EGLN1 gene. It is also known as Egl nine homolog 1. PHD2 is a α-ketoglutarate/2-oxoglutarate-dependent hydroxylase, a superfamily non-haem iron-containing proteins. In humans, PHD2 is one of the three isoforms of hypoxia-inducible factor-proline dioxygenase, which is also known as HIF prolyl-hydroxylase.

<span class="mw-page-title-main">EGLN3</span> Protein-coding gene in the species Homo sapiens

Egl nine homolog 3 is a protein that in humans is encoded by the EGLN3 gene. ELGN3 is a member of the superfamily of alpha-ketoglutarate-dependent hydroxylases, which are non-haem iron-containing proteins.

<span class="mw-page-title-main">HIF1AN</span> Protein-coding gene in the species Homo sapiens

Hypoxia-inducible factor 1-alpha inhibitor is a protein that in humans is encoded by the HIF1AN gene.

<span class="mw-page-title-main">P4HA1</span> Protein-coding gene in the species Homo sapiens

Prolyl 4-hydroxylase subunit alpha-1 is an enzyme that in humans is encoded by the P4HA1 gene.

<span class="mw-page-title-main">P4HA2</span> Protein-coding gene in the species Homo sapiens

Prolyl 4-hydroxylase subunit alpha-2 is an enzyme that in humans is encoded by the P4HA2 gene.

<span class="mw-page-title-main">HIF prolyl-hydroxylase inhibitor</span>

Not to be confused with Factor Inhibiting HIF Asparaginyl Hydroxylase Inhibitors

Hypoxia-inducible factor-asparagine dioxygenase (EC 1.14.11.30, HIF hydroxylase) is an enzyme with systematic name hypoxia-inducible factor-L-asparagine, 2-oxoglutarate:oxygen oxidoreductase (4-hydroxylating). This enzyme catalyses the following chemical reaction:

hypoxia-inducible factor-L-asparagine + 2-oxoglutarate + O2 hypoxia-inducible factor-(3S)-3-hydroxy-L-asparagine + succinate + CO2

Alpha-ketoglutarate-dependent hydroxylases are a major class of non-heme iron proteins that catalyse a wide range of reactions. These reactions include hydroxylation reactions, demethylations, ring expansions, ring closures, and desaturations. Functionally, the αKG-dependent hydroxylases are comparable to cytochrome P450 enzymes. Both use O2 and reducing equivalents as cosubstrates and both generate water.

Christopher Joseph Schofield is a Professor of Chemistry at the University of Oxford and a Fellow of the Royal Society. Chris Schofield is a professor of organic chemistry at the University of Oxford, Department of Chemistry and a Fellow of Hertford College. Schofield studied functional, structural and mechanistic understanding of enzymes that employ oxygen and 2-oxoglutarate as a co-substrate. His work has opened up new possibilities in antibiotic research, oxygen sensing, and gene regulation.

<span class="mw-page-title-main">P4HTM</span> Protein-coding gene in the species Homo sapiens

Prolyl 4-hydroxylase, transmembrane is a protein that in humans is encoded by the P4HTM gene.

<span class="mw-page-title-main">Sónia Rocha</span> Portuguese cell and molecular biologist

Sónia Maria Campos Soares da Rocha, usually referred to as Professor Sónia Rocha, is a Portuguese cell biologist who holds a personal chair in biochemistry at the University of Liverpool, where she is the head of the Department of Biochemistry. Rocha runs an active multidisciplinary cell signaling research group studying hypoxia, and focused around transcription factors such as Hypoxia-inducible factors and NF-κB. Her laboratory is currently based in the Institute of Integrative Biology.

Factor Inhibiting HIF (FIH) Asparaginyl Hydroxylase Inhibitors inhibit the FIH pathway also catalyzed by Asparaginyl Hydroxylase inhibition. Before 2010s thought to be identical to HIF prolyl-hydroxylase pathway, studies have shown FIH to be the master regulator that controls HIF transcriptional activity in an oxygen-dependent manner. and that HIF prolyl-hydroxylase inhibitors may only minimally inhibit FIH. Skeletal muscle expresses 50-fold higher levels of FIH than other tissues.

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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