Egl nine homolog 3

Details

Name
Egl nine homolog 3
Synonyms
  • 1.14.11.29
  • HIF-PH3
  • HIF-prolyl hydroxylase 3
  • HPH-1
  • HPH-3
  • Hypoxia-inducible factor prolyl hydroxylase 3
  • PHD3
  • Prolyl hydroxylase domain-containing protein 3
Gene Name
EGLN3
Organism
Humans
Amino acid sequence
>lcl|BSEQ0016716|Egl nine homolog 3
MPLGHIMRLDLEKIALEYIVPCLHEVGFCYLDNFLGEVVGDCVLERVKQLHCTGALRDGQ
LAGPRAGVSKRHLRGDQITWIGGNEEGCEAISFLLSLIDRLVLYCGSRLGKYYVKERSKA
MVACYPGNGTGYVRHVDNPNGDGRCITCIYYLNKNWDAKLHGGILRIFPEGKSFIADVEP
IFDRLLFFWSDRRNPHEVQPSYATRYAMTVWYFDAEERAEAKKKFRNLTRKTESALTED
Number of residues
239
Molecular Weight
27261.06
Theoretical pI
7.7
GO Classification
Functions
iron ion binding / L-ascorbic acid binding / oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, 2-oxoglutarate as one donor, and incorporation of one atom each of oxygen into both donors / peptidyl-proline 4-dioxygenase activity
Processes
activation of cysteine-type endopeptidase activity involved in apoptotic process / apoptotic process / cellular response to DNA damage stimulus / cellular response to hypoxia / peptidyl-proline hydroxylation to 4-hydroxy-L-proline / protein hydroxylation / regulation of cell proliferation / regulation of neuron apoptotic process / regulation of transcription from RNA polymerase II promoter in response to hypoxia / response to hypoxia
Components
cytoplasm / cytosol / nucleoplasm / nucleus
General Function
Peptidyl-proline 4-dioxygenase activity
Specific Function
Cellular oxygen sensor that catalyzes, under normoxic conditions, the post-translational formation of 4-hydroxyproline in hypoxia-inducible factor (HIF) alpha proteins. Hydroxylates a specific proline found in each of the oxygen-dependent degradation (ODD) domains (N-terminal, NODD, and C-terminal, CODD) of HIF1A. Also hydroxylates HIF2A. Has a preference for the CODD site for both HIF1A and HIF2A. Hydroxylation on the NODD site by EGLN3 appears to require prior hydroxylation on the CODD site. Hydroxylated HIFs are then targeted for proteasomal degradation via the von Hippel-Lindau ubiquitination complex. Under hypoxic conditions, the hydroxylation reaction is attenuated allowing HIFs to escape degradation resulting in their translocation to the nucleus, heterodimerization with HIF1B, and increased expression of hypoxy-inducible genes. EGLN3 is the most important isozyme in limiting physiological activation of HIFs (particularly HIF2A) in hypoxia. Also hydroxylates PKM in hypoxia, limiting glycolysis. Under normoxia, hydroxylates and regulates the stability of ADRB2. Regulator of cardiomyocyte and neuronal apoptosis. In cardiomyocytes, inhibits the anti-apoptotic effect of BCL2 by disrupting the BAX-BCL2 complex. In neurons, has a NGF-induced proapoptotic effect, probably through regulating CASP3 activity. Also essential for hypoxic regulation of neutrophilic inflammation. Plays a crucial role in DNA damage response (DDR) by hydroxylating TELO2, promoting its interaction with ATR which is required for activation of the ATR/CHK1/p53 pathway. Target proteins are preferentially recognized via a LXXLAP motif.
Pfam Domain Function
Transmembrane Regions
Not Available
Cellular Location
Nucleus
Gene sequence
>lcl|BSEQ0016717|Egl nine homolog 3 (EGLN3)
ATGCCCCTGGGACACATCATGAGGCTGGACCTGGAGAAAATTGCCCTGGAGTACATCGTG
CCCTGTCTGCACGAGGCAATGGTGGCTTGCTATCCGGGAAATGGAACAGGTTATGTTCGC
CACGTGGACAACCCCAACGGTGATGGTCGCTGCATCACCTGCATCTACTATCTGAACAAG
AATTGGGATGCCAAGCTACATGGTGGGATCCTGCGGATATTTCCAGAGGGGAAATCATTC
ATAGCAGATGTGGAGCCCATTTTTGACAGACTCCTGTTCTTCTGGTCAGATCGTAGGAAC
CCACACGAAGTGCAGCCCTCTTACGCAACCAGATATGCTATGACTGTCTGGTACTTTGAT
GCTGAAGAAAGGGCAGAAGCCAAAAAGAAATTCAGGAATTTAACTAGGAAAACTGAATCT
GCCCTCACTGAAGACTGA
Chromosome Location
14
Locus
14q13.1
External Identifiers
ResourceLink
UniProtKB IDQ9H6Z9
UniProtKB Entry NameEGLN3_HUMAN
GenBank Protein ID14547150
GenBank Gene IDAJ310545
GenAtlas IDEGLN3
HGNC IDHGNC:14661
General References
  1. Taylor MS: Characterization and comparative analysis of the EGLN gene family. Gene. 2001 Sep 5;275(1):125-32. [PubMed:11574160]
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  5. Epstein AC, Gleadle JM, McNeill LA, Hewitson KS, O'Rourke J, Mole DR, Mukherji M, Metzen E, Wilson MI, Dhanda A, Tian YM, Masson N, Hamilton DL, Jaakkola P, Barstead R, Hodgkin J, Maxwell PH, Pugh CW, Schofield CJ, Ratcliffe PJ: C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation. Cell. 2001 Oct 5;107(1):43-54. [PubMed:11595184]
  6. Semenza GL: HIF-1, O(2), and the 3 PHDs: how animal cells signal hypoxia to the nucleus. Cell. 2001 Oct 5;107(1):1-3. [PubMed:11595178]
  7. Bruick RK, McKnight SL: A conserved family of prolyl-4-hydroxylases that modify HIF. Science. 2001 Nov 9;294(5545):1337-40. Epub 2001 Oct 11. [PubMed:11598268]
  8. Oehme F, Ellinghaus P, Kolkhof P, Smith TJ, Ramakrishnan S, Hutter J, Schramm M, Flamme I: Overexpression of PH-4, a novel putative proline 4-hydroxylase, modulates activity of hypoxia-inducible transcription factors. Biochem Biophys Res Commun. 2002 Aug 16;296(2):343-9. [PubMed:12163023]
  9. Huang J, Zhao Q, Mooney SM, Lee FS: Sequence determinants in hypoxia-inducible factor-1alpha for hydroxylation by the prolyl hydroxylases PHD1, PHD2, and PHD3. J Biol Chem. 2002 Oct 18;277(42):39792-800. Epub 2002 Aug 13. [PubMed:12181324]
  10. Cioffi CL, Liu XQ, Kosinski PA, Garay M, Bowen BR: Differential regulation of HIF-1 alpha prolyl-4-hydroxylase genes by hypoxia in human cardiovascular cells. Biochem Biophys Res Commun. 2003 Apr 11;303(3):947-53. [PubMed:12670503]
  11. Metzen E, Berchner-Pfannschmidt U, Stengel P, Marxsen JH, Stolze I, Klinger M, Huang WQ, Wotzlaw C, Hellwig-Burgel T, Jelkmann W, Acker H, Fandrey J: Intracellular localisation of human HIF-1 alpha hydroxylases: implications for oxygen sensing. J Cell Sci. 2003 Apr 1;116(Pt 7):1319-26. [PubMed:12615973]
  12. Appelhoff RJ, Tian YM, Raval RR, Turley H, Harris AL, Pugh CW, Ratcliffe PJ, Gleadle JM: Differential function of the prolyl hydroxylases PHD1, PHD2, and PHD3 in the regulation of hypoxia-inducible factor. J Biol Chem. 2004 Sep 10;279(37):38458-65. Epub 2004 Jul 7. [PubMed:15247232]
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  15. Liu Y, Huo Z, Yan B, Lin X, Zhou ZN, Liang X, Zhu W, Liang D, Li L, Liu Y, Zhao H, Sun Y, Chen YH: Prolyl hydroxylase 3 interacts with Bcl-2 to regulate doxorubicin-induced apoptosis in H9c2 cells. Biochem Biophys Res Commun. 2010 Oct 15;401(2):231-7. doi: 10.1016/j.bbrc.2010.09.037. Epub 2010 Sep 16. [PubMed:20849813]
  16. Su Y, Loos M, Giese N, Hines OJ, Diebold I, Gorlach A, Metzen E, Pastorekova S, Friess H, Buchler P: PHD3 regulates differentiation, tumour growth and angiogenesis in pancreatic cancer. Br J Cancer. 2010 Nov 9;103(10):1571-9. doi: 10.1038/sj.bjc.6605936. Epub 2010 Oct 26. [PubMed:20978507]
  17. Yan B, Jiao S, Zhang HS, Lv DD, Xue J, Fan L, Wu GH, Fang J: Prolyl hydroxylase domain protein 3 targets Pax2 for destruction. Biochem Biophys Res Commun. 2011 Jun 3;409(2):315-20. doi: 10.1016/j.bbrc.2011.05.012. Epub 2011 May 14. [PubMed:21575608]
  18. Pappalardi MB, McNulty DE, Martin JD, Fisher KE, Jiang Y, Burns MC, Zhao H, Ho T, Sweitzer S, Schwartz B, Annan RS, Copeland RA, Tummino PJ, Luo L: Biochemical characterization of human HIF hydroxylases using HIF protein substrates that contain all three hydroxylation sites. Biochem J. 2011 Jun 1;436(2):363-9. doi: 10.1042/BJ20101201. [PubMed:21410436]
  19. Luo W, Hu H, Chang R, Zhong J, Knabel M, O'Meally R, Cole RN, Pandey A, Semenza GL: Pyruvate kinase M2 is a PHD3-stimulated coactivator for hypoxia-inducible factor 1. Cell. 2011 May 27;145(5):732-44. doi: 10.1016/j.cell.2011.03.054. [PubMed:21620138]
  20. Chen N, Rinner O, Czernik D, Nytko KJ, Zheng D, Stiehl DP, Zamboni N, Gstaiger M, Frei C: The oxygen sensor PHD3 limits glycolysis under hypoxia via direct binding to pyruvate kinase. Cell Res. 2011 Jun;21(6):983-6. doi: 10.1038/cr.2011.66. Epub 2011 Apr 12. [PubMed:21483450]
  21. Walmsley SR, Chilvers ER, Thompson AA, Vaughan K, Marriott HM, Parker LC, Shaw G, Parmar S, Schneider M, Sabroe I, Dockrell DH, Milo M, Taylor CT, Johnson RS, Pugh CW, Ratcliffe PJ, Maxwell PH, Carmeliet P, Whyte MK: Prolyl hydroxylase 3 (PHD3) is essential for hypoxic regulation of neutrophilic inflammation in humans and mice. J Clin Invest. 2011 Mar;121(3):1053-63. doi: 10.1172/JCI43273. Epub 2011 Feb 7. [PubMed:21317538]
  22. Geng Z, Zhu J, Cao J, Geng J, Song X, Zhang Z, Bian N, Wang Z: Effects of polynitrogen compounds on the activity of recombinant human HIF-1alpha prolyl hydroxylase 3 in E. coli. J Inorg Biochem. 2011 Mar;105(3):391-9. doi: 10.1016/j.jinorgbio.2010.12.001. Epub 2010 Dec 14. [PubMed:21421125]
  23. Xie L, Pi X, Mishra A, Fong G, Peng J, Patterson C: PHD3-dependent hydroxylation of HCLK2 promotes the DNA damage response. J Clin Invest. 2012 Aug;122(8):2827-36. doi: 10.1172/JCI62374. Epub 2012 Jul 17. [PubMed:22797300]
  24. Foxler DE, Bridge KS, James V, Webb TM, Mee M, Wong SC, Feng Y, Constantin-Teodosiu D, Petursdottir TE, Bjornsson J, Ingvarsson S, Ratcliffe PJ, Longmore GD, Sharp TV: The LIMD1 protein bridges an association between the prolyl hydroxylases and VHL to repress HIF-1 activity. Nat Cell Biol. 2012 Jan 29;14(2):201-8. doi: 10.1038/ncb2424. [PubMed:22286099]

Drug Relations

Drug Relations
DrugBank IDNameDrug groupPharmacological action?ActionsDetails
DB00126Ascorbic acidapproved, nutraceuticalunknownDetails
DB04847RoxadustatinvestigationalunknownDetails