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Identification
HMDB Protein ID HMDBP09212
Secondary Accession Numbers
  • 14994
Name Egl nine homolog 3
Synonyms
  1. HIF-PH3
  2. HIF-prolyl hydroxylase 3
  3. HPH-1
  4. HPH-3
  5. Hypoxia-inducible factor prolyl hydroxylase 3
  6. PHD3
  7. Prolyl hydroxylase domain-containing protein 3
Gene Name EGLN3
Protein Type Enzyme
Biological Properties
General Function Involved in oxidoreductase 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.
Pathways
  • HIF-1 signaling pathway
  • Renal cell carcinoma
  • The Oncogenic Action of Fumarate
  • The Oncogenic Action of Succinate
Reactions
Hypoxia-inducible factor-L-proline + Oxoglutaric acid + Oxygen → hypoxia-inducible factor-trans-4-hydroxy-L-proline + Succinic acid + CO(2) details
GO Classification
Biological Process
peptidyl-proline hydroxylation to 4-hydroxy-L-proline
regulation of neuron apoptotic process
protein hydroxylation
regulation of cell proliferation
activation of cysteine-type endopeptidase activity involved in apoptotic process
response to DNA damage stimulus
regulation of transcription from RNA polymerase II promoter in response to hypoxia
Cellular Component
cytosol
nucleoplasm
Function
ion binding
cation binding
metal ion binding
binding
catalytic activity
transition metal ion binding
l-ascorbic acid binding
iron ion binding
oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen
vitamin binding
oxidoreductase activity
Molecular Function
oxidoreductase activity, acting on single donors with incorporation of molecular oxygen, incorporation of two atoms of oxygen
L-ascorbic acid binding
iron ion binding
peptidyl-proline 4-dioxygenase activity
Process
metabolic process
oxidation reduction
Cellular Location
  1. Nucleus
  2. Cytoplasm
Gene Properties
Chromosome Location 14
Locus 14q13.1
SNPs EGLN3
Gene Sequence
>720 bp
ATGCCCCTGGGACACATCATGAGGCTGGACCTGGAGAAAATTGCCCTGGAGTACATCGTG
CCCTGTCTGCACGAGGTGGGCTTCTGCTACCTGGACAACTTCCTGGGCGAGGTGGTGGGC
GACTGCGTCCTGGAGCGCGTCAAGCAGCTGCACTGCACCGGGGCCCTGCGGGACGGCCAG
CTGGCGGGGCCGCGCGCCGGCGTCTCCAAGCGACACCTGCGGGGCGACCAGATCACGTGG
ATCGGGGGCAACGAGGAGGGCTGCGAGGCCATCAGCTTCCTCCTGTCCCTCATCGACAGG
CTGGTCCTCTACTGCGGGAGCCGGCTGGGCAAATACTACGTCAAGGAGAGGTCTAAGGCA
ATGGTGGCTTGCTATCCGGGAAATGGAACAGGTTATGTTCGCCACGTGGACAACCCCAAC
GGTGATGGTCGCTGCATCACCTGCATCTACTATCTGAACAAGAATTGGGATGCCAAGCTA
CATGGTGGGATCCTGCGGATATTTCCAGAGGGGAAATCATTCATAGCAGATGTGGAGCCC
ATTTTTGACAGACTCCTGTTCTTCTGGTCAGATCGTAGGAACCCACACGAAGTGCAGCCC
TCTTACGCAACCAGATATGCTATGACTGTCTGGTACTTTGATGCTGAAGAAAGGGCAGAA
GCCAAAAAGAAATTCAGGAATTTAACTAGGAAAACTGAATCTGCCCTCACTGAAGACTGA
Protein Properties
Number of Residues 239
Molecular Weight 27261.06
Theoretical pI 7.636
Pfam Domain Function
Signals Not Available
Transmembrane Regions Not Available
Protein Sequence
>Egl nine homolog 3
MPLGHIMRLDLEKIALEYIVPCLHEVGFCYLDNFLGEVVGDCVLERVKQLHCTGALRDGQ
LAGPRAGVSKRHLRGDQITWIGGNEEGCEAISFLLSLIDRLVLYCGSRLGKYYVKERSKA
MVACYPGNGTGYVRHVDNPNGDGRCITCIYYLNKNWDAKLHGGILRIFPEGKSFIADVEP
IFDRLLFFWSDRRNPHEVQPSYATRYAMTVWYFDAEERAEAKKKFRNLTRKTESALTED
GenBank ID Protein 14547150
UniProtKB/Swiss-Prot ID Q9H6Z9
UniProtKB/Swiss-Prot Entry Name EGLN3_HUMAN
PDB IDs Not Available
GenBank Gene ID AJ310545
GeneCard ID EGLN3
GenAtlas ID EGLN3
HGNC ID HGNC:14661
References
General References
  1. Ota T, Suzuki Y, Nishikawa T, Otsuki T, Sugiyama T, Irie R, Wakamatsu A, Hayashi K, Sato H, Nagai K, Kimura K, Makita H, Sekine M, Obayashi M, Nishi T, Shibahara T, Tanaka T, Ishii S, Yamamoto J, Saito K, Kawai Y, Isono Y, Nakamura Y, Nagahari K, Murakami K, Yasuda T, Iwayanagi T, Wagatsuma M, Shiratori A, Sudo H, Hosoiri T, Kaku Y, Kodaira H, Kondo H, Sugawara M, Takahashi M, Kanda K, Yokoi T, Furuya T, Kikkawa E, Omura Y, Abe K, Kamihara K, Katsuta N, Sato K, Tanikawa M, Yamazaki M, Ninomiya K, Ishibashi T, Yamashita H, Murakawa K, Fujimori K, Tanai H, Kimata M, Watanabe M, Hiraoka S, Chiba Y, Ishida S, Ono Y, Takiguchi S, Watanabe S, Yosida M, Hotuta T, Kusano J, Kanehori K, Takahashi-Fujii A, Hara H, Tanase TO, Nomura Y, Togiya S, Komai F, Hara R, Takeuchi K, Arita M, Imose N, Musashino K, Yuuki H, Oshima A, Sasaki N, Aotsuka S, Yoshikawa Y, Matsunawa H, Ichihara T, Shiohata N, Sano S, Moriya S, Momiyama H, Satoh N, Takami S, Terashima Y, Suzuki O, Nakagawa S, Senoh A, Mizoguchi H, Goto Y, Shimizu F, Wakebe H, Hishigaki H, Watanabe T, Sugiyama A, Takemoto M, Kawakami B, Yamazaki M, Watanabe K, Kumagai A, Itakura S, Fukuzumi Y, Fujimori Y, Komiyama M, Tashiro H, Tanigami A, Fujiwara T, Ono T, Yamada K, Fujii Y, Ozaki K, Hirao M, Ohmori Y, Kawabata A, Hikiji T, Kobatake N, Inagaki H, Ikema Y, Okamoto S, Okitani R, Kawakami T, Noguchi S, Itoh T, Shigeta K, Senba T, Matsumura K, Nakajima Y, Mizuno T, Morinaga M, Sasaki M, Togashi T, Oyama M, Hata H, Watanabe M, Komatsu T, Mizushima-Sugano J, Satoh T, Shirai Y, Takahashi Y, Nakagawa K, Okumura K, Nagase T, Nomura N, Kikuchi H, Masuho Y, Yamashita R, Nakai K, Yada T, Nakamura Y, Ohara O, Isogai T, Sugano S: Complete sequencing and characterization of 21,243 full-length human cDNAs. Nat Genet. 2004 Jan;36(1):40-5. Epub 2003 Dec 21. [PubMed:14702039 ]
  2. Gerhard DS, Wagner L, Feingold EA, Shenmen CM, Grouse LH, Schuler G, Klein SL, Old S, Rasooly R, Good P, Guyer M, Peck AM, Derge JG, Lipman D, Collins FS, Jang W, Sherry S, Feolo M, Misquitta L, Lee E, Rotmistrovsky K, Greenhut SF, Schaefer CF, Buetow K, Bonner TI, Haussler D, Kent J, Kiekhaus M, Furey T, Brent M, Prange C, Schreiber K, Shapiro N, Bhat NK, Hopkins RF, Hsie F, Driscoll T, Soares MB, Casavant TL, Scheetz TE, Brown-stein MJ, Usdin TB, Toshiyuki S, Carninci P, Piao Y, Dudekula DB, Ko MS, Kawakami K, Suzuki Y, Sugano S, Gruber CE, Smith MR, Simmons B, Moore T, Waterman R, Johnson SL, Ruan Y, Wei CL, Mathavan S, Gunaratne PH, Wu J, Garcia AM, Hulyk SW, Fuh E, Yuan Y, Sneed A, Kowis C, Hodgson A, Muzny DM, McPherson J, Gibbs RA, Fahey J, Helton E, Ketteman M, Madan A, Rodrigues S, Sanchez A, Whiting M, Madari A, Young AC, Wetherby KD, Granite SJ, Kwong PN, Brinkley CP, Pearson RL, Bouffard GG, Blakesly RW, Green ED, Dickson MC, Rodriguez AC, Grimwood J, Schmutz J, Myers RM, Butterfield YS, Griffith M, Griffith OL, Krzywinski MI, Liao N, Morin R, Palmquist D, Petrescu AS, Skalska U, Smailus DE, Stott JM, Schnerch A, Schein JE, Jones SJ, Holt RA, Baross A, Marra MA, Clifton S, Makowski KA, Bosak S, Malek J: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome Res. 2004 Oct;14(10B):2121-7. [PubMed:15489334 ]
  3. Taylor MS: Characterization and comparative analysis of the EGLN gene family. Gene. 2001 Sep 5;275(1):125-32. [PubMed:11574160 ]
  4. 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 ]
  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. 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 ]
  7. 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 ]
  8. 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 ]