EGLN1
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| Location (UCSC) | Chr 1: 231.36 – 231.42 Mb | Chr 8: 125.64 – 125.68 Mb | |||||||
| PubMed search | [3] | [4] | |||||||
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Hypoxia-inducible factor prolyl hydroxylase 2 (HIF-PH2), or prolyl hydroxylase domain-containing protein 2 (PHD2), is an enzyme encoded by the EGLN1
HIF prolyl-hydroxylase
.
The hypoxia response
angiogenic growth factors.[9] In normoxia, HIF alpha subunits are marked for the ubiquitin-proteasome degradation pathway through hydroxylation of proline-564 and proline-402 by PHD2. Prolyl hydroxylation is critical for promoting pVHL binding to HIF, which targets HIF for polyubiquitylation.[8]
Structure
PHD2 is a 46-kDa enzyme that consists of an
hydrophobic residues, possibly because such residues are less susceptible to potential oxidative damage by reactive species leaking from the iron center.[10]
PHD2 catalyses the hydroxylation of two sites on HIF-α, which are termed the N-terminal oxygen dependent degradation domain (residues 395-413, NODD) and the C-terminal oxygen dependent degradation domain (residues 556-574, CODD).induced fit mechanism was indicated from the structure, in which residues 237-254 adopt a closed loop conformation, whilst in the structure without CODD or NODD, the same residues adopted an open finger-like conformation.[11][15] Such conformational change was confirmed by NMR spectroscopy,[15] X-ray crystallography[11][15] and molecular dynamics calculations.[16] A recent study found a second peptide binding site on PHD2 although peptide binding to this alternative site did not seem to affect the catalytic activity of the enzyme.[17] Further studies are required to fully understand the biological significance of this second peptide binding site.
The enzyme has a high affinity for iron(II) and
dioxygen slightly above its atmospheric concentration, and PHD2 is thought to be the most important sensor of the cell's oxygen status.[20]
Mechanism
The enzyme incorporates one oxygen atom from dioxygen into the hydroxylated product, and one oxygen atom into the
succinate coproduct.[21] Its interactions with HIF-1α rely on a mobile loop region that helps to enclose the hydroxylation site and helps to stabilize binding of both iron and 2-oxyglutarate.[11] A feedback regulation mechanism that involves the displacement of HIF-1α by hydroxylated HIF-1α when 2-oxoglutarate is limiting was also proposed.[22]
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Biological role and disease relevance
PHD2 is the primary regulator of HIF-1α
However, although it would seem that PHD2 downregulates HIF-1α and thus also tumorigenesis, there have been suggestions of paradoxical roles of PHD2 in
gastric cancer, with PHD2-negative patients having shortened survival compared to PHD2-positive patients.[26]
Recent
genome-wide association studies have suggested that EGLN1 may be involved in the low hematocrit phenotype exhibited by the Tibetan population and hence that EGLN1 may play a role in the heritable adaptation of this population to live at high altitude.[27]
As a therapeutic target
HIF's important role as a
molecular oxygen
for binding at the active site Fe(II) ion.
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000135766 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000031987 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- PMID 11056053.
- PMID 11574160.
- ^ "Entrez Gene: EGLN1 egl nine homolog 1 (C. elegans)".
- ^ PMID 12912907.
- ^ PMID 15581484.
- ^ PMID 16782814.
- ^ PMID 19604478.
- PMID 20695530.
- S2CID 52078684.
- PMID 18063574.
- ^ PMID 27561929.
- .
- PMID 29899950.
- PMID 16880998.
- PMID 16952279.
- PMID 12788921.
- PMID 12039559.
- PMID 29522057.
- PMID 21436457.
- S2CID 24482234.
- PMID 22420978.
- PMID 22236543.
- S2CID 45471238.
- PMID 22804960.
- PMID 22687491.
- PMID 26147748.
- PMID 21665470.
- S2CID 235460239.
- PMID 12925778.
- PMID 17060326.
Further reading
- Semenza GL (2001). "HIF-1, O(2), and the 3 PHDs: how animal cells signal hypoxia to the nucleus". Cell. 107 (1): 1–3. S2CID 14922615.
- Wax SD, Tsao L, Lieb ME, et al. (1996). "SM-20 is a novel 40-kd protein whose expression in the arterial wall is restricted to smooth muscle". Lab. Invest. 74 (4): 797–808. PMID 8606489.
- Taylor MS (2001). "Characterization and comparative analysis of the EGLN gene family". Gene. 275 (1): 125–32. PMID 11574160.
- Epstein AC, Gleadle JM, McNeill LA, et al. (2001). "C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation". Cell. 107 (1): 43–54. S2CID 18372306.
- Oehme F, Ellinghaus P, Kolkhof P, et al. (2002). "Overexpression of PH-4, a novel putative proline 4-hydroxylase, modulates activity of hypoxia-inducible transcription factors". Biochem. Biophys. Res. Commun. 296 (2): 343–9. PMID 12163023.
- Ivan M, Haberberger T, Gervasi DC, et al. (2002). "Biochemical purification and pharmacological inhibition of a mammalian prolyl hydroxylase acting on hypoxia-inducible factor". Proc. Natl. Acad. Sci. U.S.A. 99 (21): 13459–64. PMID 12351678.
- Strausberg RL, Feingold EA, Grouse LH, et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. PMID 12477932.
- Metzen E, Berchner-Pfannschmidt U, Stengel P, et al. (2003). "Intracellular localisation of human HIF-1 alpha hydroxylases: implications for oxygen sensing". J. Cell Sci. 116 (Pt 7): 1319–26. PMID 12615973.
- Cioffi CL, Liu XQ, Kosinski PA, et al. (2003). "Differential regulation of HIF-1 alpha prolyl-4-hydroxylase genes by hypoxia in human cardiovascular cells". Biochem. Biophys. Res. Commun. 303 (3): 947–53. PMID 12670503.
- Aprelikova O, Chandramouli GV, Wood M, et al. (2004). "Regulation of HIF prolyl hydroxylases by hypoxia-inducible factors". J. Cell. Biochem. 92 (3): 491–501. S2CID 24455956.
- Appelhoff RJ, Tian YM, Raval RR, et al. (2004). "Differential function of the prolyl hydroxylases PHD1, PHD2, and PHD3 in the regulation of hypoxia-inducible factor". J. Biol. Chem. 279 (37): 38458–65. PMID 15247232.
- Metzen E, Stiehl DP, Doege K, et al. (2006). "Regulation of the prolyl hydroxylase domain protein 2 (phd2/egln-1) gene: identification of a functional hypoxia-responsive element". Biochem. J. 387 (Pt 3): 711–7. PMID 15563275.
- Baek JH, Mahon PC, Oh J, et al. (2005). "OS-9 interacts with hypoxia-inducible factor 1alpha and prolyl hydroxylases to promote oxygen-dependent degradation of HIF-1alpha". Mol. Cell. 17 (4): 503–12. PMID 15721254.
- Ozer A, Wu LC, Bruick RK (2005). "The candidate tumor suppressor ING4 represses activation of the hypoxia inducible factor (HIF)". Proc. Natl. Acad. Sci. U.S.A. 102 (21): 7481–6. PMID 15897452.
- Choi KO, Lee T, Lee N, et al. (2006). "Inhibition of the catalytic activity of hypoxia-inducible factor-1alpha-prolyl-hydroxylase 2 by a MYND-type zinc finger". Mol. Pharmacol. 68 (6): 1803–9. S2CID 6673747.
- To KK, Huang LE (2006). "SUPPRESSION OF HIF-1α TRANSCRIPTIONAL ACTIVITY BY THE HIF PROLYL HYDROXYLASE EGLN1". J. Biol. Chem. 280 (45): 38102–7. PMID 16157596.
- Kato H, Inoue T, Asanoma K, et al. (2006). "Induction of human endometrial cancer cell senescence through modulation of HIF-1alpha activity by EGLN1". Int. J. Cancer. 118 (5): 1144–53. PMID 16161047.
External links
- Overview of all the structural information available in the PDB for UniProt: Q9GZT9 (Egl nine homolog 1) at the PDBe-KB.
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