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.[5][6][7][8] PHD2 is a
The hypoxia response
editHIF-1
Structure
editPHD2 is a 46-kDa enzyme that consists of an N-terminal domain homologous to MYND zinc finger domains, and a C-terminal domain homologous to the 2-oxoglutarate dioxygenases. The catalytic domain consists of a double-stranded
PHD2 catalyses the hydroxylation of two sites on HIF-
The enzyme has a high affinity for iron(II) and 2-oxoglutarate (also known as
Mechanism
editThe enzyme incorporates one oxygen atom from dioxygen into the hydroxylated product, and one oxygen atom into the succinate coproduct.[21] Its interactions with HIF-1
Biological role and disease relevance
editPHD2 is the primary regulator of HIF-1
However, although it would seem that PHD2 downregulates HIF-1
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
editHIF's important role as a homeostatic mediator implicates PHD2 as a therapeutic target for a range of disorders regarding angiogenesis, erythropoeisis, and cellular proliferation. There has been interest both in potentiating and inhibiting the activity of PHD2.[9] For example, methylselenocysteine (MSC) inhibition of HIF-1
References
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Further reading
edit- Semenza GL (2001). "HIF-1, O(2), and the 3 PHDs: how animal cells signal hypoxia to the nucleus". Cell. 107 (1): 1–3. doi:10.1016/S0092-8674(01)00518-9. PMID 11595178. 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. doi:10.1016/S0378-1119(01)00633-3. 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. doi:10.1016/S0092-8674(01)00507-4. PMID 11595184. 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. doi:10.1016/S0006-291X(02)00862-8. 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. Bibcode:2002PNAS...9913459I. doi:10.1073/pnas.192342099. PMC 129695. 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. Bibcode:2002PNAS...9916899M. doi:10.1073/pnas.242603899. PMC 139241. 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. doi:10.1242/jcs.00318. 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. doi:10.1016/S0006-291X(03)00453-4. 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. doi:10.1002/jcb.20067. PMID 15156561. 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. doi:10.1074/jbc.M406026200. 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. doi:10.1042/BJ20041736. PMC 1135001. 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. doi:10.1016/j.molcel.2005.01.011. 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. Bibcode:2005PNAS..102.7481O. doi:10.1073/pnas.0502716102. PMC 1140452. 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. doi:10.1124/mol.105.015271. PMID 16155211. S2CID 6673747.
- To KK, Huang LE (2006). "SUPPRESSION OF HIF-1
α TRANSCRIPTIONAL ACTIVITY BY THE HIF PROLYL HYDROXYLASE EGLN1". J. Biol. Chem. 280 (45): 38102–7. doi:10.1074/jbc.M504342200. PMC 1307502. 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. doi:10.1002/ijc.21488. PMID 16161047.