EGLN1

HIF-1α is a ubiquitous, constitutively synthesized transcription factor responsible for upregulating the expression of genes involved in the cellular response to hypoxia. These gene products may include proteins such as glycolytic enzymes and angiogenic growth factors.{{cite journal | vauthors = Willam C, Nicholls LG, Ratcliffe PJ, Pugh CW, Maxwell PH | title = The prolyl hydroxylase enzymes that act as oxygen sensors regulating destruction of hypoxia-inducible factor alpha | journal = Advances in Enzyme Regulation | volume = 44 | pages = 75–92 | year = 2004 | pmid = 15581484 | doi = 10.1016/j.advenzreg.2003.11.017 }} 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.

File:PHD2 iron binding site.png

PHD2 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 β-helix core that is stabilized by three α-helices packed along the major β-sheet.{{cite journal | vauthors = McDonough MA, Li V, Flashman E, Chowdhury R, Mohr C, Liénard BM, Zondlo J, Oldham NJ, Clifton IJ, Lewis J, McNeill LA, Kurzeja RJ, Hewitson KS, Yang E, Jordan S, Syed RS, Schofield CJ | title = Cellular oxygen sensing: Crystal structure of hypoxia-inducible factor prolyl hydroxylase (PHD2) | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 103 | issue = 26 | pages = 9814–9819 | date = June 2006 | pmid = 16782814 | pmc = 1502536 | doi = 10.1073/pnas.0601283103 | doi-access = free | bibcode = 2006PNAS..103.9814M }} The active site, which is contained in the pocket between the β-sheets, chelates iron(II) through histidine and aspartate coordination. 2-oxoglutarate displaces a water molecule to bind iron as well.{{cite journal | vauthors = Chowdhury R, McDonough MA, Mecinović J, Loenarz C, Flashman E, Hewitson KS, Domene C, Schofield CJ | title = Structural basis for binding of hypoxia-inducible factor to the oxygen-sensing prolyl hydroxylases | journal = Structure | volume = 17 | issue = 7 | pages = 981–989 | date = July 2009 | pmid = 19604478 | doi = 10.1016/j.str.2009.06.002 | doi-access = free }} The active site is lined by hydrophobic residues, possibly because such residues are less susceptible to potential oxidative damage by reactive species leaking from the iron center.

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).{{cite journal | vauthors = Illingworth CJ, Loenarz C, Schofield CJ, Domene C | title = Chemical basis for the selectivity of the von Hippel Lindau tumor suppressor pVHL for prolyl-hydroxylated HIF-1alpha | journal = Biochemistry | volume = 49 | issue = 32 | pages = 6936–6944 | date = August 2010 | pmid = 20695530 | doi = 10.1021/bi100358t }}{{cite journal | vauthors = Abboud MI, Chowdhury R, Leung IK, Lippl K, Loenarz C, Claridge TD, Schofield CJ | title = Studies on the Substrate Selectivity of the Hypoxia-Inducible Factor Prolyl Hydroxylase 2 Catalytic Domain | journal = ChemBioChem | volume = 19 | issue = 21 | pages = 2262–2267 | date = November 2018 | pmid = 30144273 | doi = 10.1002/cbic.201800246 | hdl-access = free | s2cid = 52078684 | hdl = 11343/261073 }} These two HIF substrates are usually represented by 19 amino acid long peptides in in vitro experiments.{{cite journal | vauthors = Flashman E, Bagg EA, Chowdhury R, Mecinović J, Loenarz C, McDonough MA, Hewitson KS, Schofield CJ | title = Kinetic rationale for selectivity toward N- and C-terminal oxygen-dependent degradation domain substrates mediated by a loop region of hypoxia-inducible factor prolyl hydroxylases | journal = The Journal of Biological Chemistry | volume = 283 | issue = 7 | pages = 3808–3815 | date = February 2008 | pmid = 18063574 | doi = 10.1074/jbc.M707411200 | doi-access = free }} X-ray crystallography and NMR spectroscopy showed that both peptides bind to the same binding site on PHD2, in a cleft on the PHD2 surface.{{cite journal | vauthors = Chowdhury R, Leung IK, Tian YM, Abboud MI, Ge W, Domene C, Cantrelle FX, Landrieu I, Hardy AP, Pugh CW, Ratcliffe PJ, Claridge TD, Schofield CJ | title = Structural basis for oxygen degradation domain selectivity of the HIF prolyl hydroxylases | journal = Nature Communications | volume = 7 | pages = 12673 | date = August 2016 | pmid = 27561929 | pmc = 5007464 | doi = 10.1038/ncomms12673 | bibcode = 2016NatCo...712673C }} An 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. Such conformational change was confirmed by NMR spectroscopy, X-ray crystallography and molecular dynamics calculations.{{cite journal |vauthors=Wick CR, Lanig H, Jäger CM, Burzlaff N, Clark T | title = Structural insight into the prolyl hydroxylase PHD2: a molecular dynamics and DFT study | journal = Eur J Inorg Chem | volume = 2012 | issue = 31| pages = 4973–4985 |date=Nov 2012 | doi = 10.1002/ejic.201200391 | doi-access = free }} 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.{{cite journal | vauthors = McAllister TE, Yeh TL, Abboud MI, Leung IK, Hookway ES, King ON, Bhushan B, Williams ST, Hopkinson RJ, Münzel M, Loik ND, Chowdhury R, Oppermann U, Claridge TD, Goto Y, Suga H, Schofield CJ, Kawamura A | title = Non-competitive cyclic peptides for targeting enzyme-substrate complexes | journal = Chemical Science | volume = 9 | issue = 20 | pages = 4569–4578 | date = May 2018 | pmid = 29899950 | pmc = 5969509 | doi = 10.1039/C8SC00286J | doi-access = free }} 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 2-oxoglutarate (also known as α-ketoglutarate), and forms a long-lived complex with these factors.{{cite journal | vauthors = McNeill LA, Flashman E, Buck MR, Hewitson KS, Clifton IJ, Jeschke G, Claridge TD, Ehrismann D, Oldham NJ, Schofield CJ | title = Hypoxia-inducible factor prolyl hydroxylase 2 has a high affinity for ferrous iron and 2-oxoglutarate | journal = Molecular BioSystems | volume = 1 | issue = 4 | pages = 321–324 | date = October 2005 | pmid = 16880998 | doi = 10.1039/b511249b }} It has been proposed that cosubstrate and iron concentrations poise the HIF hydroxylases to respond to an appropriate "hypoxic window" for a particular cell type or tissue.{{cite journal | vauthors = Ehrismann D, Flashman E, Genn DN, Mathioudakis N, Hewitson KS, Ratcliffe PJ, Schofield CJ | title = Studies on the activity of the hypoxia-inducible-factor hydroxylases using an oxygen consumption assay | journal = The Biochemical Journal | volume = 401 | issue = 1 | pages = 227–234 | date = January 2007 | pmid = 16952279 | pmc = 1698668 | doi = 10.1042/BJ20061151 }} Studies have revealed that PHD2 has a K_M for dioxygen slightly above its atmospheric concentration, and PHD2 is thought to be the most important sensor of the cell's oxygen status.{{cite journal | vauthors = Hirsilä M, Koivunen P, Günzler V, Kivirikko KI, Myllyharju J | title = Characterization of the human prolyl 4-hydroxylases that modify the hypoxia-inducible factor | journal = The Journal of Biological Chemistry | volume = 278 | issue = 33 | pages = 30772–30780 | date = August 2003 | pmid = 12788921 | doi = 10.1074/jbc.M304982200 | doi-access = free }}

The enzyme incorporates one oxygen atom from dioxygen into the hydroxylated product, and one oxygen atom into the succinate coproduct.{{cite journal | vauthors = McNeill LA, Hewitson KS, Gleadle JM, Horsfall LE, Oldham NJ, Maxwell PH, Pugh CW, Ratcliffe PJ, Schofield CJ | title = The use of dioxygen by HIF prolyl hydroxylase (PHD1) | journal = Bioorganic & Medicinal Chemistry Letters | volume = 12 | issue = 12 | pages = 1547–1550 | date = June 2002 | pmid = 12039559 | doi = 10.1016/S0960-894X(02)00219-6 }} 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. A feedback regulation mechanism that involves the displacement of HIF-1α by hydroxylated HIF-1α when 2-oxoglutarate is limiting was also proposed.{{cite journal | vauthors = Abboud MI, McAllister TE, Leung IK, Chowdhury R, Jorgensen C, Domene C, Mecinović J, Lippl K, Hancock RL, Hopkinson RJ, Kawamura A, Claridge TD, Schofield CJ | title = 2-Oxoglutarate regulates binding of hydroxylated hypoxia-inducible factor to prolyl hydroxylase domain 2 | journal = Chemical Communications | volume = 54 | issue = 25 | pages = 3130–3133 | date = March 2018 | pmid = 29522057 | pmc = 5885369 | doi = 10.1039/C8CC00387D }}

File:Prolyl hydroxylase 2 (PHD2) reaction scheme.png

PHD2 is the primary regulator of HIF-1α steady state levels in the cell. A PHD2 knockdown showed increased levels of HIF-1α under normoxia, and an increase in HIF-1α nuclear accumulation and HIF-dependent transcription. HIF-1α steady state accumulation was dependent on the amount of PHD silencing effected by siRNA in HeLa cells and a variety of other human cell lines.

However, although it would seem that PHD2 downregulates HIF-1α and thus also tumorigenesis, there have been suggestions of paradoxical roles of PHD2 in tumor proliferation. For example, one animal study showed tumor reduction in PHD2-deficient mice through activation of antiproliferative TGF-β signaling.{{cite journal | vauthors = Klotzsche-von Ameln A, Muschter A, Mamlouk S, Kalucka J, Prade I, Franke K, Rezaei M, Poitz DM, Breier G, Wielockx B | title = Inhibition of HIF prolyl hydroxylase-2 blocks tumor growth in mice through the antiproliferative activity of TGFβ | journal = Cancer Research | volume = 71 | issue = 9 | pages = 3306–3316 | date = May 2011 | pmid = 21436457 | doi = 10.1158/0008-5472.CAN-10-3838 | doi-access = free }} Other in vivo models showed tumor-suppressing activity for PHD2 in pancreatic cancer as well as liver cancer.{{cite journal | vauthors = Su Y, Loos M, Giese N, Metzen E, Büchler MW, Friess H, Kornberg A, Büchler P | title = Prolyl hydroxylase-2 (PHD2) exerts tumor-suppressive activity in pancreatic cancer | journal = Cancer | volume = 118 | issue = 4 | pages = 960–972 | date = February 2012 | pmid = 21792862 | doi = 10.1002/cncr.26344 | s2cid = 24482234 | doi-access = free }}{{cite journal | vauthors = Heindryckx F, Kuchnio A, Casteleyn C, Coulon S, Olievier K, Colle I, Geerts A, Libbrecht L, Carmeliet P, Van Vlierberghe H | title = Effect of prolyl hydroxylase domain-2 haplodeficiency on the hepatocarcinogenesis in mice | journal = Journal of Hepatology | volume = 57 | issue = 1 | pages = 61–68 | date = July 2012 | pmid = 22420978 | doi = 10.1016/j.jhep.2012.02.021 }} A study of 121 human patients revealed PHD2 as a strong prognostic marker in gastric cancer, with PHD2-negative patients having shortened survival compared to PHD2-positive patients.{{cite journal | vauthors = Kamphues C, Wittschieber D, Klauschen F, Kasajima A, Dietel M, Schmidt SC, Glanemann M, Bahra M, Neuhaus P, Weichert W, Stenzinger A | title = Prolyl hydroxylase domain 2 protein is a strong prognostic marker in human gastric cancer | journal = Pathobiology | volume = 79 | issue = 1 | pages = 11–17 | date = Jan 2012 | pmid = 22236543 | doi = 10.1159/000330170 | doi-access = free }}

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.{{cite journal | vauthors = Simonson TS, Yang Y, Huff CD, Yun H, Qin G, Witherspoon DJ, Bai Z, Lorenzo FR, Xing J, Jorde LB, Prchal JT, Ge R | title = Genetic evidence for high-altitude adaptation in Tibet | journal = Science | volume = 329 | issue = 5987 | pages = 72–75 | date = July 2010 | pmid = 20466884 | doi = 10.1126/science.1189406 | s2cid = 45471238 | doi-access = free | bibcode = 2010Sci...329...72S }}

HIF'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. For example, methylselenocysteine (MSC) inhibition of HIF-1α led to tumor growth inhibition in renal cell carcinoma in a PHD-dependent manner. It is thought that this phenomenon relies on PHD-stabilization, but mechanistic details of this process have not yet been investigated.{{cite journal | vauthors = Chintala S, Najrana T, Toth K, Cao S, Durrani FA, Pili R, Rustum YM | title = Prolyl hydroxylase 2 dependent and Von-Hippel-Lindau independent degradation of Hypoxia-inducible factor 1 and 2 alpha by selenium in clear cell renal cell carcinoma leads to tumor growth inhibition | journal = BMC Cancer | volume = 12 | pages = 293 | date = July 2012 | pmid = 22804960 | pmc = 3466155 | doi = 10.1186/1471-2407-12-293 | doi-access = free }} On the other hand, screens of small-molecule chelators have revealed hydroxypyrones and hydroxypyridones as potential inhibitors for PHD2.{{cite journal | vauthors = Flagg SC, Martin CB, Taabazuing CY, Holmes BE, Knapp MJ | title = Screening chelating inhibitors of HIF-prolyl hydroxylase domain 2 (PHD2) and factor inhibiting HIF (FIH) | journal = Journal of Inorganic Biochemistry | volume = 113 | pages = 25–30 | date = August 2012 | pmid = 22687491 | pmc = 3525482 | doi = 10.1016/j.jinorgbio.2012.03.002 }} Recently, dihydropyrazoles, a triazole-based small molecule, was found to be a potent inhibitor of PHD2 that is active both in vitro and in vivo.{{cite journal | vauthors = Chan MC, Atasoylu O, Hodson E, Tumber A, Leung IK, Chowdhury R, Gómez-Pérez V, Demetriades M, Rydzik AM, Holt-Martyn J, Tian YM, Bishop T, Claridge TD, Kawamura A, Pugh CW, Ratcliffe PJ, Schofield CJ | title = Potent and Selective Triazole-Based Inhibitors of the Hypoxia-Inducible Factor Prolyl-Hydroxylases with Activity in the Murine Brain | journal = PLOS ONE | volume = 10 | issue = 7 | pages = e0132004 | date = Jul 2015 | pmid = 26147748 | pmc = 4492579 | doi = 10.1371/journal.pone.0132004 | doi-access = free | bibcode = 2015PLoSO..1032004C }} Substrate analog peptides have also been developed to exhibit inhibitory selectivity for PHD2 over factor inhibiting HIF (FIH), for which some other PHD-inhibitors show overlapping specificity.{{cite journal | vauthors = Kwon HS, Choi YK, Kim JW, Park YK, Yang EG, Ahn DR | title = Inhibition of a prolyl hydroxylase domain (PHD) by substrate analog peptides | journal = Bioorganic & Medicinal Chemistry Letters | volume = 21 | issue = 14 | pages = 4325–4328 | date = July 2011 | pmid = 21665470 | doi = 10.1016/j.bmcl.2011.05.050 }} Gasotransmitters including carbon monoxide{{cite journal | vauthors = Mbenza NM, Nasarudin N, Vadakkedath PG, Patel K, Ismail AZ, Hanif M, Wright LJ, Sarojini V, Hartinger CG, Leung IK | title = Carbon Monoxide is an Inhibitor of HIF Prolyl Hydroxylase Domain 2 | journal = ChemBioChem | volume = 22 | issue = 15 | pages = 2521–2525 | date = August 2021 | pmid = 34137488 | doi = 10.1002/cbic.202100181 | hdl-access = free | s2cid = 235460239 | hdl = 11343/298654 }} and nitric oxide{{cite journal | vauthors = Metzen E, Zhou J, Jelkmann W, Fandrey J, Brüne B | title = Nitric oxide impairs normoxic degradation of HIF-1alpha by inhibition of prolyl hydroxylases | journal = Molecular Biology of the Cell | volume = 14 | issue = 8 | pages = 3470–3481 | date = August 2003 | pmid = 12925778 | pmc = 181582 | doi = 10.1091/mbc.E02-12-0791 }}{{cite journal | vauthors = Berchner-Pfannschmidt U, Yamac H, Trinidad B, Fandrey J | title = Nitric oxide modulates oxygen sensing by hypoxia-inducible factor 1-dependent induction of prolyl hydroxylase 2 | journal = The Journal of Biological Chemistry | volume = 282 | issue = 3 | pages = 1788–1796 | date = January 2007 | pmid = 17060326 | pmc = | doi = 10.1074/jbc.M607065200 | doi-access = free }} are also inhibitors of PHD2 by competing with molecular oxygen for binding at the active site Fe(II) ion.

Additionally, PHD2 holds significant promise as a therapeutic target for ischemic conditions.{{cite journal | vauthors = Patel JI, Poyya J, Padakannaya A, Kurdekar NM, Khandagale AS, Joshi CG, Kanade SR, Satyamoorthy K | title = Mechanistic insights into gut microbe derived siderophores and PHD2 interactions with implications for HIF-1α stabilization | journal = Scientific Reports | volume = 15 | issue = 1 | pages = 1113 | date = January 2025 | pmid = 39774022 | pmc = 11707245 | doi = 10.1038/s41598-024-83730-8 | bibcode = 2025NatSR..15.1113P }} Ischemia, characterized by reduced blood flow and oxygen supply, can lead to severe tissue damage and dysfunction.{{cite journal | vauthors = Budd SL | title = Mechanisms of neuronal damage in brain hypoxia/ischemia: focus on the role of mitochondrial calcium accumulation | journal = Pharmacology & Therapeutics | volume = 80 | issue = 2 | pages = 203–229 | date = November 1998 | pmid = 9839772 | doi = 10.1016/S0163-7258(98)00029-1 }} Modulating PHD2 activity in ischemic conditions can enhance tissue survival and recovery by stabilizing HIF-1α, which in turn activates genes that facilitate adaptive responses to hypoxia. This includes promoting angiogenesis, erythropoiesis, and metabolic reprogramming, crucial for cell survival under oxygen-deprived conditions.{{cite journal | vauthors = Weidemann A, Johnson RS | title = Biology of HIF-1alpha | journal = Cell Death and Differentiation | volume = 15 | issue = 4 | pages = 621–627 | date = April 2008 | pmid = 18259201 | doi = 10.1038/cdd.2008.12 }}{{cite journal | vauthors = Poyya J, Joshi CG, Kumar DJ, Nagendra HG | title = Sequence Analysis and Phylogenetic Studies of Hypoxia-Inducible Factor-1α | journal = Cancer Informatics | volume = 16 | pages = 1176935117712242 | date = 2017-01-01 | pmid = 28615919 | pmc = 5460953 | doi = 10.1177/1176935117712242 }} Preclinical studies have suggested that inhibition of PHD2 can reduce tissue damage in models of myocardial infarction and cerebral ischemia, providing a foundation for future therapeutic strategies aimed at minimizing the consequences of acute ischemic events.{{Cite journal | vauthors = Puzio M, Moreton N, O'Connor JJ |date= March 2022 |title=Neuroprotective strategies for acute ischemic stroke: Targeting oxidative stress and prolyl hydroxylase domain inhibition in synaptic signalling |journal=Brain Disorders |volume=5 |pages=100030 |doi=10.1016/j.dscb.2022.100030 |issn=2666-4593|doi-access=free }} Ongoing research continues to explore the efficacy and safety of PHD2 inhibitors in various ischemic scenarios, with the potential to extend these findings to clinical applications.

{{reflist}}

{{refbegin|30em}}

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{{refend}}

• {{PDBe-KB2|Q9GZT9|Egl nine homolog 1}}

{{PDB Gallery|geneid=54583}}

{{Dioxygenases}}

{{Enzymes}}

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Category:Human 2OG oxygenases

Category:EC 1.14.11