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{{Infokutija gen}}
'''[[Hipoksija|Hipoksijski]]-inducibilni faktor prolil-[[hidroksilaze]] 2''' (HIF-PH2) ili '''protein 2 sa prolil-hidroksilaznim domenom''' (PHD2), znan i kao '''Egl [[homolog]] dedvet''', jest [[enzim]] koji je kod [[ljudi]] [[kodon|kodiran]] [[gen]]om '''EGLN1''' sa  [[hromosom 1|hromosoma 1]].<ref name="pmid11056053">{{cite journal |vauthors=Dupuy D, Aubert I, Duperat VG, Petit J, Taine L, Stef M, Bloch B, Arveiler B | title = Mapping, characterization, and expression analysis of the SM-20 human homologue, c1orf12, and identification of a novel related gene, SCAND2 | journal = Genomics | volume = 69 | issue = 3 | pages = 348–54 |date=Nov 2000 | pmid = 11056053 | doi = 10.1006/geno.2000.6343 }}</ref><ref name="pmid11574160">{{cite journal  | author=Taylor MS |title=Characterization and comparative analysis of the EGLN gene family |journal=Gene |volume=275 |issue= 1 |pages= 125–32 |year= 2001 |pmid= 11574160 |doi=10.1016/S0378-1119(01)00633-3  }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: EGLN1 egl nine homolog 1 (C. elegans)| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=54583}}</ref><ref name="pmid12912907">{{cite journal |vauthors=Berra E, Benizri E, Ginouvès A, Volmat V, Roux D, Pouysségur J | title = HIF prolyl-hydroxylase 2 is the key oxygen sensor setting low steady-state levels of HIF-1α in normoxia | journal = The EMBO Journal | volume = 22 | issue = 16 | pages = 4082–4090 |date=Aug 2003 | pmid = 12912907 | pmc = 175782 | doi = 10.1093/emboj/cdg392 }}</ref> PHD2 je [[alfa-ketoglutarat zavisna hidroksilaza|α-ketoglutarat/2-oksoglutarat zavisna hidroksilaza]], [[natporodica proteina]] koji ne sadrži [[gvožđe]]. Kod ljudi, PHD2 je jedan od tri [[izozim|izoforma]] [[hipoksija-inducibilni faktor prolin-dioksigenaze|hipoksija-inducibilnog faktora prolin-dioksigenaze]], koja je također poznata kao [[HIF prolil-hidroksilaza]].

==Aminokiselinska sekvenca==	
Dužina [[polipeptid]]nog lanca je 426 [[aminokiselina]], a [[molekularna masa|molekulska težina]] 46.021 [[dalton (jedinica)|Da]].<ref name="UniProt">{{cite web|url=http://www.uniprot.org/uniprot/Q9GZT9#sequences |title=UniProt, Q9GZT9 |language=en. |access-date=10. 12. 2021}}</ref>
{{legenda aminokiselina}}
<table  style="font-family:monospace;">
<tr style="text-align:right;"><th>10</th><th></th><th>20</th><th></th><th>30</th><th></th><th>40</th><th></th><th>50</th></tr>
<tr style="background-color: #eee;"><td>MANDSGGPGG</td><td style="background-color: #f9f9f9;"></td><td>PSPSERDRQY</td><td style="background-color: #f9f9f9;"></td><td>CELCGKMENL</td><td style="background-color: #f9f9f9;"></td><td>LRCSRCRSSF</td><td style="background-color: #f9f9f9;"></td><td>YCCKEHQRQD</td></tr>
<tr style="background-color: #eee;"><td>WKKHKLVCQG</td><td style="background-color: #f9f9f9;"></td><td>SEGALGHGVG</td><td style="background-color: #f9f9f9;"></td><td>PHQHSGPAPP</td><td style="background-color: #f9f9f9;"></td><td>AAVPPPRAGA</td><td style="background-color: #f9f9f9;"></td><td>REPRKAAARR</td></tr>
<tr style="background-color: #eee;"><td>DNASGDAAKG</td><td style="background-color: #f9f9f9;"></td><td>KVKAKPPADP</td><td style="background-color: #f9f9f9;"></td><td>AAAASPCRAA</td><td style="background-color: #f9f9f9;"></td><td>AGGQGSAVAA</td><td style="background-color: #f9f9f9;"></td><td>EAEPGKEEPP</td></tr>
<tr style="background-color: #eee;"><td>ARSSLFQEKA</td><td style="background-color: #f9f9f9;"></td><td>NLYPPSNTPG</td><td style="background-color: #f9f9f9;"></td><td>DALSPGGGLR</td><td style="background-color: #f9f9f9;"></td><td>PNGQTKPLPA</td><td style="background-color: #f9f9f9;"></td><td>LKLALEYIVP</td></tr>
<tr style="background-color: #eee;"><td>CMNKHGICVV</td><td style="background-color: #f9f9f9;"></td><td>DDFLGKETGQ</td><td style="background-color: #f9f9f9;"></td><td>QIGDEVRALH</td><td style="background-color: #f9f9f9;"></td><td>DTGKFTDGQL</td><td style="background-color: #f9f9f9;"></td><td>VSQKSDSSKD</td></tr>
<tr style="background-color: #eee;"><td>IRGDKITWIE</td><td style="background-color: #f9f9f9;"></td><td>GKEPGCETIG</td><td style="background-color: #f9f9f9;"></td><td>LLMSSMDDLI</td><td style="background-color: #f9f9f9;"></td><td>RHCNGKLGSY</td><td style="background-color: #f9f9f9;"></td><td>KINGRTKAMV</td></tr>
<tr style="background-color: #eee;"><td>ACYPGNGTGY</td><td style="background-color: #f9f9f9;"></td><td>VRHVDNPNGD</td><td style="background-color: #f9f9f9;"></td><td>GRCVTCIYYL</td><td style="background-color: #f9f9f9;"></td><td>NKDWDAKVSG</td><td style="background-color: #f9f9f9;"></td><td>GILRIFPEGK</td></tr>
<tr style="background-color: #eee;"><td>AQFADIEPKF</td><td style="background-color: #f9f9f9;"></td><td>DRLLFFWSDR</td><td style="background-color: #f9f9f9;"></td><td>RNPHEVQPAY</td><td style="background-color: #f9f9f9;"></td><td>ATRYAITVWY</td><td style="background-color: #f9f9f9;"></td><td>FDADERARAK</td></tr>
<tr style="background-color: #eee;"><td>VKYLTGEKGV</td><td style="background-color: #f9f9f9;"></td><td>RVELNKPSDS</td><td style="background-color: #f9f9f9;"></td><td>VGKDVF</td></tr>
</table>

==Struktura==
[[slika:PHD2 iron binding site.png|thumb|left|[[Mjesto vezanja]] gvožđa u PHD2]]
PHD2 je enzim od 46 kDa koji se sastoji od [[N-terminal]]nog domena, [[homolog]]nog domena [[MYND cinkov prst|MYND cinkovom prstu]] i [[C-terminal]]nog domena homolognog 2-oksoglutarat [[dioksigenaza|dioksigenazi]]. Katalitski domen sastoji se od dvolančanog [[Beta-heliks|β-heliksnog]] jezgra koje je stabilizirano sa tri [[alfa-heliks|α-heliksa]] spakovana duž glavnog [[beta-list|β-lista]].<ref name="pmid16782814">{{cite journal | vauthors = McDonough M, Li V, Flashman E, Chowdhury R, Mohr C, Liénard ZJ, Oldham N, Clifton I, Lewis J, McNeill L, Kurzeja R, Hewitson K, Yang E, Jordan S, Syed R, Schofield C | title = Cellular oxygen sensing: Crystal structure of hypoxia-inducible factor prolyl hydroxylase (PHD2) | journal = Proc Natl Acad Sci USA | volume = 103 | issue = 26 | pages = 9814–9 |date=Jun 2006 | pmid = 16782814 | pmc =  1502536| doi = 10.1073/pnas.0601283103 | bibcode = 2006PNAS..103.9814M | doi-access = free }}</ref> [[Aktivno mjesto]], koje se nalazi u džepu između β-listova, helatira [[gvožđe]](II) koordinacijom [[histidin]]a i [[aspartat]]a. 2-oksoglutarat istiskuje molekulu vode da bi se vezao i gvožđe.<ref name="pmid19604478">{{cite journal |vauthors=Chowdhury R, McDonough M, Mecinović J, Loenarz C, Flashman E, Hewitson K, Domene C, Schofield C | title = Structural basis for binding of hypoxia-inducible factor to the oxygen-sensing prolyl hydroxylases | journal = Structure | volume = 17 | issue = 7 | pages = 981–9 |date=Jul 2009 | pmid = 19604478 | doi = 10.1016/j.str.2009.06.002 | doi-access = free }}</ref> Aktivno mjesto obloženo je [[hidrofob]]nim ostacima, vjerovatno zato što su takvi ostaci manje podložni potencijalnim oksidativnim oštećenjima [[ROS|reaktivnim vrstama kisika]] koje ističu iz centra gvožđa.<ref name="pmid16782814"/>

PHD2 katalizira hidroksilaciju dva mjesta na HIF-α, koja se nazivaju [[N-terminal]]ni domen razgradnje zavisan od kisika (ostaci 395-413, NODD) i [[C-terminal]]ni domen razgradnje zavisan od kisika (ostaci 556-574, CODD).<ref name="pmid20695530">{{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-1α  | journal = Biochemistry | volume = 49 | issue = 32 | pages = 6936–6944 |date=Aug 2010 | pmid = 20695530 | doi = 10.1021/bi100358t }}</ref><ref name="pmid30144273">{{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=Aug 2018 | pmid = 30144273 | doi = 10.1002/cbic.201800246 | s2cid = 52078684 | url = https://ora.ox.ac.uk/objects/uuid:747a3412-18c3-4fc3-90c4-604818216520 | hdl = 11343/261073 | hdl-access = free }}</ref> Ova dva HIF [[supstrat (biohemija)|supstrata]] obično su predstavljena [[peptid]]ima dugim 19-aminokiselinskim sekvencama u eksperimentima "[[in vitro]]".<ref name="pmid18063574">{{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 = J Biol Chem | volume = 283 | issue = 7 | pages = 3808–3815 |date=Feb 2008 | pmid = 18063574 | doi = 10.1074/jbc.M707411200 | doi-access = free }}</ref> [[Rendgenska kristalografija]] i [[NMR|NMR spektroskopija]] su pokazali da se oba peptida vezuju za isto [[mjesto vezivanja]] na PHD2, u rascjepu na površini PHD2.<ref name="pmid19604478"/><ref name="pmid27561929">{{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 = Nat Commun | volume = 7 | pages = 12673 |date=Aug 2016 | pmid = 27561929 | pmc =5007464 | doi = 10.1038/ncomms12673 | bibcode = 2016NatCo...712673C }}</ref> [[Inducirano uklapanje]] mehanizam je naznačen iz strukture, u kojoj ostaci 237-254 usvajaju konformaciju zatvorene petlje, dok u strukturi bez CODD ili NODD, isti ostaci imaju otvorenu konformaciju poput prsta.<ref name="pmid19604478"/><ref name="pmid27561929"/> Takva konformacijska promjena potvrđena je NMR spektroskopijom,<ref name="pmid27561929"/> rentgenskom kristalografijom<ref name="pmid19604478"/><ref name="pmid27561929"/> i proračunima molekulske dinamike.<ref name="ejic201200391">{{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  }}</ref> Nedavna studija pronašla je drugo [[mjesto vezivanja]] [[peptid]]a na PHD2, iako se čini da vezivanje peptida za ovo alternativno mjesto nije uticalo na katalitsku aktivnost enzima.<ref name="C8SC00286J">{{cite journal |vauthors=McAllister TE, Yeh TL, Abboud MI, Leung IK, Hookway ES, King ON, Bhushan B, Williams ST, Hopkinson RJ, Muenzel 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 = Chem Sci | volume = 9| issue = 20| pages = 4569–4578|date=2018 | pmid = 29899950| pmc = 5969509| doi = 10.1039/C8SC00286J  | doi-access = free}}</ref> Potrebne su daljnje studije kako bi se u potpunosti razumio biološki značaj ovog drugog mjesta vezivanja peptida.

[[Enzim]] ima visok afinitet za [[gvožđe]](II) i [[Alfa-ketoglutarna kiselina|2-oksoglutarat]] (također poznat kao α-ketoglutarat), i sa ovim faktorima formira dugovječni kompleks.<ref name="pmid16880998">{{cite journal |vauthors=McNeill L, Flashman E, Buck M, Hewitson K, Clifton I, Jeschke G, Claridge T, Ehrismann D, Oldham N, Schofield C | title = Hypoxia-inducible factor prolyl hydroxylase 2 has a high affinity for ferrous iron and 2-oxoglutarate | journal = Mol. Biosyst. | volume = 1 | issue = 4 | pages = 321–4 |date=Oct 2005 | pmid = 16880998 | doi = 10.1039/b511249b }}</ref> Predloženo je da koncentracije kosupstrata i gvožđa podstiču HIF hidroksilaze da reaguju na odgovarajući "hipoksijski prozor" za određeni tip ćelije ili tkiva.<ref name="pmid16952279">{{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 = Biochem. J. | volume = 401 | issue = 1 | pages = 227–34 |date=Jan 2007 | pmid = 16952279 | pmc = 1698668 | doi = 10.1042/BJ20061151 }}</ref> Studije su otkrile da PHD2 ima [[Michaelis-Mentenova kinetika|K<sub>M</sub>]] za [[dioksigen]] malo iznad svoje atmosferske koncentracije, a PHD2 se smatra najvažnijim senzorom ćelijskog status< kisika.<ref name="pmid12788921">{{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 = J. Biol. Chem. | volume = 278 | issue = 33 | pages = 30772–80 |date=Aug 2003 | pmid = 12788921 | doi = 10.1074/jbc.M304982200 | doi-access = free }}</ref>

==Hipoksijski odgocvor==
[[HIF1A|HIF-1α]] je sveprisutan, konstitutivno sintetiziran [[transkripcijski faktor]], odgovoran za povećanje [[ekspresije gena]] uključenih u ćelijski odgovor na [[hipoksija|hipoksiju]]. Ovi genski proizvodi mogu uključivati proteine kao što su [[glikoliza|glikolitski]] enzimi i [[angiogeneza|angiogeni]] [[faktori rasta]].<ref name="pmid15581484">{{cite journal |vauthors=William C, Nicholls L, Ratcliffe P, Pugh C, Maxwell P | title = The prolyl hydroxylase enzymes that act as oxygen sensors regulating destruction of hypoxia-inducible factor α | journal = Advan. Enzyme Regul. | volume = 44 | pages = 75–92 | year = 2004 | pmid = 15581484 | doi = 10.1016/j.advenzreg.2003.11.017 }}</ref> Kod normoksije, podjedinice HIF alfa su označene za  degradacije [[proteasom|ubikvitin-proteasomskim]] putem [[hidroksilacija]] [[prolin]]a-564 i prolina-402 putem PHD2. Hidroksilacija prolila je kritična za promociju [[Von Hippel–Lindauov tumorski supresor|pVHL]] vezivanja za HIF, koji cilja HIF za poliubikvitilaciju.<ref name="pmid12912907"/>

==Mehanizam==
Enzim uključuje jedan atom kisika iz diokisika u hidroksilirani proizvod i jedan atom kisika u [[sukcinat]]nom koproizvod.<ref name="pmid12039559">{{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 = Bioorg. Med. Chem. | volume = 12 | issue = 12 | pages = 1547–50 |date=Jun 2002 | pmid = 12039559 | doi = 10.1016/S0960-894X(02)00219-6}}</ref> Njegove interakcije sa HIF-1α oslanjaju se na regiju mobilne petlje, koja pomaže da se zatvori mjesto hidroksilacije i  u stabilizaciji vezivanja gvožđa i 2-oksi[[glutarat]]a.<ref name="pmid19604478"/> A također je predložena i [[Povratna sprega|regulacija mehanizma povratnih informacija]] koji uključuje zamjenu HIF-1α hidroksiliranim HIF-1α, kada je 2-oksoglutarat ograničavajući.<ref name="pmid29522057">{{cite journal |authors=Abboud MI, McAllister TE, Leung IKH, Chowdhury R, Jorgensen C, Domene C, Mecinović J, Lippl K, Hancock RL, Hopkinson RJ, Kawamura A, Claridge TDW, Schofield CJ | title = 2-Oxoglutarate regulates binding of hydroxylated hypoxia-inducible factor to prolyl hydroxylase domain 2 | journal = Chem. Commun. | volume = 54| issue = 25| pages = 3130–3133|date=Mar 2018 | pmid = 29522057 | pmc = 5885369| doi = 10.1039/C8CC00387D}}</ref>
[[Slika:Prolyl hydroxylase 2 (PHD2) reaction scheme.png|thumb|center|500px|PHD2 djeluje kao dioksigenaza da hidroksilira prolin i pretvori 2-oksoglutarat u sukcinat.]]

==Biološka uloga i klinički značaj==
PHD2 je primarni regulator [[stabilno stanje|stabilnog stanja]]  nivoa HIF-1α u ćeliji. PHD2 [[genski nokaut|genski nokdaun]] je pokazao povećane nivoe HIF-1α pod normoksijom, i povećanje jedarne akumulacije HIF-1α i transkripcije zavisne od HIF. Akumulacija HIF-1α u stabilnom stanju ovisila je o količini utišavanja PHD-a na koju je uticala [[siRNK]] u [[HeLa]] ćelijama i nizu drugih ljudskih ćelijskih linija.<ref name="pmid12912907" />

Međutim, iako se čini da PHD2 smanjuje regulaciju HIF-1α, a time i [[tumorigeneza|tumorigenezu]], postoje sugestije o paradoksalnoj ulozi PHD2 u proliferaciji [[tumor]]a. Naprimjer, jedna studija na životinjama pokazala je smanjenje tumora kod miševa s nedostatkom PHD2,  aktivacijom antiproliferativne [[TGF beta signalni put|TGF-β signalizacije]].<ref name="pmid21436457">{{cite journal |vauthors=Ameln AK, 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 Res. | volume = 71 | issue = 9 | pages = 3306–16 |date=maj 2011 | pmid = 21436457 | doi = 10.1158/0008-5472.CAN-10-3838| doi-access = free }}</ref> Ostali  modeli ''[[in vivo]]'' pokazali su aktivnost [[gen supresije tumora|supresije tumora]] za PHD2 kod [[rak gušterače|karcinoma gušterače]], kao i [[rak jetre|raka jetre]].<ref name="pmid21792862">{{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 = 960–72 |date=Feb 2012 | pmid = 21792862 | doi = 10.1002/cncr.26344 | s2cid = 24482234 }}</ref><ref name="pmid22420978">{{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 = J. Hepatol. | volume = 57 | issue = 1 | pages = 61–8 |date=Jul 2012 | pmid = 22420978 | doi = 10.1016/j.jhep.2012.02.021 }}</ref> Studija na 121 pacijentu otkrila je PHD2 kao jak prognostički marker za [[karcinom želuca]], s PHD2 negativnim pacijentima koji imaju skraćeno preživljavanje u poređenju sa PHD2 pozitivnim.<ref name="pmid22236543">{{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 }}</ref>

Nedavne [[GWAS|studije asocijacija na genomu]] sugerirale su da EGLN1 može biti uključen u [[fenotip]] niskog [[hematokrit]]a koji pokazuje [[tibet]]ska [[populacija]] i stoga EGLN1 može imati ulogu u nasljednoj adaptaciji ove populacije da živi pri velikim [[nadmorska visina|nadmorskim visinama]].<ref name="pmid20466884">{{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 = 72–5 |date=Jul 2010 | pmid = 20466884 | doi = 10.1126/science.1189406 | bibcode = 2010Sci...329...72S | s2cid = 45471238 }}</ref>

==Kao terapeutski cilj==
Važna uloga HIF-a kao [[homeostaza|homeostatskog]] medijatora implicira PHD2 kao terapeutsku metu za niz poremećaja u vezi sa [[angiogeneza|angiogenezom]], [[eritropoeza|eritropoezom]] i [[ćelijska proliferacija|ćelijskom proliferacijom]]. Postojao je interes i za pojačavanje i za inhibiciju aktivnosti PHD2.<ref name="pmid15581484"/> Naprimjer, [[metilselenocistein]]ska (MSC) inhibicija HIF-1α dovela je do inhibicije rasta tumora u [[rak bubrega|karcinomu bubrežnih ćelija]] na način ovisan o PHD-u. Smatra se da se ovaj fenomen oslanja na PHD-stabilizaciju, ali mehanistički detalji ovog procesa još nisu istraženi.<ref name="bmc-chintala">{{cite journal |vauthors=Chintala S, Najrana T, Toth K, Cao S, Durrani F, Pili R, Rustum Y | 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 | year = 2012 | pmid = 22804960| pmc = 3466155| doi = 10.1186/1471-2407-12-293 }}</ref> S druge strane, pregledi malih molekula helatora otkrili su hidroksipirone i hidroksipiridone kao potencijalne inhibitore za PHD2.<ref name="pmid22687491">{{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 = J. Inorg. Biochem. | volume = 113 | pages = 25–30 |date=Aug 2012 | pmid = 22687491 | pmc = 3525482 | doi = 10.1016/j.jinorgbio.2012.03.002 }}</ref> Nedavno je otkriveno da su dihidropirazoli, male molekule na bazi [[triazol]]a, moćni inhibitori PHD2 koji su aktivni i ''[[in vitro]]'' i ''[[in vivo]]''.<ref name="pmid26147748">{{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 = 6 | issue = 10 | pages = e0132004 |date=Jul 2015 | pmid = 26147748 | pmc = 4492579  | doi = 10.1371/journal.pone.0132004 | bibcode = 2015PLoSO..1032004C | doi-access = free }}</ref> Također razvijeni su supstratni analogni peptidi za  inhibitornu selektivnost PHD2 u odnosu na faktor koji inhibira HIF (FIH), za koji neki drugi PHD-inhibitori pokazuju preklapajuću specifičnost.<ref name="pmid21665470">{{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 = Bioorg. Med. Chem. Lett. | volume = 21 | issue = 14 | pages = 4325–8 |date=Jul 2011 | pmid = 21665470 | doi = 10.1016/j.bmcl.2011.05.050 }}</ref> [[neurotransmiter|Plinotransmiteri]], uključujući [[ugljik-monoksid]] i [[dušik-oksid]],<ref name="pmid12925778">{{cite journal | vauthors = Metzen E, Zhou J, Jelkmann W, Fandrey J, Brüne B | title = Nitric Oxide Impairs Normoxic Degradation of HIF-1α by Inhibition of Prolyl Hydroxylases | journal = Molecular Biology of the Cell | volume = 14 | issue = 8 | pages = 3470–3481 | date = august 2003 | pmid = 12925778 | doi = 10.1091/mbc.E02-12-0791 | pmc = 181582 }}</ref><ref name="pmid17060326">{{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 = Journal of Biological Chemistry | volume = 282 | issue = 3 | pages = 1788–1796 | date = januar 2007 | pmid = 17060326 | doi = 10.1074/jbc.M607065200 | pmc = | doi-access = free }}</ref> također su inhibitori PHD2, tako što se takmiče sa [[ozon|molekulskim kisikom]] za vezivanje na aktivnom mjestu iona Fe(II).

==Reference==
{{reflist}}

==Dopunska literatura==
{{refbegin |33em}}
*{{cite journal  | author=Semenza GL |title=HIF-1, O(2), and the 3 PHDs: how animal cells signal hypoxia to the nucleus |journal=Cell |volume=107 |issue= 1 |pages= 1–3 |year= 2001 |pmid= 11595178 |doi=10.1016/S0092-8674(01)00518-9  |s2cid=14922615 |doi-access=free }}
*{{cite journal  |vauthors=Wax SD, Tsao L, Lieb ME |title=SM-20 is a novel 40-kd protein whose expression in the arterial wall is restricted to smooth muscle |journal=Lab. Invest. |volume=74 |issue= 4 |pages= 797–808 |year= 1996 |pmid= 8606489 |display-authors=etal}}
*{{cite journal  | author=Taylor MS |title=Characterization and comparative analysis of the EGLN gene family |journal=Gene |volume=275 |issue= 1 |pages= 125–32 |year= 2001 |pmid= 11574160 |doi=10.1016/S0378-1119(01)00633-3  }}
*{{cite journal  |vauthors=Epstein AC, Gleadle JM, McNeill LA |title=C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation |journal=Cell |volume=107 |issue= 1 |pages= 43–54 |year= 2001 |pmid= 11595184 |doi=10.1016/S0092-8674(01)00507-4  |s2cid=18372306 |display-authors=etal|doi-access=free }}
*{{cite journal  |vauthors=Oehme F, Ellinghaus P, Kolkhof P |title=Overexpression of PH-4, a novel putative proline 4-hydroxylase, modulates activity of hypoxia-inducible transcription factors |journal=Biochem. Biophys. Res. Commun. |volume=296 |issue= 2 |pages= 343–9 |year= 2002 |pmid= 12163023 |doi=10.1016/S0006-291X(02)00862-8  |display-authors=etal}}
*{{cite journal  |vauthors=Ivan M, Haberberger T, Gervasi DC |title=Biochemical purification and pharmacological inhibition of a mammalian prolyl hydroxylase acting on hypoxia-inducible factor |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=99 |issue= 21 |pages= 13459–64 |year= 2002 |pmid= 12351678 |doi= 10.1073/pnas.192342099  | pmc=129695 |bibcode=2002PNAS...9913459I |display-authors=etal|doi-access=free }}
*{{cite journal  |vauthors=Strausberg RL, Feingold EA, Grouse LH |title=Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=99 |issue= 26 |pages= 16899–903 |year= 2003 |pmid= 12477932 |doi= 10.1073/pnas.242603899  | pmc=139241 |display-authors=etal|doi-access=free }}
*{{cite journal  |vauthors=Metzen E, Berchner-Pfannschmidt U, Stengel P |title=Intracellular localisation of human HIF-1 alpha hydroxylases: implications for oxygen sensing |journal=J. Cell Sci. |volume=116 |issue= Pt 7 |pages= 1319–26 |year= 2003 |pmid= 12615973 |doi=10.1242/jcs.00318  |display-authors=etal|doi-access=free }}
*{{cite journal  |vauthors=Cioffi CL, Liu XQ, Kosinski PA |title=Differential regulation of HIF-1 alpha prolyl-4-hydroxylase genes by hypoxia in human cardiovascular cells |journal=Biochem. Biophys. Res. Commun. |volume=303 |issue= 3 |pages= 947–53 |year= 2003 |pmid= 12670503 |doi=10.1016/S0006-291X(03)00453-4  |display-authors=etal}}
*{{cite journal  |vauthors=Aprelikova O, Chandramouli GV, Wood M |title=Regulation of HIF prolyl hydroxylases by hypoxia-inducible factors |journal=J. Cell. Biochem. |volume=92 |issue= 3 |pages= 491–501 |year= 2004 |pmid= 15156561 |doi= 10.1002/jcb.20067 |s2cid=24455956 |display-authors=etal|url=https://zenodo.org/record/1229216 }}
*{{cite journal  |vauthors=Appelhoff RJ, Tian YM, Raval RR |title=Differential function of the prolyl hydroxylases PHD1, PHD2, and PHD3 in the regulation of hypoxia-inducible factor |journal=J. Biol. Chem. |volume=279 |issue= 37 |pages= 38458–65 |year= 2004 |pmid= 15247232 |doi= 10.1074/jbc.M406026200 |display-authors=etal|doi-access=free }}
*{{cite journal  |vauthors=Metzen E, Stiehl DP, Doege K |title=Regulation of the prolyl hydroxylase domain protein 2 (phd2/egln-1) gene: identification of a functional hypoxia-responsive element |journal=Biochem. J. |volume=387 |issue= Pt 3 |pages= 711–7 |year= 2006 |pmid= 15563275 |doi= 10.1042/BJ20041736  | pmc=1135001 |display-authors=etal}}
*{{cite journal  |vauthors=Baek JH, Mahon PC, Oh J |title=OS-9 interacts with hypoxia-inducible factor 1alpha and prolyl hydroxylases to promote oxygen-dependent degradation of HIF-1alpha |journal=Mol. Cell |volume=17 |issue= 4 |pages= 503–12 |year= 2005 |pmid= 15721254 |doi= 10.1016/j.molcel.2005.01.011 |display-authors=etal|doi-access=free }}
*{{cite journal  |vauthors=Ozer A, Wu LC, Bruick RK |title=The candidate tumor suppressor ING4 represses activation of the hypoxia inducible factor (HIF) |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=102 |issue= 21 |pages= 7481–6 |year= 2005 |pmid= 15897452 |doi= 10.1073/pnas.0502716102  | pmc=1140452 |bibcode=2005PNAS..102.7481O |doi-access=free }}
*{{cite journal  |vauthors=Choi KO, Lee T, Lee N |title=Inhibition of the catalytic activity of hypoxia-inducible factor-1alpha-prolyl-hydroxylase 2 by a MYND-type zinc finger |journal=Mol. Pharmacol. |volume=68 |issue= 6 |pages= 1803–9 |year= 2006 |pmid= 16155211 |doi= 10.1124/mol.105.015271 |s2cid=6673747 |display-authors=etal}}
*{{cite journal  |vauthors=To KK, Huang LE |title=SUPPRESSION OF HIF-1α TRANSCRIPTIONAL ACTIVITY BY THE HIF PROLYL HYDROXYLASE EGLN1 |journal=J. Biol. Chem. |volume=280 |issue= 45 |pages= 38102–7 |year= 2006 |pmid= 16157596 |doi= 10.1074/jbc.M504342200  | pmc=1307502 |doi-access=free }}
*{{cite journal  |vauthors=Kato H, Inoue T, Asanoma K |title=Induction of human endometrial cancer cell senescence through modulation of HIF-1alpha activity by EGLN1 |journal=Int. J. Cancer |volume=118 |issue= 5 |pages= 1144–53 |year= 2006 |pmid= 16161047 |doi= 10.1002/ijc.21488 |display-authors=etal|doi-access=free }}
{{refend}}

== Vanjski linkovi ==
* {{PDBe-KB2|Q9GZT9|Egl nine homolog 1}}

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Nazad na EGLN1.
Preuzeto iz "https://bs.wikipedia.org/wiki/EGLN1"