PTGS2

PTGS2
Dostupne strukture
PDB	Pretraga ortologa: PDBe RCSB
Spisak PDB ID kodova
	5F1A, 5F19, 5IKQ, 5IKT, 5IKV, 5IKR
Identifikatori
Aliasi	PTGS2
Vanjski ID-jevi	OMIM: 600262 MGI: 97798 HomoloGene: 31000 GeneCards: PTGS2
EC broj	1.14.99.1
Lokacija gena (čovjek)
Hrom.	Hromosom 1 (čovjek)
Kraj	186,680,922 bp
Lokacija gena (miš)
Hrom.	Hromosom 1 (miš)
Kraj	149,983,978 bp
Obrazac RNK ekspresije
	Više referentnih podataka o ekspresiji
Ontologija gena
Molekularna funkcija	• arachidonate 15-lipoxygenase activity; • vezivanje iona metala; • heme binding; • vezivanje enzima; • oxidoreductase activity; • protein homodimerization activity; • dioxygenase activity; • GO:0001948, GO:0016582 vezivanje za proteine; • peroxidase activity; • prostaglandin-endoperoxide synthase activity; • oxidoreductase activity, acting on single donors with incorporation of molecular oxygen, incorporation of two atoms of oxygen; • aktivnost sa transferazom;
Ćelijska komponenta	• citoplazma; • endoplasmic reticulum lumen; • membrana; • Kaveole; • neuron projection; • organelle membrane; • Endoplazmatski retikulum; • intracellular membrane-bounded organelle; • endoplasmic reticulum membrane; • GO:0009327 makromolekulani kompleks;
Biološki proces	• response to fructose; • Učenje; • response to organic substance; • lipoxygenase pathway; • cellular response to mechanical stimulus; • response to manganese ion; • Angiogeneza; • cellular response to hypoxia; • embryo implantation; • negative regulation of cell population proliferation; • response to cytokine; • negative regulation of smooth muscle contraction; • Memorija; • GO:0001306 response to oxidative stress; • maintenance of blood-brain barrier; • response to lithium ion; • response to tumor necrosis factor; • fatty acid biosynthetic process; • positive regulation of synaptic transmission, glutamatergic; • positive regulation of vasoconstriction; • response to organonitrogen compound; • inflammatory response; • positive regulation of smooth muscle contraction; • bone mineralization; • response to fatty acid; • response to vitamin D; • cellular response to UV; • positive regulation of fever generation; • cellular response to fluid shear stress; • positive regulation of synaptic plasticity; • regulation of blood pressure; • response to lipopolysaccharide; • positive regulation of platelet-derived growth factor production; • regulation of inflammatory response; • brown fat cell differentiation; • Nocicepcija; • response to radiation; • prostaglandin biosynthetic process; • cellular response to ATP; • Ovulacija; • positive regulation of smooth muscle cell proliferation; • hair cycle; • response to estradiol; • positive regulation of cell death; • positive regulation of cell migration involved in sprouting angiogenesis; • GO:1904578 response to organic cyclic compound; • lipid metabolism; • positive regulation of nitric oxide biosynthetic process; • response to glucocorticoid; • cyclooxygenase pathway; • fatty acid metabolic process; • positive regulation of fibroblast growth factor production; • decidualization; • regulation of cell population proliferation; • positive regulation of cell population proliferation; • negative regulation of calcium ion transport; • positive regulation of apoptotic process; • positive regulation of transforming growth factor beta production; • positive regulation of vascular endothelial growth factor production; • positive regulation of brown fat cell differentiation; • negative regulation of synaptic transmission, dopaminergic; • cellular oxidant detoxification; • GO:0010260 starenje; • NAD biosynthesis via nicotinamide riboside salvage pathway; • cellular response to heat; • positive regulation of prostaglandin biosynthetic process; • positive regulation of peptidyl-serine phosphorylation; • negative regulation of apoptotic process; • negative regulation of cysteine-type endopeptidase activity involved in apoptotic process; • cellular response to non-ionic osmotic stress; • negative regulation of intrinsic apoptotic signaling pathway in response to osmotic stress; • cellular response to lead ion; • response to angiotensin; • prostaglandin metabolic process; • positive regulation of protein import into nucleus; • cytokine-mediated signaling pathway; • long-chain fatty acid biosynthetic process; • negative regulation of cell cycle; • regulation of neuroinflammatory response;
	Izvori:Amigo / QuickGO
Ortolozi
	5743
	19225
	ENSG00000073756
	ENSMUSG00000032487
	P35354
	Q05769
	NM_000963
	NM_011198
	NP_000954
	NP_035328
	Wikipodaci
Pogledaj/uredi – čovjek	Pogledaj/uredi – miš

Prostaglandin-endoperoksid sintaza 2 (prostaglandin sintaza G/H i ciklooksigenaza) (HUGO-ovi simboli PTGS2; HGNC ID, HGNC:9605), znana i kao ciklooksigenaza-2 ili COX-2, jest enzim koji je kod ljudi kodiran genom PTGS2 sa hromosoma 1^[5] Kod ljudi je to jedna od dviju ciklooksigenaza. Učestvuje u konverziji arahidonske kiseline u prostaglandin H2, važnog prekursora prostaciklina, koji se ispoljava u u upalama.

Aminokiselinska sekvenca

Dužina polipeptidnog lanca je 604 aminokiseline, a molekulska težina 68.996 Da.^[6]

C: Cistein

D: Asparaginska kiselina

E: Glutaminska kiselina

F: Fenilalanin

G: Glicin

H: Histidin

I: Izoleucin

K: Lizin

L: Leucin

M: Metionin

N: Asparagin

P: Prolin

Q: Glutamin

R: Arginin

S: Serin

T: Treonin

V: Valin

W: Triptofan

Y: Tirozin

10	20	30	40	50
MLARALLLCA	VLALSHTANP	CCSHPCQNRG	VCMSVGFDQY	KCDCTRTGFY
GENCSTPEFL	TRIKLFLKPT	PNTVHYILTH	FKGFWNVVNN	IPFLRNAIMS
YVLTSRSHLI	DSPPTYNADY	GYKSWEAFSN	LSYYTRALPP	VPDDCPTPLG
VKGKKQLPDS	NEIVEKLLLR	RKFIPDPQGS	NMMFAFFAQH	FTHQFFKTDH
KRGPAFTNGL	GHGVDLNHIY	GETLARQRKL	RLFKDGKMKY	QIIDGEMYPP
TVKDTQAEMI	YPPQVPEHLR	FAVGQEVFGL	VPGLMMYATI	WLREHNRVCD
VLKQEHPEWG	DEQLFQTSRL	ILIGETIKIV	IEDYVQHLSG	YHFKLKFDPE
LLFNKQFQYQ	NRIAAEFNTL	YHWHPLLPDT	FQIHDQKYNY	QQFIYNNSIL
LEHGITQFVE	SFTRQIAGRV	AGGRNVPPAV	QKVSQASIDQ	SRQMKYQSFN
EYRKRFMLKP	YESFEELTGE	KEMSAELEAL	YGDIDAVELY	PALLVEKPRP
DAIFGETMVE	VGAPFSLKGL	MGNVICSPAY	WKPSTFGGEV	GFQIINTASI
QSLICNNVKG	CPFTSFSVPD	PELIKTVTIN	ASSSRSGLDD	INPTVLLKER
STEL

Struktura

PTGS2 (COX-2) postoji kao homodimer, sa svakim monomer sa molekulskom masom od oko po 70 kDa. Tercijarne i kvatarnarne strukture enzima PTGS1 (COX-1) i PTGS2 (COX-2) su gotovo identične. Svaka podjedinica ima tri po različita strukturna domena: kratki N-terminalni epidermni faktor rasta (EGF) domen; α-heliksni dio koji veže membranu i C-terminalni katalitski domen. PTGS (COX, koji se može zamijeniti sa "citohrom-oksidazom") enzimi su monotopni membranski proteini; membransko-vezujući domen sastoji se od niza amfipatskih α-heliksa sa nekoliko hidrofobnih aminokiselina izloženih monoslojnoj membrani. PTGS1 (COX-1) i PTGS2 (COX-2) su bifunkcionalni enzimi koji provode dvije uzastopne hemijske reakcije na prostorno različitim, ali mehanički spojenim aktivnim mjestima. Aktivna mjesta i ciklooksigenaza i peroksidaza nalaze se u katalitskom domenu, koji čini približno 80% proteina. Katalitski domen je homologan peroksidazama sisara, kao što je mijeloperoksidaza.^[8]^[9] Utvrđeno je da ljudski PTGS2 (COX-2) funkcionira kao konformacijski heterodimer koji ima katalitski monomer (E-cat) i alosterni monomer (E-allo). Hem se vezuje samo za peroksidazno mjesto E-cat dok supstrati, kao i određeni inhibitori (npr. celekoksib), vezuju COX mjesto E-cat. E-cat regulira E-allo na način koji ovisi o tome koji je ligand vezan za E-allo. Supstrat i nesupstrat masne+h kiselina (FAs) i neki PTGS (COX) inhibitori (npr. naproksen) vezuju se prvenstveno za PTGS (COX) mjesto u E-allo. Arahidonska kiselina može se vezati za E-cat i E-allo, ali afinitet AA za E-allo je 25 puta veći nego za Ecat. Palmitinska kiselina, efikasan stimulator huPGHS-2, vezuje samo E-allo u kokristalima palmitinske kiseline/mišjeg PGHS-2. Nesupstratne FA mogu potencirati ili oslabiti PTGS (COX) inhibitore, u zavisnosti od masne kiseline i os toga da li se inhibitor vezuje za E-cat ili E-allo. Studije sugeriraju da je koncentracija i sastav bazena slobodnih masnih kiselina u okruženju u kojem PGHS-2 funkcionira u ćelijama, koji se također naziva FA ton, ključni faktor koji regulira aktivnost PGHS-2 i njegov odgovor na PTGS ( COX) inhibitor.^[7]

Funkcija

PTGS2 (COX-2), pretvara arahidonsku kiselinu (AA) u prostaglandin endoperoksid H2. PTGS su mete za NSAID i inhibitore specifične za PTGS2 (COX-2) koji se nazivaju koksibi. PTGS-2 je homodimerna sekvenca. Svaki monomer enzima ima peroksidazu i aktivno mjesto PTGS (COX). PTGS (COX) enzimi kataliziraju konverziju arahidonske kiseline u prostaglandine u dva koraka. Prvo, vodik se apstrahuje iz ugljika 13 arahidonske kiseline, a zatim se dvije molekule kisika dodaju na PTGS2 (COX-2), dajući PGG2. Drugo, PGG2 se redukuje u PGH2 na aktivnom mjestu peroksidaze. Sintetizirani PGH2 se pretvara u prostaglandine (PGD2, PGE2, PGF_2α), prostaciklin (PGI2) ili tromboksan A2 pomoću tkivno specifičnih izomeraza.^[10]

Dok metabolizira arahidonsku kiselinu prvenstveno u PGG2, COX-2, također pretvara ovu masnu kiselinu u male količine racemske mješavine 15-hidroksiikozatetraenske kiseline (tj. 15-HETE) sastavljene od ~22% 15(R )-HETE i ~78% 15(S)-HETE stereoizomeri, kao i male količine 11(R)-HETE.^[11] Dva 15-HETE stereoizomera imaju unutrašnju biološku aktivnost, ali, što je možda još važnije, mogu se dalje metabolizirati u glavnu klasu agenasa, lipoksine. Nadalje, COX-2 tretiran aspirinom metabolizira arahidonsku kiselinu gotovo isključivo u 15(R)-HETE, koji se produkt može dalje metabolizirati u epi-lipoksine.^[12] Lipoksini i epilipoksini su moćni antiupalni agensi i mogu doprinijeti ukupnom djelovanju dva COX-a, kao i u aspirinu.

COX-2 prirodno inhibira kalcitriol (aktivni oblik vitamina D).^[13]^[14]

Klinički značaj

PTGS2 (COX-2) nije eksprimiran u normalnim uslovima u većini ćelija, ali povišeni nivoi se nalaze tokom upala. PTGS1 (COX-1) je konstitutivno izražen u mnogim tkivima i dominantan je oblik u sluznici želuca i u bubrezima. Inhibicija PTGS1 (COX-1) smanjuje baznu proizvodnju citoprotektivnih PGE2 i PGI2 u želucu, što može izazvati čir na želucu. Pošto se PTGS2 (COX-2) generalno eksprimira samo u ćelijama u kojima su prostaglandini povećani (npr. tokom upale), sumnjalo se da kandidati za lijekove koji selektivno inhibiraju PTGS2 (COX-2) pokazuju manje nusefekata^[9] ali se pokazalo da značajno povećava rizik od kardiovaskularnih događaja, kao što su srčani i moždani udar. Dva različita mehanizma mogu objasniti kontradiktorne efekte. Niske doze aspirina štite od srčanog i moždanog udara, blokiranjem PTGS1 (COX-1) od stvaranja prostaglandina zvanog tromboksan A2. On spaja trombocite i podstiče zgrušavanje; inhibiranje ovoga pomaže u prevenciji srčanih bolesti. S druge strane, PTGS2 (COX-2) je važniji izvor prostaglandina, posebno prostaciklina koji se nalazi u sluznici krvnih sudova. Prostaciklin opušta ili odljepljuje trombocite, pa selektivni inhibitori COX-2 (koksibi) povećavaju rizik od kardiovaskularnih događaja zbog zgrušavanja.^[16]

Nesteroidni antiupalni lijekovi (NSAID) inhibiraju proizvodnju prostaglandina PTGS1 (COX-1) i PTGS2 (COX-2). NSAID selektivni za inhibiciju PTGS2 (COX-2) imaju manju vjerovatnoću od uobičajenih lijekova da izazovu gastrointestinalne nuspojave, ali mogu uzrokovati kardiovaskularne poteškoće, kao što su srčana insuficijencija, infarkt miokarda i moždani udar. Studije s ljudskim Famakološk i genegtičke studije na genetički manipuliranim glodarima i drugim životinjskim modelima i randomizirana ispitivanja pokazuju da je to zbog supresije PTGS2 (COX-2) zavisnih kardioprotektivnih prostaglandina, a prostaciklina posebno.^[17]

Ekspresija PTGS2 (COX-2) je pojačana kod mnogih karcinoma. Prekomjerna ekspresija PTGS2 (COX-2) zajedno sa povećanom angiogenezom i ekspresijom SLC2A1 (GLUT-1) značajno je povezana s karcinomom žučne kese.^[18] Nadalje, proizvod PTGS2 (COX-2), PGH₂ pretvara se od prostaglandin E2 sintaze u PGE₂, što zauzvrat može stimulirati napredovanje raka. Shodno tome, inhibicija PTGS2 (COX-2) može imati koristi u prevenciji i liječenju ovih tipova raka.^[19]^[20]

Ekspresija COX-2 pronađena je u ljudskim idiopatskim epiretinalnim membranama.^[21] Blokiranje ciklooksigenaza i lornoksikamnom akutnom stadiju upale smanjilo je učestalost formiranja membrane za 43% u dispaznom modelu PVR i za 31% u konkanavalinu jedan. Lornoxicam ne samo da je normalizirao ekspresiju ciklooksigenaza u oba modela PVR, već je neutralizirao i promjene debljine retine i eožnjače, uzrokovane injekcijom proupalnih agenasa. Ove činjenice naglašavaju značaj ciklooksigenaza i prostaglandina u razvoju PVR.^[22]

Povećanje regulacije gena PTGS2 također je povezano s više faza ljudske reprodukcije. Prisutnost gena se nalazi u horionskoj ploči, u amnionskom epitelu, sincitiotrofoblastima, viloznim fibroblastima, horionskim trofoblastima, amnionskim trofoblastima, kao i baznoj ploči placente, u deciduumskim ćelijama i ekstraviloznim citotrofoblastima. Tokom procesa horioamnionitis/deciduitisa, regulacija PTGS2 u amnionu i horiodecidua je jedan od tri ograničena efekta upale u maternici. Povećana ekspresija gena PTGS2 u fetusnim membranama povezana je sa prisustvom upale, što uzrokuje ekspresiju gena za prostaglandin maternice i imunolokalizaciju proteinskog puta prostaglandina u ćelijama horionskog trofoblasta i susednim deciduama ili horionu. PTGS2 povezan je sa upalnim sistemom i primećen je u upalnim leukocitima. Zapaženo je da postoji pozitivna korelacija sa ekspresijom PTGS2 u amnionu tokom spontanog porođaja i otkriveno je da je povećana ekspresija sa gestacijskom dobi nakon prisustva porođaja, bez uočenih promjena u amnionu i horiodecidui, tokom prijevremenih ili terminskih porođaja. Dodatno, oksitocin stimulira ekspresiju PTGS2 u miometrijskim ćelijama.^[23]

Pokazalo se da nositelji mutantnog alela PTGS2 5939Cu kineskoj populaciji Han imaju veći rizik od karcinoma želuca. Osim toga, pronađena je veza između infekcije Helicobacter pylori i prisustva alela 5939C.^[24]

Interakcije

Pokazalo se da PTGS2 ima interakcije sa kaveolinom 1.^[25]

Također pogledajte

Reference

^ ^a ^b ^c GRCh38: Ensembl release 89: ENSG00000073756 - Ensembl, maj 2017
^ ^a ^b ^c GRCm38: Ensembl release 89: ENSMUSG00000032487 - Ensembl, maj 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.
^ Hla T, Neilson K (august 1992). "Human cyclooxygenase-2 cDNA". Proc. Natl. Acad. Sci. U.S.A. 89 (16): 7384–8. Bibcode:1992PNAS...89.7384H. doi:10.1073/pnas.89.16.7384. PMC 49714. PMID 1380156.
^ "UniProt, P35354" (jezik: engleski). Pristupljeno 16. 12. 2021.
^ ^a ^b Dong L, Vecchio AJ, Sharma NP, Jurban BJ, Malkowski MG, Smith WL (maj 2011). "Human cyclooxygenase-2 is a sequence homodimer that functions as a conformational heterodimer". J. Biol. Chem. 286 (21): 19035–46. doi:10.1074/jbc.M111.231969. PMC 3099718. PMID 21467029.
^ Picot D, Loll PJ, Garavito RM (januar 1994). "The X-ray crystal structure of the membrane protein prostaglandin H2 synthase-1". Nature. 367 (6460): 243–9. Bibcode:1994Natur.367..243P. doi:10.1038/367243a0. PMID 8121489. S2CID 4340064.
^ ^a ^b Kurumbail RG, Kiefer JR, Marnett LJ (decembar 2001). "Cyclooxygenase enzymes: catalysis and inhibition". Curr. Opin. Struct. Biol. 11 (6): 752–60. doi:10.1016/S0959-440X(01)00277-9. PMID 11751058.
^ O'Banion MK (1999). "Cyclooxygenase-2: molecular biology, pharmacology, and neurobiology". Crit Rev Neurobiol. 13 (1): 45–82. doi:10.1615/critrevneurobiol.v13.i1.30. PMID 10223523.
^ Mulugeta S, Suzuki T, Hernandez NT, Griesser M, Boeglin WE, Schneider C (2010). "Identification and absolute configuration of dihydroxy-arachidonic acids formed by oxygenation of 5S-HETE by native and aspirin-acetylated COX-2". J. Lipid Res. 51 (3): 575–85. doi:10.1194/jlr.M001719. PMC 2817587. PMID 19752399.
^ Serhan CN (2005). "Lipoxins and aspirin-triggered 15-epi-lipoxins are the first lipid mediators of endogenous anti-inflammation and resolution". Prostaglandins Leukot. Essent. Fatty Acids. 73 (3–4): 141–62. doi:10.1016/j.plefa.2005.05.002. PMID 16005201.
^ Wang Q1, He Y, Shen Y, Zhang Q, Chen D, Zuo C, Qin J, Wang H, Wang J, Yu Y. (2014). "Vitamin D inhibits COX-2 expression and inflammatory response by targeting thioesterase superfamily member 4". J Biol Chem. 289 (17): 11681–11694. doi:10.1074/jbc.M113.517581. PMC 4002078. PMID 24619416.CS1 održavanje: upotreba parametra authors (link)
^ Kassi E1, Adamopoulos C, Basdra EK, Papavassiliou AG. (2013). "Role of Vitamin D in Atherosclerosis". Circulation. 128 (23): 2517–2531. doi:10.1161/CIRCULATIONAHA.113.002654. PMID 24297817.CS1 održavanje: upotreba parametra authors (link)
^ PDB 3PGH
^ Ruan, C. H.; So, S. P.; Ruan, K. H. (2011). "Inducible COX-2 dominates over COX-1 in prostacyclin biosynthesis: Mechanisms of COX-2 inhibitor risk to heart disease". Life Sciences. 88 (1–2): 24–30. doi:10.1016/j.lfs.2010.10.017. PMC 3046773. PMID 21035466.
^ Wang D, Patel VV, Ricciotti E, Zhou R, Levin MD, Gao E, Yu Z, Ferrari VA, Lu MM, Xu J, Zhang H, Hui Y, Cheng Y, Petrenko N, Yu Y, FitzGerald GA (maj 2009). "Cardiomyocyte cyclooxygenase-2 influences cardiac rhythm and function". Proc. Natl. Acad. Sci. U.S.A. 106 (18): 7548–52. Bibcode:2009PNAS..106.7548W. doi:10.1073/pnas.0805806106. PMC 2670242. PMID 19376970.
^ Legan M (august 2010). "Cyclooxygenase-2, p53 and glucose transporter-1 as predictors of malignancy in the development of gallbladder carcinomas". Bosn J Basic Med Sci. 10 (3): 192–6. doi:10.17305/bjbms.2010.2684. PMC 5504494. PMID 20846124.
^ EntrezGene 5743
^ Menter DG, Schilsky RL, DuBois RN (mart 2010). "Cyclooxygenase-2 and cancer treatment: understanding the risk should be worth the reward". Clin. Cancer Res. 16 (5): 1384–90. doi:10.1158/1078-0432.CCR-09-0788. PMC 4307592. PMID 20179228.
^ KASE, SATORU; SAITO, WATARU; OHNO, SHIGEAKI; ISHIDA, SUSUMU (2010). "Cyclo-Oxygenase-2 Expression in Human Idiopathic Epiretinal Membrane". Retina. 30 (5): 719–723. doi:10.1097/iae.0b013e3181c59698. PMID 19996819. S2CID 205650971.
^ Tikhonovich, Marina V.; Erdiakov, Aleksei K.; Gavrilova, Svetlana A. (21. 6. 2017). "Nonsteroid anti-inflammatory therapy suppresses the development of proliferative vitreoretinopathy more effectively than a steroid one". International Ophthalmology (jezik: engleski). 38 (4): 1365–1378. doi:10.1007/s10792-017-0594-3. ISSN 0165-5701. PMID 28639085. S2CID 4017540.
^ Phillips, Robert J et al. “Prostaglandin pathway gene expression in human placenta, amnion and choriodecidua is differentially affected by preterm and term labour and by uterine inflammation.” BMC pregnancy and childbirth vol. 14 241. 22 Jul. 2014, doi:10.1186/1471-2393-14-241
^ Li Y, He W, Liu T, Zhang Q (decembar 2010). "A new cyclo-oxygenase-2 gene variant in the Han Chinese population is associated with an increased risk of gastric carcinoma". Mol Diagn Ther. 14 (6): 351–5. doi:10.1007/bf03256392. PMID 21275453. S2CID 1229751.
^ Liou JY, Deng WG, Gilroy DW, Shyue SK, Wu KK (septembar 2001). "Colocalization and interaction of cyclooxygenase-2 with caveolin-1 in human fibroblasts". J. Biol. Chem. 276 (37): 34975–82. doi:10.1074/jbc.M105946200. PMID 11432874.

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[15] PDB 3PGH

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