View source for Cyclooxygenase-2

{{Short description|Human enzyme involved in inflammation}}
{{Redirect|COX-2|COX2|Cytochrome c oxidase subunit 2}}
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{{Infobox gene}}

'''Cyclooxygenase-2''' ('''COX-2'''), also known as '''prostaglandin-endoperoxide synthase 2''' ([[Human Genome Organisation|HUGO]] '''PTGS2'''), is an [[enzyme]] that in humans is encoded by the ''PTGS2'' [[gene]].<ref name="pmid1380156">{{cite journal | vauthors = Hla T, Neilson K | title = Human cyclooxygenase-2 cDNA | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 89 | issue = 16 | pages = 7384–7388 | date = August 1992 | pmid = 1380156 | pmc = 49714 | doi = 10.1073/pnas.89.16.7384 | doi-access = free | bibcode = 1992PNAS...89.7384H }}</ref> In humans it is one of three [[cyclooxygenase]]s. It is involved in the conversion of [[arachidonic acid]] to [[prostaglandin H2|prostaglandin H<sub>2</sub>]], an important precursor of [[prostacyclin]], which is expressed in [[inflammation]].

== Function ==
<!--[[Image:Enzymatic oxidation of arachidonic acid.png|thumb|left| Figure 2. PTGS (COX) enzymes produce [[PGH2|PGH<sub>2</sub>]] from [[Arachidonic acid|AA]] in 12 two consecutive chemical reactions. PGH<sub>2</sub> is converted to other [[prostanoid]]s (at the bottom) by tissue-specific enzymes called isomerases. In the first step of the reaction, two moles of oxygen are added to AA to yield PGG<sub>2</sub>. This is referred to as the PTGS (COX) reaction. The latter is followed by the [[peroxidase]] reaction, which reduces [[PGG2|PGG<sub>2</sub>]] to give PGH2<sub>2</sub>. The PTGS (COX) reaction and the [[peroxidase]] reaction occur at two different locations in PTGS (COX) enzymes. In addition to [[prostaglandins]], PTGS (COX) enzymes also produce small amounts of mono-oxygenated [[metabolite]]s of AA called HETEs.]]-->

PTGS2 (COX-2),  converts [[arachidonic acid|arachidonic acid (AA)]] to prostaglandin endoperoxide H2. PTGSs are targets for [[NSAID]]s and PTGS2 (COX-2) specific inhibitors called coxibs. PTGS-2 is a sequence homodimer. Each [[monomer]] of the enzyme has a [[peroxidase]] and a PTGS (COX) [[active site]]. The PTGS (COX) enzymes catalyze the conversion of AA to [[prostaglandins]] in two steps. First, hydrogen is abstracted from carbon 13 of arachidonic acid, and then two molecules of oxygen are added by the PTGS2 (COX-2), giving [[PGG2|PGG<sub>2</sub>]]. Second, PGG<sub>2</sub> is reduced to [[PGH2|PGH<sub>2</sub>]] in the peroxidase active site. The synthesized PGH<sub>2</sub> is  converted to prostaglandins ([[PGD2|PGD<sub>2</sub>]], [[PGE2|PGE<sub>2</sub>]], [[Prostaglandin F2alpha|PGF<sub>2α</sub>]]), [[prostacyclin]] (PGI<sub>2</sub>), or [[thromboxane A2|thromboxane A<sub>2</sub>]] by tissue-specific isomerases (Figure 2).<ref name="pmid10223523">{{cite journal | vauthors = O'Banion MK | title = Cyclooxygenase-2: molecular biology, pharmacology, and neurobiology | journal = Critical Reviews in Neurobiology | volume = 13 | issue = 1 | pages = 45–82 | year = 1999 | pmid = 10223523 | doi = 10.1615/critrevneurobiol.v13.i1.30 }}</ref>

While metabolizing arachidonic acid primarily to PGG<sub>2</sub>, COX-2 also converts this fatty acid to small amounts of a racemic mixture of [[15-hydroxyicosatetraenoic acid]]s (i.e., 15-HETEs) composed of ~22% 15(''R'')-HETE and ~78% 15(''S'')-HETE [[stereoisomers]] as well as a small amount of 11(''R'')-HETE.<ref name="pmid19752399">{{cite journal | vauthors = Mulugeta S, Suzuki T, Hernandez NT, Griesser M, Boeglin WE, Schneider C | title = Identification and absolute configuration of dihydroxy-arachidonic acids formed by oxygenation of 5S-HETE by native and aspirin-acetylated COX-2 | journal = Journal of Lipid Research | volume = 51 | issue = 3 | pages = 575–585 | date = March 2010 | pmid = 19752399 | pmc = 2817587 | doi = 10.1194/jlr.M001719 | doi-access = free }}</ref> The two 15-HETE stereoisomers have intrinsic biological activities but, perhaps more importantly, can be further metabolized to a major class of agents, the [[lipoxins]].  Furthermore, [[aspirin]]-treated COX-2 metabolizes arachidonic acid almost exclusively to 15(''R'')-HETE which product can be further metabolized to epi-[[lipoxins]].<ref name="pmid16005201">{{cite journal | vauthors = Serhan CN | title = Lipoxins and aspirin-triggered 15-epi-lipoxins are the first lipid mediators of endogenous anti-inflammation and resolution | journal = Prostaglandins, Leukotrienes, and Essential Fatty Acids | volume = 73 | issue = 3–4 | pages = 141–162 | year = 2005 | pmid = 16005201 | doi = 10.1016/j.plefa.2005.05.002 }}</ref>  The lipoxins and epi-lipoxins are potent anti-inflammatory agents and may contribute to the overall activities of the two COX's as well as to aspirin.{{citation needed|date=January 2024}}

COX-2 is naturally inhibited by [[calcitriol]] (the active form of vitamin D).<ref name="pmid24619416">{{cite journal | vauthors = Wang Q, He Y, Shen Y, Zhang Q, Chen D, Zuo C, Qin J, Wang H, Wang J, Yu Y | title = Vitamin D inhibits COX-2 expression and inflammatory response by targeting thioesterase superfamily member 4 | journal = The Journal of Biological Chemistry | volume = 289 | issue = 17 | pages = 11681–11694 | date = April 2014 | pmid = 24619416 | pmc = 4002078 | doi = 10.1074/jbc.M113.517581 | doi-access = free }}</ref><ref name="pmid24297817">{{cite journal | vauthors = Kassi E, Adamopoulos C, Basdra EK, Papavassiliou AG | title = Role of vitamin D in atherosclerosis | journal = Circulation | volume = 128 | issue = 23 | pages = 2517–2531 | date = December 2013 | pmid = 24297817 | doi = 10.1161/CIRCULATIONAHA.113.002654 | doi-access = free }}</ref>

== Mechanism ==

[[File:AACOX.png|thumb|left| [[Arachidonic acid]] bound to the PTGS2 (COX-2) enzyme. [[Polar bond|Polar]] interactions between [[arachidonic acid]] (cyan) and [[serine|Ser]]-530 and [[tyrosine|Tyr]]-385 residues are shown with yellow dashed lines. The substrate is stabilized by hydrophobic interactions.<ref>{{PDB|3OLT}}</ref> ]]

[[File:PGG2 mechanism.png|thumb| Mechanism of COX activation and catalysis. A [[hydroperoxide]] oxidizes the heme  to a [[ferryl-oxo]] derivative that either is [[redox|reduced]] in the first step of the [[peroxidase]] cycle or oxidizes [[Tyrosine]] 385 to a [[tyrosyl radical]]. The tyrosyl radical can then oxidize the 13-pro(S) hydrogen of [[arachidonic acid]] to initiate the COX  cycle.]]

Both the peroxidase and PTGS activities are inactivated during catalysis by mechanism-based, first-order processes, which means that PGHS-2 peroxidase or PTGS activities fall to zero within 1–2 minutes, even in the presence of sufficient substrates.<ref name="pmid8969167">{{cite journal | vauthors = Smith WL, Garavito RM, DeWitt DL | title = Prostaglandin endoperoxide H synthases (cyclooxygenases)-1 and -2 | journal = The Journal of Biological Chemistry | volume = 271 | issue = 52 | pages = 33157–33160 | date = December 1996 | pmid = 8969167 | doi = 10.1074/jbc.271.52.33157 | doi-access = free }}</ref><ref name="pmid10092596">{{cite journal | vauthors = Wu G, Wei C, Kulmacz RJ, Osawa Y, Tsai AL | title = A mechanistic study of self-inactivation of the peroxidase activity in prostaglandin H synthase-1 | journal = The Journal of Biological Chemistry | volume = 274 | issue = 14 | pages = 9231–9237 | date = April 1999 | pmid = 10092596 | doi = 10.1074/jbc.274.14.9231 | doi-access = free }}</ref><ref name="pmid8631960">{{cite journal | vauthors = Callan OH, So OY, Swinney DC | title = The kinetic factors that determine the affinity and selectivity for slow binding inhibition of human prostaglandin H synthase 1 and 2 by indomethacin and flurbiprofen | journal = The Journal of Biological Chemistry | volume = 271 | issue = 7 | pages = 3548–3554 | date = February 1996 | pmid = 8631960 | doi = 10.1074/jbc.271.7.3548 | doi-access = free }}</ref>

The conversion of arachidonic acid to PGG<sub>2</sub> can be shown as a series of [[radical reaction]]s analogous to polyunsaturated [[fatty acid]] [[autoxidation]].<ref name = "Porter_1986">{{cite journal | vauthors = Porter NA | title = Mechanisms for the autoxidation of polyunsaturated lipids | journal = Accounts of Chemical Research | volume = 19 | issue = 9 | pages = 262–8 | year = 1986 | doi = 10.1021/ar00129a001 }}</ref> The 13-pro(S) -hydrogen is abstracted and dioxygen  traps the [[pentadienyl]] radical at carbon 11. The 11-peroxyl radical cyclizes at carbon 9 and the carbon-centered radical generated at C-8 cyclizes at carbon 12, generating the [[endoperoxide]]. The [[allyl]]ic radical generated is trapped by dioxygen at carbon 15 to form the 15-(S) -peroxyl radical; this radical is then reduced to [[PGG2|PGG<sub>2</sub>]]. This is supported by the following evidence: 1) a significant [[kinetic isotope effect]] is observed for the abstraction of the 13-pro (S)-hydrogen; 2) carbon-centered radicals are trapped during [[catalysis]];<ref name="pmid6246094">{{cite journal | vauthors = Mason RP, Kalyanaraman B, Tainer BE, Eling TE | title = A carbon-centered free radical intermediate in the prostaglandin synthetase oxidation of arachidonic acid. Spin trapping and oxygen uptake studies | journal = The Journal of Biological Chemistry | volume = 255 | issue = 11 | pages = 5019–5022 | date = June 1980 | pmid = 6246094 | doi = 10.1016/S0021-9258(19)70741-8 | doi-access = free }}</ref> 3) small amounts of [[oxidation]] products are formed due to the oxygen trapping of an allylic radical intermediate at positions 13 and 15.<ref name="pmid3119336">{{cite journal | vauthors = Hecker M, Ullrich V, Fischer C, Meese CO | title = Identification of novel arachidonic acid metabolites formed by prostaglandin H synthase | journal = European Journal of Biochemistry | volume = 169 | issue = 1 | pages = 113–123 | date = November 1987 | pmid = 3119336 | doi = 10.1111/j.1432-1033.1987.tb13587.x | doi-access = free }}</ref><ref name="pmid9048568">{{cite journal | vauthors = Xiao G, Tsai AL, Palmer G, Boyar WC, Marshall PJ, Kulmacz RJ | title = Analysis of hydroperoxide-induced tyrosyl radicals and lipoxygenase activity in aspirin-treated human prostaglandin H synthase-2 | journal = Biochemistry | volume = 36 | issue = 7 | pages = 1836–1845 | date = February 1997 | pmid = 9048568 | doi = 10.1021/bi962476u }}</ref>

Another mechanism in which the 13-pro (S)-hydrogen is [[deprotonation|deprotonated]] and the [[carbanion]] is [[oxidation|oxidized]] to a [[radical (chemistry)|radical]] is theoretically possible. However, oxygenation of 10,10-difluoroarachidonic acid to 11-(S)-hydroxyeicosa-5,8,12,14-tetraenoic acid is not consistent with the generation of a carbanion intermediate because it would eliminate fluoride to form a conjugated diene.<ref name=Kwok_1987>{{cite journal | vauthors = Kwok PY, Muellner FW, Fried J | title = Enzymatic conversions of 10,10-difluoroarachidonic acid with PGH synthase and soybean lipoxygenase | journal = Journal of the American Chemical Society |date=June 1987 | volume = 109 | issue = 12 | pages = 3692–3698 | doi = 10.1021/ja00246a028 | bibcode = 1987JAChS.109.3692K }}</ref>  The absence of endoperoxide-containing products derived from 10,10-difluoroarachidonic acid has been thought to indicate the importance of a C-10 carbocation in PGG<sub>2</sub>  synthesis.<ref name="pmid10338019">{{cite journal | vauthors = Dean AM, Dean FM | title = Carbocations in the synthesis of prostaglandins by the cyclooxygenase of PGH synthase? A radical departure! | journal = Protein Science | volume = 8 | issue = 5 | pages = 1087–1098 | date = May 1999 | pmid = 10338019 | pmc = 2144324 | doi = 10.1110/ps.8.5.1087 }}</ref> However, the cationic mechanism requires that endoperoxide formation comes before the removal of the 13-pro (S)-hydrogen. This is not consistent with the results of the isotope experiments of arachidonic acid oxygenation.<ref name="pmid6070851">{{cite journal | vauthors = Hamberg M, Samuelsson B | title = On the mechanism of the biosynthesis of prostaglandins E-1 and F-1-alpha | journal = The Journal of Biological Chemistry | volume = 242 | issue = 22 | pages = 5336–5343 | date = November 1967 | pmid = 6070851 | doi = 10.1016/S0021-9258(18)99433-0 | doi-access = free }}</ref>

== Structure ==

[[Image:Cyclooxygenase inhibitors.png|thumb|As shown, different ligands bind either the allosteric or the catalytic subunit. Allosteric subunit binds a non-substrate, activating FA (e.g., palmitic acid). The allosteric subunit with bound fatty acid activates the catalytic subunit by decreasing the Km for AA.<ref name="Dong 2011">{{cite journal | vauthors = Dong L, Vecchio AJ, Sharma NP, Jurban BJ, Malkowski MG, Smith WL | title = Human cyclooxygenase-2 is a sequence homodimer that functions as a conformational heterodimer | journal = The Journal of Biological Chemistry | volume = 286 | issue = 21 | pages = 19035–19046 | date = May 2011 | pmid = 21467029 | pmc = 3099718 | doi = 10.1074/jbc.M111.231969 | doi-access = free }}</ref>]]

PTGS2 (COX-2) exists as a homodimer, each monomer with a molecular mass of about 70 kDa. The tertiary and quaternary structures of PTGS1 (COX-1) and PTGS2 (COX-2) enzymes are almost identical. Each subunit has three different structural domains: a short [[N-terminus|N-terminal]] epidermal growth factor ([[EGF-like domain|EGF]]) domain; an [[alpha helix|α-helical]] membrane-binding moiety; and a [[C-terminus|C-terminal]] catalytic domain. PTGS (COX, which can be confused with "[[cytochrome oxidase]]") enzymes are [[integral monotopic protein|monotopic]] membrane proteins; the membrane-binding domain consists of a series of [[amphiphile|amphipathic]] α helices with several [[hydrophobic]] [[amino acids]] exposed to a membrane monolayer. PTGS1 (COX-1) and PTGS2 (COX-2) are bifunctional enzymes that carry out two consecutive chemical reactions in spatially distinct but mechanistically [[coupling|coupled]] active sites. Both the [[cyclooxygenase]] and the [[peroxidase]] active sites are located in the catalytic domain, which accounts for approximately 80% of the protein. The catalytic domain is [[Homology (biology)|homologous]] to mammalian peroxidases such as [[myeloperoxidase]].<ref name="pmid8121489">{{cite journal | vauthors = Picot D, Loll PJ, Garavito RM | title = The X-ray crystal structure of the membrane protein prostaglandin H2 synthase-1 | journal = Nature | volume = 367 | issue = 6460 | pages = 243–249 | date = January 1994 | pmid = 8121489 | doi = 10.1038/367243a0 | s2cid = 4340064 | bibcode = 1994Natur.367..243P }}</ref><ref name="pmid11751058">{{cite journal | vauthors = Kurumbail RG, Kiefer JR, Marnett LJ | title = Cyclooxygenase enzymes: catalysis and inhibition | journal = Current Opinion in Structural Biology | volume = 11 | issue = 6 | pages = 752–760 | date = December 2001 | pmid = 11751058 | doi = 10.1016/S0959-440X(01)00277-9 }}</ref>

It has been found that human PTGS2 (COX-2) functions as a conformational heterodimer having a catalytic monomer (E-cat) and an allosteric monomer (E-allo). [[Heme]] binds only to the [[peroxidase]] site of E-cat while substrates, as well as certain [[Enzyme inhibitor|inhibitors]] (e.g. [[celecoxib]]), bind the COX site of E-cat. E-cat is regulated by E-allo in a way dependent on what ligand is bound to E-allo. [[Substrate (chemistry)|Substrate]] and non-substrate [[fatty acid]]s (FAs) and some PTGS (COX) inhibitors (e.g. [[naproxen]]) preferentially bind to the PTGS (COX) site of E-allo. [[Arachidonic acid]] can bind to E-cat and E-allo, but the affinity of AA for E-allo is 25 times that for Ecat. Palmitic acid, an efficacious stimulator of [[PGHS-2|huPGHS-2]], binds only E-allo in palmitic acid/murine PGHS-2 co-crystals. Non-substrate FAs can potentiate or [[attenuation|attenuate]]  PTGS (COX) inhibitors depending on the [[fatty acid]] and whether the inhibitor binds E-cat or E-allo. Studies suggest that the concentration and composition of the free fatty acid pool in the environment in which PGHS-2 functions in cells, also referred to as the FA tone, is a key factor regulating the activity of PGHS-2  and its response to PTGS (COX) inhibitors.<ref name="Dong 2011"/>

== Clinical significance ==
[[File:Flurbiprofen in COX-2.png|thumb|left|[[NSAID]] (non-specific inhibitor of PTGS2 (COX-2)) [[flurbiprofen]] (green) bound to PTGS2 (COX-2). Flurbiprofen is stabilized via hydrophobic interactions and polar interactions ([[Tyrosine|Tyr]]-355 and [[Arginine|Arg]]-120).<ref>{{PDB|3PGH}}</ref> ]]

PTGS2 (COX-2) is unexpressed under normal conditions in most cells, but elevated levels are found during [[inflammation]]. PTGS1 (COX-1) is constitutively expressed in many tissues and is the predominant form in gastric mucosa and in the kidneys.<ref>{{cite journal | vauthors = Ali A, Wani AB, Malla BA, Poyya J, Dar NJ, Ali F, Ahmad SB, Rehman MU, Nadeem A | title = Network Pharmacology Integrated Molecular Docking and Dynamics to Elucidate Saffron Compounds Targeting Human COX-2 Protein | journal = Medicina | volume = 59 | issue = 12 | pages = 2058 | date = November 2023 | pmid = 38138161 | pmc = 10744988 | doi = 10.3390/medicina59122058 | doi-access = free }}</ref> Inhibition of PTGS1 (COX-1) reduces the [[basal production]] of cytoprotective [[PGE2|PGE<sub>2</sub>]] and [[PGI2|PG1<sub>2</sub>]] in the [[stomach]], which may contribute to [[gastric ulcer]]ation. Since PTGS2 (COX-2) is generally expressed only in cells where [[prostaglandin]]s are upregulated (e.g., during inflammation), drug-candidates that selectively inhibit PTGS2 (COX-2) were suspected to show fewer [[side-effects]]<ref name=pmid11751058 /> but proved to substantially increase risk for cardiovascular events such as heart attack and stroke. Two different mechanisms may explain contradictory effects. Low-dose aspirin protects against heart attacks and strokes by blocking PTGS1 (COX-1) from forming a prostaglandin called thromboxane A2.  It sticks platelets together and promotes clotting; inhibiting this helps prevent heart disease. On the other hand, PTGS2 (COX-2) is a more important source of prostaglandins, particularly prostacyclin which is found in blood vessel lining.  Prostacyclin relaxes or unsticks platelets, so [[COX-2 inhibitor|selective COX-2 inhibitors]] (coxibs) increase risk of cardiovascular events due to clotting.<ref name="pmid21035466">{{cite journal | vauthors = Ruan CH, So SP, Ruan KH | title = Inducible COX-2 dominates over COX-1 in prostacyclin biosynthesis: mechanisms of COX-2 inhibitor risk to heart disease | journal = Life Sciences | volume = 88 | issue = 1–2 | pages = 24–30 | date = January 2011 | pmid = 21035466 | pmc = 3046773 | doi = 10.1016/j.lfs.2010.10.017 }}</ref>

[[Non-steroidal anti-inflammatory drug]]s (NSAIDs) inhibit [[prostaglandin]] production by PTGS1 (COX-1) and PTGS2 (COX-2). NSAIDs selective for inhibition of PTGS2 (COX-2) are less likely than traditional drugs to cause  [[gastrointestinal]] adverse effects, but could cause [[cardiovascular]] events, such as [[heart failure]], [[myocardial infarction]], and [[stroke]]. Studies with human [[pharmacology]] and [[genetics]], genetically manipulated [[rodents]], and other animal models and randomized trials indicate that this is due to suppression of PTGS2 (COX-2)-dependent cardioprotective [[prostaglandins]],  [[prostacyclin]] in particular.<ref name = "card">{{cite journal | vauthors = 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 | title = Cardiomyocyte cyclooxygenase-2 influences cardiac rhythm and function | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 106 | issue = 18 | pages = 7548–7552 | date = May 2009 | pmid = 19376970 | pmc = 2670242 | doi = 10.1073/pnas.0805806106 | doi-access = free | bibcode = 2009PNAS..106.7548W }}</ref>

The expression of PTGS2 (COX-2) is upregulated in many cancers. The overexpression of PTGS2 (COX-2) along with increased angiogenesis and SLC2A1 (GLUT-1) expression is significantly associated  with gallbladder carcinomas.<ref name="pmid20846124">{{cite journal | vauthors = Legan M | title = Cyclooxygenase-2, p53 and glucose transporter-1 as predictors of malignancy in the development of gallbladder carcinomas | journal = Bosnian Journal of Basic Medical Sciences | volume = 10 | issue = 3 | pages = 192–196 | date = August 2010 | pmid = 20846124 | pmc = 5504494 | doi = 10.17305/bjbms.2010.2684 }}</ref>  Furthermore, the product of PTGS2 (COX-2), [[Prostaglandin H2|PGH<sub>2</sub>]] is converted by [[PTGES2|prostaglandin E<sub>2</sub> synthase]] into [[Prostaglandin E2|PGE<sub>2</sub>]], which in turn can stimulate cancer progression.  Consequently, inhibiting PTGS2 (COX-2) may have benefit in the prevention and treatment of these types of cancer.<ref name = "entrez">{{EntrezGene|5743}}</ref><ref name="pmid20179228">{{cite journal | vauthors = Menter DG, Schilsky RL, DuBois RN | title = Cyclooxygenase-2 and cancer treatment: understanding the risk should be worth the reward | journal = Clinical Cancer Research | volume = 16 | issue = 5 | pages = 1384–1390 | date = March 2010 | pmid = 20179228 | pmc = 4307592 | doi = 10.1158/1078-0432.CCR-09-0788 }}</ref>

COX-2 expression was found in human idiopathic epiretinal membranes.<ref>{{cite journal | vauthors = Kase S, Saito W, Ohno S, Ishida S | title = Cyclo-oxygenase-2 expression in human idiopathic epiretinal membrane | journal = Retina | volume = 30 | issue = 5 | pages = 719–723 | date = May 2010 | pmid = 19996819 | doi = 10.1097/iae.0b013e3181c59698 | s2cid = 205650971 }}</ref> Cyclooxygenases blocking by [[lornoxicam]] in acute stage of inflammation reduced the frequency of membrane formation by 43% in the [[dispase]] model of [[Proliferative vitreoretinopathy|PVR]] and by 31% in the [[Concanavalin A|concanavalin]] one. [[Lornoxicam]] not only normalized the expression of cyclooxygenases in both models of PVR, but also neutralized the changes of the [[retina]] and the [[choroid]] thickness caused by the injection of pro-inflammatory agents. These facts underline the importance of cyclooxygenases and prostaglandins in the development of PVR.<ref>{{cite journal | vauthors = Tikhonovich MV, Erdiakov AK, Gavrilova SA | title = Nonsteroid anti-inflammatory therapy suppresses the development of proliferative vitreoretinopathy more effectively than a steroid one | journal = International Ophthalmology | volume = 38 | issue = 4 | pages = 1365–1378 | date = August 2018 | pmid = 28639085 | doi = 10.1007/s10792-017-0594-3 | s2cid = 4017540 }}</ref>

PTGS2 gene upregulation has also been linked with multiple stages of human reproduction. Presence of gene is found in the [[Chorion|chorionic plate]], in the [[Amniotic epithelial cell|amnion epithelium]], [[syncytiotrophoblasts]], villous fibroblasts, chorionic [[trophoblast]]s, [[Amniotic stem cells|amniotic trophoblasts]], as well as the [[Placenta|basal plate of the placenta]], in the [[decidual cells]] and [[Cytotrophoblast|extravillous cytotrophoblasts]]. During the process of [[chorioamnionitis]]/deciduitis, the upregulation of PTGS2 in the [[amnion]] and choriodecidua is one of three limited effects of inflammation in the [[uterus]]. Increased expression of the PTGS2 gene in the [[fetal membranes]] is connected to the presence of inflammation, causing uterine prostaglandin gene expression and immunolocalization of [[prostaglandin]] pathway proteins in chorionic trophoblast cells and adjacent decidua, or choriodecidua. PTGS2 is linked with the inflammatory system and has been observed in inflammatory [[leukocytes]]. It has been noted that there is a positive correlation with PTGS2 expression in the amnion during spontaneous labour and was discovered to have increased expression with gestational age following the presence of labour with no change observed in amnion and choriodecidua during either preterm or term labour. Additionally, [[oxytocin]] stimulates the expression of PTGS2 in [[Myometrium|myometrial cells]].<ref>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</ref>

The mutant allele PTGS2 5939C carriers among the Han Chinese population have been shown to have a higher risk of [[gastric cancer]]. In addition, a connection was found between ''[[Helicobacter pylori]]'' infection and the presence of the 5939C allele.<ref name="pmid21275453">{{cite journal | vauthors = Li Y, He W, Liu T, Zhang Q | title = A new cyclo-oxygenase-2 gene variant in the Han Chinese population is associated with an increased risk of gastric carcinoma | journal = Molecular Diagnosis & Therapy | volume = 14 | issue = 6 | pages = 351–355 | date = December 2010 | pmid = 21275453 | doi = 10.1007/bf03256392 | s2cid = 1229751 }}</ref>

During an ischemic stroke, the deprivation of oxygen and glucose triggers a cascade of inflammatory responses, leading to increased COX-2 expression, particularly in neurons, glial cells, and endothelial cells.<ref>{{cite journal | vauthors = Wei J, Du K, Cai Q, Ma L, Jiao Z, Tan J, Xu Z, Li J, Luo W, Chen J, Gao J, Zhang D, Huang C | title = Lead induces COX-2 expression in glial cells in a NFAT-dependent, AP-1/NFκB-independent manner | journal = Toxicology | volume = 325 | pages = 67–73 | date = November 2014 | pmid = 25193092 | pmc = 4238429 | doi = 10.1016/j.tox.2014.08.012 | bibcode = 2014Toxgy.325...67W }}</ref> This upregulation contributes to the production of pro-inflammatory prostaglandins such as PGE2, which exacerbates neuronal damage by promoting excitotoxicity, oxidative stress, and apoptosis.<ref>{{cite journal | vauthors = Lima IV, Bastos LF, Limborço-Filho M, Fiebich BL, de Oliveira AC | title = Role of prostaglandins in neuroinflammatory and neurodegenerative diseases | journal = Mediators of Inflammation | volume = 2012 | issue = 1 | pages = 946813 | date = 2012 | pmid = 22778499 | pmc = 3385693 | doi = 10.1155/2012/946813 | doi-access = free }}</ref> Additionally, COX-2-derived prostaglandins can impair the integrity of the BBB, allowing peripheral immune cells and inflammatory mediators to infiltrate the brain, further worsening cerebral injury.

== Interactions ==
PTGS2 has been shown to [[Protein-protein interaction|interact]] with [[caveolin 1]].<ref name="pmid11432874">{{cite journal | vauthors = Liou JY, Deng WG, Gilroy DW, Shyue SK, Wu KK | title = Colocalization and interaction of cyclooxygenase-2 with caveolin-1 in human fibroblasts | journal = The Journal of Biological Chemistry | volume = 276 | issue = 37 | pages = 34975–34982 | date = September 2001 | pmid = 11432874 | doi = 10.1074/jbc.M105946200 | doi-access = free }}</ref>
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== History ==
PTGS2 (COX-2) was discovered in 1991 by the [[Daniel L. Simmons|Daniel Simmons]] laboratory<!--year from abstract--><ref name="pmid1849272">{{cite journal | vauthors = Xie WL, Chipman JG, Robertson DL, Erikson RL, Simmons DL | title = Expression of a mitogen-responsive gene encoding prostaglandin synthase is regulated by mRNA splicing | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 88 | issue = 7 | pages = 2692–2696 | date = April 1991 | pmid = 1849272 | pmc = 51304 | doi = 10.1073/pnas.88.7.2692 | doi-access = free | bibcode = 1991PNAS...88.2692X }}</ref>{{Better source needed|date=June 2011}} at [[Brigham Young University]].

== See also ==
* [[Arachidonic acid]]
* [[Cyclooxygenase]]
* [[PTGS1|Cyclooxygenase 1]]
* [[NSAID]]
* [[Discovery and development of cyclooxygenase 2 inhibitors|Discovery and development of COX-2 selective inhibitors]]
* [[COX-2 selective inhibitor]]

== References ==
{{reflist|35em}}

== Further reading ==
{{refbegin|35em}}
* {{cite journal | vauthors = Richards JA, Petrel TA, Brueggemeier RW | title = Signaling pathways regulating aromatase and cyclooxygenases in normal and malignant breast cells | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 80 | issue = 2 | pages = 203–212 | date = February 2002 | pmid = 11897504 | doi = 10.1016/S0960-0760(01)00187-X | s2cid = 12728545 }}
* {{cite journal | vauthors = Wu T, Wu H, Wang J, Wang J | title = Expression and cellular localization of cyclooxygenases and prostaglandin E synthases in the hemorrhagic brain | journal = Journal of Neuroinflammation | volume = 8 | pages = 22 | date = March 2011 | pmid = 21385433 | pmc = 3062590 | doi = 10.1186/1742-2094-8-22 | doi-access = free }}
* {{cite journal | vauthors = Koki AT, Khan NK, Woerner BM, Seibert K, Harmon JL, Dannenberg AJ, Soslow RA, Masferrer JL | title = Characterization of cyclooxygenase-2 (COX-2) during tumorigenesis in human epithelial cancers: evidence for potential clinical utility of COX-2 inhibitors in epithelial cancers | journal = Prostaglandins, Leukotrienes, and Essential Fatty Acids | volume = 66 | issue = 1 | pages = 13–18 | date = January 2002 | pmid = 12051953 | doi = 10.1054/plef.2001.0335 }}
* {{cite journal | vauthors = Saukkonen K, Rintahaka J, Sivula A, Buskens CJ, Van Rees BP, Rio MC, Haglund C, Van Lanschot JJ, Offerhaus GJ, Ristimaki A | title = Cyclooxygenase-2 and gastric carcinogenesis | journal = APMIS | volume = 111 | issue = 10 | pages = 915–925 | date = October 2003 | pmid = 14616542 | doi = 10.1034/j.1600-0463.2003.1111001.x | s2cid = 23257867 }}
* {{cite journal | vauthors = Sinicrope FA, Gill S | title = Role of cyclooxygenase-2 in colorectal cancer | journal = Cancer and Metastasis Reviews | volume = 23 | issue = 1–2 | pages = 63–75 | year = 2004 | pmid = 15000150 | doi = 10.1023/A:1025863029529 | s2cid = 21521040 }}
* {{cite journal | vauthors = Jain S, Khuri FR, Shin DM | title = Prevention of head and neck cancer: current status and future prospects | journal = Current Problems in Cancer | volume = 28 | issue = 5 | pages = 265–286 | year = 2004 | pmid = 15375804 | doi = 10.1016/j.currproblcancer.2004.05.003 }}
* {{cite journal | vauthors = Saba N, Jain S, Khuri F | title = Chemoprevention in lung cancer | journal = Current Problems in Cancer | volume = 28 | issue = 5 | pages = 287–306 | year = 2004 | pmid = 15375805 | doi = 10.1016/j.currproblcancer.2004.05.005 }}
* {{cite journal | vauthors = Cardillo I, Spugnini EP, Verdina A, Galati R, Citro G, Baldi A | title = Cox and mesothelioma: an overview | journal = Histology and Histopathology | volume = 20 | issue = 4 | pages = 1267–1274 | date = October 2005 | pmid = 16136507 | doi = 10.14670/HH-20.1267 }}
* {{cite journal | vauthors = Brueggemeier RW, Díaz-Cruz ES | title = Relationship between aromatase and cyclooxygenases in breast cancer: potential for new therapeutic approaches | journal = Minerva Endocrinologica | volume = 31 | issue = 1 | pages = 13–26 | date = March 2006 | pmid = 16498361 }}
* {{cite journal | vauthors = Fujimura T, Ohta T, Oyama K, Miyashita T, Miwa K | title = Role of cyclooxygenase-2 in the carcinogenesis of gastrointestinal tract cancers: a review and report of personal experience | journal = World Journal of Gastroenterology | volume = 12 | issue = 9 | pages = 1336–1345 | date = March 2006 | pmid = 16552798 | pmc = 4124307 | doi = 10.3748/wjg.v12.i9.1336 | doi-access = free }}
* {{cite journal | vauthors = Bingham S, Beswick PJ, Blum DE, Gray NM, Chessell IP | title = The role of the cylooxygenase pathway in nociception and pain | journal = Seminars in Cell & Developmental Biology | volume = 17 | issue = 5 | pages = 544–554 | date = October 2006 | pmid = 17071117 | doi = 10.1016/j.semcdb.2006.09.001 }}
* {{cite book | vauthors = Minghetti L, Pocchiari M | title = Cyclooxygenase-2, prostaglandin E2, and microglial activation in prion diseases | series = International Review of Neurobiology | volume = 82 | pages = 265–75 | year = 2007 | pmid = 17678966 | doi = 10.1016/S0074-7742(07)82014-9 | isbn = 978-0-12-373989-6 }}
{{refend}}

== External links ==
* [http://www.nextbio.com/b/home/home.nb?q=cox-2#fid=22358&tab=lit Nextbio] {{Webarchive|url=https://web.archive.org/web/20191018160248/https://www.nextbio.com/b/authentication/login.nb#fid=22358&tab=lit |date=2019-10-18 }}
* [http://www.uphs.upenn.edu/news/News_Releases/2012/05/risk/ NSAIDs and Cardiovascular Risk Explained, According to Studies from the Perelman School of Medicine]
* {{cite journal | vauthors = Wolfe MM | title = Rofecoxib, Merck, and the FDA | journal = The New England Journal of Medicine | volume = 351 | issue = 27 | pages = 2875–8; author reply 2875–8 | date = December 2004 | pmid = 15625749 | doi = 10.1056/NEJM200412303512719 }}

{{Eicosanoid metabolism enzymes}}
{{Prostanoidergics}}

[[Category:Prostaglandins]]