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34-465: 5F1A , 5F19 , 5IKQ , 5IKT , 5IKV , 5IKR 5743 19225 ENSG00000073756 ENSMUSG00000032487 P35354 Q05769 NM_000963 NM_011198 NP_000954 NP_035328 Cyclooxygenase-2 ( COX-2 ), also known as prostaglandin-endoperoxide synthase 2 ( HUGO PTGS2 ), is an enzyme that in humans is encoded by the PTGS2 gene . In humans it is one of three cyclooxygenases . It

68-695: 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 PGG 2 . Second, PGG 2 is reduced to PGH 2 in the peroxidase active site. The synthesized PGH 2 is converted to prostaglandins ( PGD 2 , PGE 2 , PGF 2α ), prostacyclin (PGI 2 ), or thromboxane A 2 by tissue-specific isomerases (Figure 2). While metabolizing arachidonic acid primarily to PGG 2 , COX-2 also converts this fatty acid to small amounts of

102-618: A conceptual level and with an international perspective. To this end, CELS mission is to explore and inform professional discourse on the ethical aspects of genetics and genomics, normally though scholarly engagement, thought-provoking papers, and policy guiding statements. The first meeting of the HUGO Ethics Committee took place in Amsterdam in October 1992, chaired by Nancy Wexler (Columbia University). In 2010, under

136-933: 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 selective COX-2 inhibitors (coxibs) increase risk of cardiovascular events due to clotting. Non-steroidal anti-inflammatory drugs (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

170-602: A racemic mixture of 15-hydroxyicosatetraenoic acids (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. 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 . The lipoxins and epi-lipoxins are potent anti-inflammatory agents and may contribute to

204-410: A series of radical reactions analogous to polyunsaturated fatty acid autoxidation . 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 allylic radical generated is trapped by dioxygen at carbon 15 to form

238-570: A short N-terminal epidermal growth factor ( EGF ) domain; an α-helical membrane-binding moiety; and a C-terminal catalytic domain. PTGS (COX, which can be confused with " cytochrome oxidase ") enzymes are monotopic membrane proteins; the membrane-binding domain consists of a series of 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 coupled active sites. Both

272-662: A vision for Ecogenomics: the Ecological Genome Project ( Human Genomics 17: 115), 2023 The Human Genome Organisation (HUGO) and the 2020 COVID-19 pandemic ( Human Genomics 15:12), 2021 Statement on Bioinformatics and Capturing the Benefits of Genome Sequencing for Society ( Human Genomics 13, 24), 2019 Falling giants and the rise of gene editing: ethics, private interests and the public good (not endorsed by HUGO Board; Human Genomics 11, 20), 2017 Ethical issues of CRISPR technology and gene editing through

306-567: Is due to suppression of PTGS2 (COX-2)-dependent cardioprotective prostaglandins , prostacyclin in particular. 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. Furthermore, the product of PTGS2 (COX-2), PGH 2 is converted by prostaglandin E 2 synthase into PGE 2 , which in turn can stimulate cancer progression. Consequently, inhibiting PTGS2 (COX-2) may have benefit in

340-411: Is involved in the conversion of arachidonic acid to prostaglandin H 2 , an important precursor of prostacyclin , which is expressed in inflammation . PTGS2 (COX-2), converts arachidonic acid (AA) to prostaglandin endoperoxide H2. PTGSs are targets for NSAIDs and PTGS2 (COX-2) specific inhibitors called coxibs. PTGS-2 is a sequence homodimer. Each monomer of the enzyme has a peroxidase and

374-435: 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

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408-433: Is the weakness of doubly allylic C-H bonds, leading to pentadienyl radicals. A range of reactions with oxygen occur. Products include fatty acid hydroperoxides , epoxy-hydroxy polyunsaturated fatty acids, jasmonates , divinylether fatty acids , and leaf aldehydes . Some of these derivatives are signallng molecules, some are used in plant defense ( antifeedants ), some are precursors to other metabolites that are used by

442-565: The basal plate of the placenta , in the decidual cells and 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

476-412: 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 homologous to mammalian peroxidases such as myeloperoxidase . 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

510-517: The peroxidase site of E-cat while substrates, as well as certain 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 and non-substrate fatty acids (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

544-474: The 13-pro (S)-hydrogen is deprotonated and the carbanion is oxidized to a 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. The absence of endoperoxide-containing products derived from 10,10-difluoroarachidonic acid has been thought to indicate

578-446: The 15-(S) -peroxyl radical; this radical is then reduced to PGG 2 . 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 ; 3) small amounts of oxidation products are formed due to the oxygen trapping of an allylic radical intermediate at positions 13 and 15. Another mechanism in which

612-690: The Chen Foundation, HUGO presents the Chen Award to those with research accomplishments in human genetics and genomics in Asia Pacific. In 2020, HUGO merged with the Human Genomic Variation Society (HGVS) and Human Variome Project (HVP). HUGO's Committee on Ethics, Law and Society (CELS) is an interdisciplinary academic working group that is a uniquely positioned to analyse bioethical matters in genomics at

646-691: The Principled Conduct of Genetics Research, March 1996 Pentadienyl In organic chemistry , pentadiene is any hydrocarbon with an open chain of five carbons , connected by two single bonds and two double bonds . All those compounds have the same molecular formula C 5 H 8 . The inventory of pentadienes include: Well known derivatives containing pentadiene groups include hexadienes , cyclopentadiene , and especially three fatty acids linoleic acid , α- linolenic acid , and arachidonic acid as well as their triglycerides (fats). 1,4-Pentadiene can be prepared from 1,5-pentadiol via

680-410: The affinity of AA for E-allo is 25 times that for Ecat. Palmitic acid, an efficacious stimulator of huPGHS-2 , binds only E-allo in palmitic acid/murine PGHS-2 co-crystals. Non-substrate FAs can potentiate or 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

714-497: The case of edibles, to rancidification . Metals accelerate the degradation. In organometallic chemistry , the pentadienyl anion is a ligand, the acyclic analogue of the more-common cyclopentadienyl anion . The pentadienyl anion is generated by deprotonation of pentadiene . A number of complexes are known, including bis(pentadienyl) iron, Fe(C 5 H 7 ) 2 , the "open" analog of ferrocene . Only few pentadienyl complexes feature simple C 5 H 7 ligands. More common

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748-487: 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. PTGS2 gene upregulation has also been linked with multiple stages of human reproduction. Presence of gene is found in the chorionic plate , in the amnion epithelium , syncytiotrophoblasts , villous fibroblasts, chorionic trophoblasts , amniotic trophoblasts , as well as

782-655: The diacetate. 1,3-Pentadiene, like 1,3-butadiene , undergoes a variety of cycloaddition reactions. For example, it forms a sulfolene upon treatment with sulfur dioxide . Pentadienyl refers to the organic radical , anion, or cation with the formula [CH 2 (CH) 3 CH 2 ] , where z = 0, −1, +1, respectively. Methylene-interrupted polyenes are 1,4-pentadiene groups found in polyunsaturated fatty acids linoleic acid , α- linolenic acid , and arachidonic acid . These pentadiene derivatives are susceptible to lipid peroxidation , far moreso than monounsaturated or saturated fatty acids. The basis for this reactivity

816-460: 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. 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

850-620: The expression of PTGS2 in myometrial cells . 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. PTGS2 has been shown to interact with caveolin 1 . PTGS2 (COX-2) was discovered in 1991 by the Daniel Simmons laboratory at Brigham Young University. Human Genome Organisation HUGO

884-579: The importance of a C-10 carbocation in PGG 2 synthesis. 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. 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:

918-663: The kidneys. Inhibition of PTGS1 (COX-1) reduces the basal production of cytoprotective PGE 2 and PG1 2 in the stomach , which may contribute to gastric ulceration . Since PTGS2 (COX-2) is generally expressed only in cells where prostaglandins are upregulated (e.g., during inflammation), drug-candidates that selectively inhibit PTGS2 (COX-2) were suspected to show fewer side-effects 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

952-758: The leadership of then HUGO president Edison Liu (The Jackson Laboratory) and a new chair Ruth Chadwick (Cardiff University), the committee became the HUGO Committee on Ethics, Law and Society (CELS). Benjamin Capps was nominated to be the present chair at the HUGO Human Genome Meeting, held in Barcelona in 2017. 2017–present: Benjamin Capps (UK, Canada) 2010–2017: Ruth Chadwick (UK) 1996–2008: Bartha Knoppers (Canada) 1992–1996: Nancy Wexler (US) The Human Genome Organisation (HUGO) and

986-823: The lens of solidarity ( British Medical Bulletin 122(1): 17-29), 2017 Imagined Futures: Capturing the Benefits of Genome Sequencing for Society ( Technical Report ) 2013 Statement on Supreme Court: Genes are not patentable, June 2013 Statement on Pharmacogenomics (PGx): Solidarity, Equity and Governance, April 2007 Statement on Stem Cells, November 2004 Statement on the scope of gene patents, research exemption, and licensing of patented gene sequences for diagnostics, 2003 Statement on Human Genomic Databases, December 2003 Statement in Gene Therapy Research, April 2001 Statement on Benefit Sharing, April 2000 Statement on Cloning, March 1999 Statement on DNA Sampling: Control and Access, February 1998 Statement on

1020-505: The overall activities of the two COX's as well as to aspirin. COX-2 is naturally inhibited by calcitriol (the active form of vitamin D). 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. The conversion of arachidonic acid to PGG 2 can be shown as

1054-472: The plant. Cyclooxygenases ("COX") are enzymes that generate prostanoids , including thromboxane and prostaglandins such as prostacyclin . Aspirin and ibuprofen exert their effects through inhibition of COX. Fats containing 1,4-pentadiene groups are drying oils , i.e. film-forming liquids suitable as paints. One practical consequence is that polyunsaturated fatty acids have poor shelf life owing to their tendency toward autoxidation , leading, in

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1088-429: The prevention and treatment of these types of cancer. COX-2 expression was found in human idiopathic epiretinal membranes. Cyclooxygenases blocking by lornoxicam in acute stage of inflammation reduced the frequency of membrane formation by 43% in the dispase model of PVR and by 31% in the concanavalin one. Lornoxicam not only normalized the expression of cyclooxygenases in both models of PVR, but also neutralized

1122-631: Was elected at the meeting with a total of 42 scientists from 17 different countries, with Victor A. McKusick serving as founding President. In 2016, HUGO was located at the EWHA Womans University in Seoul, South Korea. In 2020, the HUGO headquarters moved to Farmington, Connecticut, US. HUGO has convened a Human Genome Meeting (HGM) every year since 1996. In partnership with geneticist Yuan-Tsong Chen and Alice Der-Shan Chen, founders of

1156-462: Was established at the first meeting on genome mapping and sequencing at Cold Spring Harbor in 1988. The idea of starting the organization stemmed from South African biologist Sydney Brenner , who is best known for his significant contributions to work on the genetic code and other areas of molecular biology, as well as winning the 2002 Nobel Prize in Physiology or Medicine . A Founding Council

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