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53-461: 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

106-691: 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

159-431: A bicyclic peroxide ("endoperoxide") derived from arachidonic acid . Many aspects of biodegradation or aging are attributed to the formation and decay of peroxides formed from oxygen in air. Countering these effects, an array of biological and artificial antioxidants destroy peroxides. In fireflies , oxidation of luciferins , which is catalyzed by luciferases , yields a peroxy compound 1,2-dioxetane . The dioxetane

212-405: A cold place promptly after the synthesis. 3) The containers are made of non-reactive materials such as stainless steel, some aluminium alloys or dark glass. For safe handling of concentrated organic peroxides, an important parameter is temperature of the sample, which should be maintained below the self accelerating decomposition temperature of the compound. The shipping of organic peroxides

265-599: 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

318-550: A cool, opaque container, as heating and illumination accelerate their chemical reactions . Small amounts of peroxides, which emerge from storage or reaction vessels are neutralized using reducing agents such as iron(II) sulfate . Safety measures in industrial plants producing large amounts of peroxides include the following: 1) The equipment is located within reinforced concrete structures with foil windows, which would relieve pressure and not shatter in case of explosion. 2) The products are bottled in small containers and are moved to

371-468: A hydroxyl (-OH) terminus and (ii) by the presence of alkyl vs acyl substituents. One gap in the classes of organic peroxides is diphenyl peroxide. Quantum chemical calculations predict that it undergoes a nearly barrierless reaction akin to the benzidine rearrangement . The O−O bond length in peroxides is about 1.45  Å , and the R−O−O angles (R = H, C) are about 110° (water-like). Characteristically,

424-933: 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

477-602: 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

530-410: 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

583-570: 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

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636-830: A variety of industrial applications. Benzoyl peroxide , peroxyesters / peroxyketals , and alkylperoxy monocarbonates are used in production of polystyrene , expanded polystyrene , and High Impact Polystyrene , and benzoyl peroxide is utilized for many acrylate based adhesive applications. Thermoplastic production techniques for many industrial polymerization applications include processes which are carried out in bulk, solution, or suspension type batches. Relevant polymers include: polyvinyl chloride (PVC), low-density polyethylene (LDPE), high-density polyethylene (HDPE), polymethyl methacrylate (PMMA), Polystyrene , and Polycarbonates . Benzoyl peroxide and hydrogen peroxide are used as bleaching and "maturing" agents for treating flour to make its grain release gluten more easily;

689-646: 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

742-430: Is rubrene . Six-membered cyclic peroxides are called endo peroxides. The four-membered dioxetanes can be obtained by 2+2 cycloaddition of oxygen to alkenes . The hazards associated with storage of ethers in air is attributed to the formation of hydroperoxides via the direct albeit slow reaction of triplet oxygen with C-H bonds . Organic peroxides are widely used to initiate polymerization of olefins , e.g.

795-475: Is adjusted by suitable choice of temperature and type of peroxide. Methyl ethyl ketone peroxide , benzoyl peroxide and to a smaller degree acetone peroxide are used as initiators for radical polymerization of some thermosets , e.g. unsaturated polyester and vinyl ester resins, often encountered when making fiberglass or carbon fiber composites (CFRP), with examples including boats, RV units, bath tubs, pools, sporting equipment, wind turbine blades, and

848-501: Is also efficient in reducing egg production in Schistosoma haematobium infection. tert-Butyl hydroperoxide is used for epoxidation and hydroxylation reagents in conjunction with metal catalysts. Several analytical methods are used for qualitative and quantitative determination of peroxides. A simple qualitative detection of peroxides is carried out with the iodine-starch reaction . Here peroxides, hydroperoxides or peracids oxidize

901-567: 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

954-411: 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

1007-435: 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

1060-440: Is unstable and decays spontaneously to carbon dioxide and excited ketones , which release excess energy by emitting light ( bioluminescence ). Many peroxides are used as a radical initiators , e.g., to enable polymerization of acrylates. Industrial resins based on acrylic and/or methacrylic acid esters are invariably produced by radical polymerization with organic peroxides at elevated temperatures. The polymerization rate

1113-443: Is useful for comparing the relative concentration of peroxy groups in formulations, which is related to the energy content. In general, energy content increases with active oxygen content, and thus the higher the molecular weight of the organic groups, the lower the energy content and, usually, the lower the hazard. The term active oxygen is used to specify the amount of peroxide present in any organic peroxide formulation. One of

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1166-416: The acrylic , unsaturated polyester, and vinyl ester resins used in glass-reinforced plastics . MEKP and benzoyl peroxide are commonly used for this purpose. However, the same property also means that organic peroxides can explosively combust. Organic peroxides, like their inorganic counterparts, are often powerful bleaching agents. Organic peroxides are classified (i) by the presence or absence of

1219-565: 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

1272-412: 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

1325-510: 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

1378-556: The rate of peroxide decomposition generates heat at a faster rate than it can be dissipated to the environment. Temperature is the main factor in the rate of decomposition. The lowest temperature at which a packaged organic peroxide will undergo a self-accelerating decomposition within a week is defined as the self-accelerating decomposition temperature (SADT). A large fire at the Arkema Chemical Plant in Crosby, Texas (USA) in 2017

1431-474: 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

1484-446: 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

1537-658: 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

1590-499: The C−O−O−R (R = H, C) dihedral angles are about 120°. The O−O bond is relatively weak, with a bond dissociation energy of 45–50  kcal/mol (190–210  kJ/mol ), less than half the strengths of C−C, C−H, and C−O bonds. Peroxides play important roles in biology. Hundreds of peroxides and hydroperoxides are known, being derived from fatty acids, steroids, and terpenes. The prostaglandins are biosynthesized by initial formation of

1643-644: The Principled Conduct of Genetics Research, March 1996 Endoperoxide In organic chemistry , organic peroxides are organic compounds containing the peroxide functional group ( R−O−O−R′ ). If the R′ is hydrogen , the compounds are called hydroperoxides , which are discussed in that article. The O−O bond of peroxides easily breaks, producing free radicals of the form RO (the dot represents an unpaired electron ). Thus, organic peroxides are useful as initiators for some types of polymerization , such as

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1696-406: The added potassium iodide into iodine , which reacts with starch producing a deep-blue color. Commercial paper indicators using this reaction are available. This method is also suitable for quantitative evaluation, but it can not distinguish between different types of peroxide compounds. Discoloration of various indigo dyes in presence of peroxides is used instead for this purpose. For example,

1749-410: 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

1802-453: The alternative is letting the flour slowly oxidize by air, which is too slow for the industrialized era. Benzoyl peroxide is an effective topical medication for treating most forms of acne . Dialkyl peroxides, e.g., dicumyl peroxide , are synthesized by addition of hydrogen peroxide to alkenes or by O-alkylation of hydroperoxides. Diacyl peroxides are typically prepared by treating hydrogen peroxide with acid chlorides or acid anhydrides in

1855-415: The base-catalyzed Kornblum–DeLaMare rearrangement , which involves the breaking of bonds within peroxides to form these products. Some peroxides are drugs , whose action is based on the formation of radicals at desired locations in the organism. For example, artemisinin and its derivatives, such as artesunate , possess the most rapid action of all current drugs against falciparum malaria . Artesunate

1908-487: 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

1961-457: 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

2014-607: 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

2067-688: The formation of polyethylene . A key step is homolysis : The tendency to homolyze is also exploited to modify polymers by grafting or visbreaking , or cross-link polymers to create a thermoset . When used for these purposes, the peroxide is highly diluted, so the heat generated by the exothermic decomposition is safely absorbed by the surrounding medium (e.g. polymer compound or emulsion ). Especially when in concentrated form, organic peroxides can decompose by self-oxidation, since organic peroxides contain both an oxidizer (the O-O bond) and fuel (C-H and C-C bonds). A "self-accelerating decomposition" occurs when

2120-415: The hydrogen peroxide the anthraquinone is catalytically reduced to anthrahydroquinone and reused in the process. There are other hydroquinones reacting in a similar fashion. Organoperoxides can be reduced to alcohols with lithium aluminium hydride , as described in this idealized equation: The phosphite esters and tertiary phosphines also effect reduction: Cleavage to ketones and alcohols occurs in

2173-576: 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:

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2226-663: 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

2279-731: 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

2332-814: 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

2385-453: The loss of blue color in leuco- methylene blue is selective for hydrogen peroxide. Quantitative analysis of hydroperoxides can be performed using potentiometric titration with lithium aluminium hydride . Another way to evaluate the content of peracids and peroxides is the volumetric titration with alkoxides such as sodium ethoxide . Each peroxy group is considered to contain one active oxygen atom. The concept of active oxygen content

2438-502: 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

2491-413: The oxygen atoms in each peroxide group is considered "active". The theoretical amount of active oxygen can be described by the following equation: where p is the number of peroxide groups in the molecule, and m is the molecular mass of the pure peroxide. Organic peroxides are often sold as formulations that include one or more phlegmatizing agents . That is, for safety sake or performance benefits

2544-537: The presence of base: The reaction competes with hydrolysis of the acylating agent but the hydroperoxide anion is a superior nucleophile relative to hydroxide. Unsymmetrical diacyl peroxides can be produced by treating acyl chlorides with the peroxy acid. Peresters , an example being tert -Butyl peroxybenzoate , are produced by treating acid anhydrides or acid chlorides with hydroperoxides. Cyclic peroxides can be obtained by cycloaddition of singlet oxygen (generated by UV radiation) to dienes. An important example

2597-429: 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

2650-458: The properties of an organic peroxide formulation are commonly modified by the use of additives to phlegmatize (desensitize), stabilize, or otherwise enhance the organic peroxide for commercial use. Commercial formulations occasionally consist of mixtures of organic peroxides, which may or may not be phlegmatized. Peroxides are also strong oxidizers and easily react with skin, cotton and wood pulp. For safety reasons, peroxidic compounds are stored in

2703-618: Was caused by the decomposition of various organic peroxides following power failure and subsequent loss of cooling systems. This occurred due to extreme flooding from Hurricane Harvey , which destroyed main and back-up power generators at the site. Hydroperoxides are intermediates or reagents in major commercial processes. In the cumene process , acetone and phenol are produced by decomposition of cumene hydroperoxide (Me = methyl): Anthrahydroquinone reacts spontaneously with oxygen to form anthraquinone and hydrogen peroxide, possibly through some organic peroxide intermediate. After extraktion of

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2756-613: 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

2809-456: 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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