Prostaglandin-endoperoxide synthase 2 (prostaglandin G/H synthase and cyclooxygenase)

PDB rendering based on 6COX
Symbols PTGS2; COX-2; COX2; GRIPGHS; PGG/HS; PGHS-2; PHS-2; hCox-2
External IDs OMIM600262 MGI97798 HomoloGene31000 GeneCards: PTGS2 Gene
EC number
RNA expression pattern
PBB GE PTGS2 204748 at.png
More reference expression data
Species Human Mouse
Entrez 5743 19225
Ensembl ENSG00000073756 ENSMUSG00000032487
UniProt P35354 Q3UMR6
RefSeq (mRNA) NM_000963.2 NM_011198.3
RefSeq (protein) NP_000954.1 NP_035328.2
Location (UCSC) Chr 1:
186.64 – 186.65 Mb
Chr 1:
151.95 – 151.96 Mb
PubMed search [1] [2]

Prostaglandin-endoperoxide synthase 2, also known as cyclooxygenase-2 or simply COX-2, is an enzyme which in humans is encoded by the PTGS2 gene.[1]



COX-2 was discovered in 1991 by the Daniel Simmons laboratory[2] at Brigham Young University.


COX-2 exists as a homodimer, each monomer has a molecular mass of about 70kDa. The tertiary and quaternary structures of COX-1 and COX-2 enzymes are almost identical. Each subunit has three different structural domains: a short N-terminal epidermal growth factor (EGF) domain; an α-helical membrane-binding moiety; and a C-terminal catalytic domain. COX 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. COX-1 and COX-2 are bifunctional enzymes that carry out two consecutive chemical reactions in spatially distinct but mechanistically 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 homologous to mammalian peroxidases such as myeloperoxidase.[3][4]

Figure 1. 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.[5]

It has been found that human PGHS-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 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 acid (FAs) and some COX inhibitors (e.g. naproxen) preferentially bind to the COX site of E-allo. AA 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 huPGHS-2, binds only E-allo in palmitic acid/murine PGHS-2 co-crystals. Non-substrate FAs can potentiate or attenuate 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 COX inhibitors.(Figure 1)[5]


Figure 2. COX enzymes produce PGH2 from AA in two consecutive chemical reactions. PGH2 is converted to other prostanoids (at the bottom) by tissue-specific enzymes called isomerases. In the first step of the reaction two moles of oxygen are added to arachidonic acid to yield PGG2. This is referred to as the COX reaction. The latter is followed by the peroxidase reaction, which reduces PGG2 to give PGH2. The COX reaction and the peroxidase reaction occur at two different locations in COX enzymes. In addition to prostaglandins, COX enzymes also produce small amounts of mono-oxygenated metabolites of AA called HETEs.

Prostaglandin endoperoxide H synthase, COX 2, converts arachidonic acid (AA) to prostaglandin endoperoxide H2. PGHSs are targets for NSAIDs and COX-2 specific inhibitors called coxibs. PGHS-2 is a sequence homodimer. Each monomer of the enzyme has a peroxidase and a COX active site. The COX enzymes catalyze the conversion of arachidonic acid to prostaglandins in a two steps. Firstly, hydrogen is abstracted from carbon 13 of arachidonic acid, and then two molecules of oxygen are added by the COX-2, giving PGG2. Secondly, PGG2 is reduced to PGH2 in the peroxidase active site. The synthesized PGH2 is converted to prostaglandins (PGD2, PGE2, PGF2R), prostacyclin (PGI2), or thromboxane A2 by tissue-specific isomerases.(Figure 2)[6]

Both the peroxidase and the cyclooxygenase activities are inactivated during catalysis by mechanism-based, first-order processes, which means that PGHS-2 peroxidase or cyclooxygenase activities fall to zero within 1–2 min even in the presence of sufficient substrates.[7][8][9]

Arachidonic acid bound to the COX-2 enzyme. polar interactions between Archidonic Acid (cyan) and Ser-530 and Tyr-385 residues are shown with yellow dashed lines. The substrate is stabilized by hydrophobic interactions.[10]


The conversion of arachidonic acid to PGG2 can be shown as a series of radical reactions analogous to polyunsaturated fatty acid autoxidation (Figure 3.).[11] 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 the 15-(S) -peroxyl radical; this radical is then reduced to PGG2 . 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;[12] 3) small amounts of oxidation products are formed due to the oxygen trapping of an allylic radical intermediate at positions 13 and 15.[13][14] Another mechanism shown in Figure 4 in which the 13-pro (S )-hydrogen is deprotonated and the carbanion is oxidized to a radical is theoretically possible. Although, 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 the it would eliminate fluoride to form a conjugated diene.[15] 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 PGG2 synthesis.[16] 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.[17]

Figure 3. Mechanism of COX activation and catalysis. A hydroperoxide oxidizes the heme to a ferryl-oxo derivative that is either reduced in the first step of the peroxidase cycle or it can oxidize 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.

Clinical significance

Cyclooxygenase-2 (COX-2, prostaglandin H synthase-2, PGHS-2) is unexpressed under normal conditions in most cells, but elevated levels are found during inflammation. COX-1 (prostaglandin H2 synthase 1) is constitutively expressed in many tissues and is the predominant form in gastric mucosa and in the kidneys. Inhibition of COX-1 reduces the basal production of cytoprotective PGE2 and PGI2 in the stomach, which may contribute to gastric ulceration. Since COX-2 is generally expressed only in cells where prostaglandins are upregulated (e.g. during inflammation), drug-candidates that selectively inhibit COX-2 are thought to show fewer side effects.[4]

Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit prostaglandin production by cyclooxygenases (COX) 1 and 2. NSAIDs selective for inhibition of COX-2 are less likely than traditional drugs to cause gastrointenstinal 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 COX-2-dependent cardioprotective prostaglandins, prostacyclin in particular.[18]

NSAID (non-specific inhibitor of COX-2) Flurbiprofen (green) bound to COX-2. Flurbiprofen is stabilized via hydrophobic interactions and polar interactions (Tyr-355 and Arg-120).[19]

The expression of COX-2 is upregulated in many cancers. The overexpression of COX-2 along with increased angiogenesis and GLUT-1 expression is significantly associated with gallbladder carcinomas.[20] Furthermore the product of COX-2, PGH2 is converted by prostaglandin E2 synthase into PGE2 which in turn can stimulate cancer progression. Consequently inhibiting COX-2 may have benefit in the prevention and treatment of these types of cancer.[21][22]

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.[23]


PTGS2 has been shown to interact with Caveolin 1.[24]


  1. ^ Hla, T.; Neilson, K (1992). "Human Cyclooxygenase-2 cDNA". Proceedings of the National Academy of Sciences 89 (16): 7384–8. doi:10.1073/pnas.89.16.7384. PMC 49714. PMID 1380156. 
  2. ^ Xie, W. (1991). "Expression of a Mitogen-Responsive Gene Encoding Prostaglandin Synthase is Regulated by mRNA Splicing". Proceedings of the National Academy of Sciences 88 (7): 2692–6. doi:10.1073/pnas.88.7.2692. PMC 51304. PMID 1849272. [non-primary source needed]
  3. ^ Picot, Daniel; Loll, Patrick J.; Garavito, R. Michael (1994). "The X-ray crystal structure of the membrane protein prostaglandin H2 synthase-1". Nature 367 (6460): 243–9. doi:10.1038/367243a0. PMID 8121489. 
  4. ^ a b Kurumbail, R; Kiefer, JR; Marnett, LJ (2001). "Cyclooxygenase enzymes: Catalysis and inhibition". Current Opinion in Structural Biology 11 (6): 752–60. doi:10.1016/S0959-440X(01)00277-9. PMID 11751058. 
  5. ^ a b Dong, L.; Vecchio, A. J.; Sharma, N. P.; Jurban, B. J.; Malkowski, M. G.; Smith, W. L. (2011). "Human Cyclooxygenase-2 is a Sequence Homodimer That Functions as a Conformational Heterodimer". Journal of Biological Chemistry 286 (21): 19035–46. doi:10.1074/jbc.M111.231969. PMC 3099718. PMID 21467029. 
  6. ^ O'Banion, MK (1999). "Cyclooxygenase-2: Molecular biology, pharmacology, and neurobiology". Critical reviews in neurobiology 13 (1): 45–82. PMID 10223523. 
  7. ^ Garavito, R. M.; Garavito, RM; Dewitt, DL (1996). "Prostaglandin Endoperoxide H Synthases (Cyclooxygenases)-1 and -2". Journal of Biological Chemistry 271 (52): 33157–60. doi:10.1074/jbc.271.52.33157. PMID 8969167. 
  8. ^ Wu, G.; Wei, C; Kulmacz, RJ; Osawa, Y; Tsai, AL (1999). "A Mechanistic Study of Self-inactivation of the Peroxidase Activity in Prostaglandin H Synthase-1". Journal of Biological Chemistry 274 (14): 9231–7. doi:10.1074/jbc.274.14.9231. PMID 10092596. 
  9. ^ So, O.-Y.; So, OY; Swinney, DC (1996). "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 of Biological Chemistry 271 (7): 3548–54. doi:10.1074/jbc.271.7.3548. PMID 8631960. 
  10. ^ PDB 3OLT
  11. ^ Porter, Ned A. (1986). "Mechanisms for the autoxidation of polyunsaturated lipids". Accounts of Chemical Research 19 (9): 262–8. doi:10.1021/ar00129a001. 
  12. ^ Mason, Ronald P.; Kalyanaraman, B.; Tainer, Beth E.; Eling, Thomas E. (1980). "A carbon-centered free radical intermediate in the prostaglandin synthetase oxidation of arachidonic acid. Spin trapping and oxygen uptake studies". The Journal of biological chemistry 255 (11): 5019–22. PMID 6246094. 
  13. ^ Hecker, Markus; Ullrich, Volker; Fischer, Christine; Meese, Claus O. (1987). "Identification of novel arachidonic acid metabolites formed by prostaglandin H synthase". European Journal of Biochemistry 169 (1): 113–23. doi:10.1111/j.1432-1033.1987.tb13587.x. PMID 3119336. 
  14. ^ Xiao, Guishan; Tsai, Ah-Lim; Palmer, Graham; Boyar, William C.; Marshall, Paul J.; Kulmacz, Richard J. (1997). "Analysis of Hydroperoxide-Induced Tyrosyl Radicals and Lipoxygenase Activity in Aspirin-Treated Human Prostaglandin H Synthase-2†". Biochemistry 36 (7): 1836–45. doi:10.1021/bi962476u. PMID 9048568. 
  15. ^ Kwok, Pui Yan; Muellner, Frank W.; Fried, Josef (1987). "Enzymatic conversions of 10,10-difluoroarachidonic acid with PGH synthase and soybean lipoxygenase". Journal of the American Chemical Society 109 (12): 3692–8. doi:10.1021/ja00246a028. 
  16. ^ Dean, Antony M.; Dean, Francis M. (1999). "Carbocations in the synthesis of prostaglandins by the cyclooxygenase of pgh synthase? A radical departure!". Protein Science 8 (5): 1087–98. doi:10.1110/ps.8.5.1087. PMC 2144324. PMID 10338019. 
  17. ^ Hamberg, Mats; Samuelsson, Bengt (1967). "On the mechanism of the biosynthesis of prostaglandins E-1 and F-1-alpha". The Journal of biological chemistry 242 (22): 5336–43. PMID 6070851. 
  18. ^ Wang, D.; Patel, V. V.; Ricciotti, E.; Zhou, R.; Levin, M. D.; Gao, E.; Yu, Z.; Ferrari, V. A. et al. (2009). "Cardiomyocyte cyclooxygenase-2 influences cardiac rhythm and function". Proceedings of the National Academy of Sciences 106 (18): 7548–52. doi:10.1073/pnas.0805806106. 
  19. ^ PDB 3PGH
  20. ^ Legan, M (2010). "Cyclooxygenase-2, p53 and glucose transporter-1 as predictors of malignancy in the development of gallbladder carcinomas". Bosnian journal of basic medical sciences / Udruzenje basicnih mediciniskih znanosti = Association of Basic Medical Sciences 10 (3): 192–6. PMID 20846124. 
  21. ^ EntrezGene 5743
  22. ^ Menter, D. G.; Schilsky, R. L.; Dubois, R. N. (2010). "Cyclooxygenase-2 and Cancer Treatment: Understanding the Risk Should Be Worth the Reward". Clinical Cancer Research 16 (5): 1384–90. doi:10.1158/1078-0432.CCR-09-0788. PMID 20179228. 
  23. ^ Li, Y; He, W; Liu, T; Zhang, Q (2010). "A new cyclo-oxygenase-2 gene variant in the Han Chinese population is associated with an increased risk of gastric carcinoma". Molecular diagnosis & therapy 14 (6): 351–5. doi:10.2165/11586400-000000000-00000. PMID 21275453. 
  24. ^ Liou, J.-Y.; Deng, WG; Gilroy, DW; Shyue, SK; Wu, KK (2001). "Colocalization and Interaction of Cyclooxygenase-2 with Caveolin-1 in Human Fibroblasts". Journal of Biological Chemistry 276 (37): 34975–82. doi:10.1074/jbc.M105946200. PMID 11432874. 

Further reading

  • Wang, D.; Patel, V. V.; Ricciotti, E.; Zhou, R.; Levin, M. D.; Gao, E.; Yu, Z.; Ferrari, V. A. et al. (2009). "Cardiomyocyte cyclooxygenase-2 influences cardiac rhythm and function". Proceedings of the National Academy of Sciences 106 (18): 7548–52. doi:10.1073/pnas.0805806106. 
  • Richards, J; Petrel, TA; Brueggemeier, RW (2002). "Signaling pathways regulating aromatase and cyclooxygenases in normal and malignant breast cells". The Journal of Steroid Biochemistry and Molecular Biology 80 (2): 203–12. doi:10.1016/S0960-0760(01)00187-X. PMID 11897504. 
  • Koki, A (2002). "Characterization of cyclooxygenase-2 (COX-2) during tumorigenesis in human epithelial cancers: Evidence for potential clinical utility of COX-2 inhibitors in epithelial cancers". Prostaglandins, Leukotrienes and Essential Fatty Acids 66: 13–8. doi:10.1054/plef.2001.0335. 
  • Saukkonen, Kirsi; Rintahaka, Johanna; Sivula, Anna; Buskens, Christianne J.; Van Rees, Bastiaan P.; Rio, Marie-Christine; Haglund, CAJ; Van Lanschot, J. JAN B. et al. (2003). "Cyclooxygenase-2 and gastric carcinogenesis". APMIS 111 (10): 915–25. doi:10.1034/j.1600-0463.2003.1111001.x. PMID 14616542. 
  • Sinicrope, Frank A.; Gill, Sharlene (2004). "Role of cyclooxygenase-2 in colorectal cancer". Cancer and Metastasis Reviews 23 (1–2): 63–75. doi:10.1023/A:1025863029529. PMID 15000150. 
  • Jain, S; Khuri, FR; Shin, DM (2004). "Prevention of head and neck cancer: Current status and future prospects". Current Problems in Cancer 28 (5): 265–86. doi:10.1016/j.currproblcancer.2004.05.003. PMID 15375804. 
  • Saba, N; Jain, S; Khuri, F (2004). "Chemoprevention in lung cancer". Current Problems in Cancer 28 (5): 287–306. doi:10.1016/j.currproblcancer.2004.05.005. PMID 15375805. 
  • Cardillo, I; Spugnini, EP; Verdina, A; Galati, R; Citro, G; Baldi, A (2005). "Cox and mesothelioma: An overview". Histology and histopathology 20 (4): 1267–74. PMID 16136507. 
  • Brueggemeier, RW; Díaz-Cruz, ES (2006). "Relationship between aromatase and cyclooxygenases in breast cancer: Potential for new therapeutic approaches". Minerva endocrinologica 31 (1): 13–26. PMID 16498361. 
  • Fujimura, T; Ohta, T; Oyama, K; Miyashita, T; Miwa, K (2006). "Role of cyclooxygenase-2 in the carcinogenesis of gastrointestinal tract cancers: A review and report of personal experience". World journal of gastroenterology : WJG 12 (9): 1336–45. PMID 16552798. 
  • Bingham, Sharon; Beswick, Paul J.; Blum, David E.; Gray, Norman M.; Chessell, Iain P. (2006). "The role of the cylooxygenase pathway in nociception and pain". Seminars in Cell & Developmental Biology 17 (5): 544–54. doi:10.1016/j.semcdb.2006.09.001. PMID 17071117. 
  • Minghetti, L; Pocchiari, M (2007). Cyclooxygenase‐2, Prostaglandin E2, and Microglial Activation in Prion Diseases. 82. pp. 265–75. doi:10.1016/S0074-7742(07)82014-9. 

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