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HGNC Approved Gene Symbol: PTGS1
Cytogenetic location: 9q33.2 Genomic coordinates (GRCh38): 9:122,370,533-122,395,703 (from NCBI)
Prostaglandin-endoperoxide synthase (PTGS; EC 1.14.99.1; fatty acid cyclooxygenase; PGH synthase) is the key enzyme in prostaglandin biosynthesis. The cyclooxygenase activity of the enzyme is inhibited by nonsteroidal antiinflammatory drugs (NSAID) such as aspirin and endomethacin. Two isoforms of PTGS has been identified: a constitutive isoform (PTGS1; COX1) and an inducible isoform (PTGS2, COX2; 600262) (Funk et al., 1991; Vane et al., 1994).
Yokoyama and Tanabe (1989) deduced the complete amino acid sequence of human prostaglandin-endoperoxide synthase by sequence analysis of human genomic DNA coding for the enzyme. There were 599 amino acid residues with a calculated molecular mass of approximately 68 kD. PTGS1 encodes a 2.8-kb mRNA.
Using ovine Ptgs1 to screen a lung fibroblast cDNA library, Diaz et al. (1992) cloned a splice variant of PTGS1, which they designated PGG/HS. The variant contains the entire translated region of PTGS1 except for the last 111 basepairs of exon 9. The deduced full-length protein contains 599 amino acid and 4 putative N-glycosylation sites, whereas the splice variant lacks residues 396 to 432, including the last N-glycosylated asparagine. PCR detected both full-length and truncated transcripts in the 5 cartilage and fibroblast samples examined. Northern blot analysis of normal lung fibroblast mRNA detected transcripts of 2.7 and 5.5 kb.
COX3 Isoform
Chandrasekharan et al. (2002) described a third distinct COX isozyme, COX3, as well as 2 smaller COX1-derived proteins (partial COX1 or PCOX1 proteins). COX3 and 1 of the PCOX1 proteins (PCOX1A) are made from the COX1 gene but retain intron 1 in their mRNAs. PCOX1 proteins additionally contain an in-frame deletion of exons 5-8 of the COX1 mRNA. COX3 and PCOX mRNAs are expressed in canine cerebral cortex and in lesser amounts in other tissues analyzed. In humans, COX3 mRNA is expressed as a transcript of approximately 5.2 kb and is most abundant in cerebral cortex and heart. Intron 1 is conserved in length and in sequence in mammalian COX1 genes. This intron contains an open reading frame that introduces an insertion of 30 to 34 amino acids, depending on the mammalian species, into the hydrophobic signal peptide that directs COX1 into the lumen of the endoplasmic reticulum and nuclear envelope. COX3 and PCOX1A are expressed efficiently in insect cells as membrane-bound proteins. The signal peptide is not cleaved from either protein and both proteins are glycosylated. COX3, but not PCOX1A, possesses glycosylation-dependent cyclooxygenase activity. Comparison of canine COX3 activity with murine COX1 and COX2 demonstrated that this enzyme is selectively inhibited by analgesic/antipyretic drugs such as acetaminophen, phenacetin, antipyrine, and dipyrone, and is potently inhibited by some nonsteroidal antiinflammatory drugs. Thus, inhibition of COX3 could represent a primary central mechanism by which these drugs decrease pain and possibly fever.
Yokoyama and Tanabe (1989) determined that the PTGS1 gene contains 11 exons and spans 22 kb.
By analysis of a human/hamster somatic hybrid DNA panel, Funk et al. (1991) demonstrated that the PTGS1 gene maps to chromosome 9. The PTGS1 gene maps to chromosome 9q32-q33.3 (Lee et al., 2007).
Diaz et al. (1992) found that expression of both the full-length PTGS1 transcript and a shorter splice variant was upregulated in cultured normal lung fibroblasts following treatment with serum, TGFB (see 190180), interleukin-1-beta (147720), TNF-alpha (191160), and phorbol esters. The full-length transcript was preferentially upregulated.
To explore the role of cyclooxygenase in endothelial cell migration and angiogenesis, Tsujii et al. (1998) used 2 in vitro model systems involving coculture of endothelial cells with colon carcinoma cells. Treatment of endothelial cells with aspirin or a COX1 antisense oligonucleotide inhibits COX1 activity/expression and suppresses tube formation. Tsujii et al. (1998) also found that COX1 regulates angiogenesis in endothelial cells.
Kirschenbaum et al. (2000) studied the immunohistochemical localization of PTGS1 and PTGS2 in the human male fetal and adult reproductive tracts. There was no PTGS1 expression in fetal samples (prostate, seminal vesicles, or ejaculatory ducts), and only minimal expression in adult tissues. The authors concluded that PTGS2 is the predominant isoform expressed in the fetal male reproductive tract, and its expression may be regulated by androgens.
Qin et al. (2003) found that expression of COX1 or COX2 in hamster and human cells exogenously and endogenously expressing human amyloid precursor protein (APP; 104760) induced production of the amyloid peptides A-beta(1-40) and A-beta(1-42), as well as the gamma-secretase-generated C-terminal fragment of APP. Peptide production was coincident with the secretion of prostaglandin-E2 into the culture medium. Treatment of APP-overexpressing cells with ibuprofen or with a specific gamma-secretase inhibitor significantly attenuated COX1- and COX2-mediated APP peptide production.
Pharmacology and NSAID Inhibition
Prostaglandin H2 synthase is known to pharmacologists (Vane et al., 1994) as cyclooxygenase (COX), and its 2 isoforms are known as COX1 and COX2. Vane et al. (1994) outlined the actions of the 2 isoforms of COX. Stemming from this outline was a hypothesis that the therapeutic effects of drugs such as aspirin are due to inhibition of COX2, whereas the unwanted side-effects (and the action on platelets) result from inhibition of COX1.
The use of aspirin in the prevention of heart attacks and strokes is based on the unique activity of the drug in low doses on platelets, which contain COX1. The action of low-dose aspirin on platelets is unique for 2 reasons: first, the anucleate platelets cannot regenerate enzymes, so when COX1 is irreversibly inhibited by aspirin, the platelet cannot produce thromboxane A-2 for the rest of its life in the circulation (up to 10 days). Second, as aspirin is absorbed into the presystemic circulation, the platelets in the blood meet it in much higher concentrations than in the arterial circulation. Thus, low-dose aspirin (e.g., 81 mg rather than the usual tablet of 325 mg) has a selective effect on COX1 in platelets, sparing that in the endothelial cells.
Aspirin acts by irreversibly acetylating a serine residue at position 529 in platelet PGHS1 (Funk et al., 1991). Catella-Lawson et al. (2001) found that concomitant administration of the nonsteroidal antiinflammatory drug (NSAID) ibuprofen with aspirin antagonized the irreversible platelet inhibition induced by aspirin. Taking ibuprofen after aspirin did not antagonize the effects of aspirin, as indicated by inhibition of serum thromboxane B2 formation and platelet aggregation.
PGHS is an integral membrane protein located primarily in the endoplasmic reticulum. It is bifunctional: the initial cyclooxygenase reaction, the target for NSAIDs, converts arachidonic acid to PGG2, while the subsequent peroxidase reaction converts PGG2 to PGH2. There are 2 isozymes of PGHS, PGHS1 and PGHS2, which differ in their regulation of expression and tissue distribution. Ovine PGHS1 is a 576-amino acid, glycosylated protein with an apparent subunit relative molecular mass of 70,000. PGHS1 is considered to be involved in cell-cell signaling and maintaining tissue homeostasis, whereas PGHS2 expression occurs in a limited number of cell types and is regulated by specific stimulatory events, leading to the hypothesis that PGHS2 is responsible for the prostanoid biosynthesis involved in inflammation and mitogenesis. Picot et al. (1994) determined the 3-dimensional structure of PGHS1 by x-ray crystallography. They concluded that the enzyme is in a monotopic arrangement with respect to the cell membrane, that is, it integrates into only a single leaflet of the lipid bilayer.
Malkowski et al. (2000) determined the structure of PGHS1 at 3-angstrom resolution with arachidonic acid bound in a chemically productive conformation.
Association with NSAID Metabolism Pending Confirmation
Lee et al. (2007) sequenced the PTGS1 gene in 92 healthy individuals (24 African, 24 Asian, 24 European/Caucasian, and 20 anonymous). Forty-five variants were identified, including 7 encoding amino acid substitutions. In vitro studies in nonhuman cells showed that some variants had significantly decreased metabolic activity compared to wildtype (100%): R53H (35%), R78W (36%), K185T (59%), G230S (57%), and L237M (51%). No significant differences were observed with the R8W (104%), P17L (113%), and V481I (121%) variants. Inhibition studies with indomethacin demonstrated that the P17L and G230S variants had significantly lower inhibitory concentration values compared to wildtype, suggesting these variants significantly increased COX1 sensitivity to indomethacin inhibition. Lee et al. (2007) concluded that some genetic variants in the human PTGS1 gene may alter basal PTGS1-mediated arachidonic acid metabolism and NSAID-mediated inhibition of PTGS1 activity in vitro.
Langenbach et al. (1995) used homologous recombination to disrupt the mouse Ptgs1 gene encoding COX1. Homozygous Ptgs1 mutant mice survived well, had no gastric pathology, and showed less indomethacin-induced gastric ulceration than wildtype mice, even though their gastric prostaglandin E2 levels were about 1% of wildtype. Homozygous mutant mice had reduced platelet aggregation and a decreased inflammatory response to arachidonic acid, but not to tetradecanoyl phorbol acetate. Ptgs1 homozygous mutant females mated to homozygous mutant males produced few live offspring. Langenbach et al. (1995) stated that COX1-deficient mice provided a useful model for distinguishing the physiologic roles of the 2 cyclooxygenases, COX1 and COX2.
Gavett et al. (1999) studied allergen-induced pulmonary inflammation and airway hyperresponsiveness in wildtype mice and in PTGS1 -/- and PTGS2 -/- mice. Among the nonimmunized groups, PGE2 (a PTGS-derived eicosanoid that shows beneficial effects in lung after allergen exposure) was dramatically reduced in bronchoalveolar lavage (BAL) fluid from PTGS1 -/- mice relative to wildtype or PTGS2 -/- mice. PTGS1 is, therefore, the predominant enzyme that biosynthesizes PGE2 in the normal mouse lung. After ovalbumin sensitization and challenge, lung inflammation indices (BAL cells, proteins, IgE, and lung histopathology) were significantly greater in PTGS1 -/- than in PTGS2 -/- mice, and both were far greater than in wildtype mice. Both allergic PTGS1 -/- and PTGS2 -/- mice exhibited decreased baseline respiratory system compliance, whereas only allergic PTGS1 -/- mice showed increased baseline resistance and responsiveness to methacholine, a cholinergic agonist. The authors concluded that PTGS1 and PTGS2 products limit allergic lung inflammation and IgE secretion and promote normal lung function.
Warner and Mitchell (2002) commented on the significance of the work concerning COX3. They pointed out that humans have been using nonsteroidal antiinflammatory drugs (NSAIDs) in various forms for more than 3,500 years. As many as 120 billion aspirin tablets may be consumed annually. Understanding of the role of cyclooxygenases in the mechanism of action of aspirin began in the 1970s; the study reported by Chandrasekharan et al. (2002) extended the understanding to acetaminophen and other analgesic/antipyretic drugs.
Catella-Lawson, F., Reilly, M. P., Kapoor, S. C., Cucchiara, A. J., DeMarco, S., Tournier, B., Vyas, S. N., FitzGerald, G. A. Cyclooxygenase inhibitors and the antiplatelet effects of aspirin. New Eng. J. Med. 345: 1809-1817, 2001. [PubMed: 11752357] [Full Text: https://doi.org/10.1056/NEJMoa003199]
Chandrasekharan, N. V., Dai, H., Roos, K. L. T., Evanson, N. K., Tomsik, J., Elton, T. S., Simmons, D. L. COX-3, a cyclooxygenase-1 variant inhibited by acetaminophen and other analgesic/antipyretic drugs: cloning, structure, and expression. Proc. Nat. Acad. Sci. 99: 13926-13931, 2002. [PubMed: 12242329] [Full Text: https://doi.org/10.1073/pnas.162468699]
Diaz, A., Reginato, A. M., Jimenez, S. A. Alternative splicing of human prostaglandin G/H synthase mRNA and evidence of differential regulation of the resulting transcripts by transforming growth factor beta-1, interleukin 1-beta, and tumor necrosis factor alpha. J. Biol. Chem. 267: 10816-10822, 1992. [PubMed: 1587858]
Funk, C. D., Funk, L. B., Kennedy, M. E., Pong, A. S., Fitzgerald, G. A. Human platelet/erythroleukemia cell prostaglandin G/H synthase: cDNA cloning, expression, and gene chromosomal assignment. FASEB J. 5: 2304-2312, 1991. [PubMed: 1907252]
Gavett, S. H., Madison, S. L., Chulada, P. C., Scarborough, P. E., Qu, W., Boyle, J. E., Tiano, H. F., Lee, C. A., Langenbach, R., Roggli, V. L., Zeldin, D. C. Allergic lung responses are increased in prostaglandin H synthase-deficient mice. J. Clin. Invest. 104: 721-732, 1999. [PubMed: 10491407] [Full Text: https://doi.org/10.1172/JCI6890]
Kirschenbaum, A., Liotta, D. R., Yao, S., Liu, X.-H., Klausner, A. P., Unger, P., Shapiro, E., Leav, I., Levine, A. C. Immunohistochemical localization of cyclooxygenase-1 and cyclooxygenase-2 in the human fetal and adult male reproductive tracts. J. Clin. Endocr. Metab. 85: 3436-3441, 2000. [PubMed: 10999846] [Full Text: https://doi.org/10.1210/jcem.85.9.6780]
Langenbach, R., Morham, S. G., Tiano, H. F., Loftin, C. D., Ghanayem, B. I., Chulada, P. C., Mahler, J. F., Lee, C. A., Goulding, E. H., Kluckman, K. D., Kim, H. S., Smithies, O. Prostaglandin synthase 1 gene disruption in mice reduces arachidonic acid-induced inflammation and indomethacin-induced gastric ulceration. Cell 83: 483-492, 1995. [PubMed: 8521478] [Full Text: https://doi.org/10.1016/0092-8674(95)90126-4]
Lee, C. R., Bottone, F. G., Jr., Krahn, J. M., Li, L., Mohrenweiser, H. W., Cook, M. E., Petrovich, R. M., Bell, D. A., Eling, T. E., Zeldin, D. C. Identification and functional characterization of polymorphisms in human cyclooxygenase-1 (PTGS1). Pharmacogenet. Genomics 17: 145-160, 2007. [PubMed: 17301694] [Full Text: https://doi.org/10.1097/01.fpc.0000236340.87540.e3]
Malkowski, M. G., Ginell, S. L., Smith, W. L., Garavito, R. M. The productive conformation of arachidonic acid bound to prostaglandin synthase. Science 289: 1933-1937, 2000. [PubMed: 10988074] [Full Text: https://doi.org/10.1126/science.289.5486.1933]
Picot, D., Loll, P. J., Garavito, R. M. The x-ray crystal structure of the membrane protein prostaglandin H-2 synthase-1. Nature 367: 243-249, 1994. [PubMed: 8121489] [Full Text: https://doi.org/10.1038/367243a0]
Qin, W., Ho, L., Pompl, P. N., Peng, Y., Zhao, Z., Xiang, Z., Robakis, N. K., Shioi, J., Suh, J., Pasinetti, G. M. Cyclooxygenase (COX)-2 and COX-1 potentiate beta-amyloid peptide generation through mechanisms that involve gamma-secretase activity. J. Biol. Chem. 278: 50970-50977, 2003. [PubMed: 14507922] [Full Text: https://doi.org/10.1074/jbc.M307699200]
Tsujii, M., Kawano, S., Tsuji, S., Sawaoka, H., Hori, M., DuBois, R. N. Cyclooxygenase regulates angiogenesis induced by colon cancer cells. Cell 93: 705-716, 1998. Note: Erratum: Cell 94: 273 only, 1998. [PubMed: 9630216] [Full Text: https://doi.org/10.1016/s0092-8674(00)81433-6]
Vane, J. R., Mitchell, J. A., Appleton, I., Tomlinson, A., Bishop-Bailey, D., Croxtall, J., Willoughby, D. A. Inducible isoforms of cyclooxygenase and nitric-oxide synthase in inflammation. Proc. Nat. Acad. Sci. 91: 2046-2050, 1994. [PubMed: 7510883] [Full Text: https://doi.org/10.1073/pnas.91.6.2046]
Warner, T. D., Mitchell, J. A. Cyclooxygenase-3 (COX-3): filling in the gaps toward a COX continuum? (Commentary) Proc. Nat. Acad. Sci. 99: 13371-13373, 2002. [PubMed: 12374850] [Full Text: https://doi.org/10.1073/pnas.222543099]
Yokoyama, C., Tanabe, T. Cloning of human gene encoding prostaglandin endoperoxide synthase and primary structure of the enzyme. Biochem. Biophys. Res. Commun. 165: 888-894, 1989. [PubMed: 2512924] [Full Text: https://doi.org/10.1016/s0006-291x(89)80049-x]