2008/02/05 by Carol A. Rouzer, Lawrence J. Marnett · 1 citation
Biochemistry, Genetics and Molecular Biology · Chemistry · Medicine · #Agonist #Arachidonic acid #Biochemistry #Biosynthesis #Cannabis and Cannabinoid Research #Chemistry #Cyclooxygenase #Eicosanoids and Hypertension Pharmacology #Endocannabinoid system #Enzyme #Inflammatory mediators and NSAID effects #Internal medicine #Lipid signaling #Medicine #Platelet #Prostaglandin #Receptor #Thromboxane #Thromboxane A2
paper · pdf · doi:10.1074/jbc.r800005200
openalex publication_date 2008/02/05 · openalex created_date 2025/10/10 · openalex updated_date 2026/08/01
The two cyclooxygenase (COX) enzymes catalyze the oxygenation of arachidonic acid to prostaglandin endoperoxides, which are the common intermediates in the biosynthesis of the bioactive lipids prostaglandins and thromboxane. COX-1 and COX-2 are ∼60% identical in amino acid sequence, exhibit highly homologous three-dimensional structures, and appear functionally similar at the biochemical level. Recent work has uncovered a subtle functional difference between the two enzymes, namely the ability of COX-2 to efficiently utilize neutral derivatives (esters and amides) of arachidonic acid as substrates. Foremost among these neutral substrates are the endocannabinoids 2-arachidonoylglycerol and arachidonoylethanolamide. This raises the possibility that COX-2 oxygenation plays a role in a novel signaling pathway dependent on agonist-induced release of endocannabinoids and their selective oxygenation by COX-2. Among the products of COX-2 oxygenation of endocannabinoids are glyceryl prostaglandins, some of which (e.g. glyceryl prostaglandin E2 and glyceryl prostaglandin I2) exhibit interesting biological activities in inflammatory, neurological, and vascular systems. These compounds are produced in intact cells stimulated with physiological agonists and have been isolated from in vivo sources. Important concepts relevant to the hypothesis of a COX-2-selective signaling pathway are presented. The two cyclooxygenase (COX) enzymes catalyze the oxygenation of arachidonic acid to prostaglandin endoperoxides, which are the common intermediates in the biosynthesis of the bioactive lipids prostaglandins and thromboxane. COX-1 and COX-2 are ∼60% identical in amino acid sequence, exhibit highly homologous three-dimensional structures, and appear functionally similar at the biochemical level. Recent work has uncovered a subtle functional difference between the two enzymes, namely the ability of COX-2 to efficiently utilize neutral derivatives (esters and amides) of arachidonic acid as substrates. Foremost among these neutral substrates are the endocannabinoids 2-arachidonoylglycerol and arachidonoylethanolamide. This raises the possibility that COX-2 oxygenation plays a role in a novel signaling pathway dependent on agonist-induced release of endocannabinoids and their selective oxygenation by COX-2. Among the products of COX-2 oxygenation of endocannabinoids are glyceryl prostaglandins, some of which (e.g. glyceryl prostaglandin E2 and glyceryl prostaglandin I2) exhibit interesting biological activities in inflammatory, neurological, and vascular systems. These compounds are produced in intact cells stimulated with physiological agonists and have been isolated from in vivo sources. Important concepts relevant to the hypothesis of a COX-2-selective signaling pathway are presented. Cyclooxygenases (COX-1 and COX-2) 2The abbreviations used are:COXcyclooxygenase (prostaglandin G/H synthase)AAarachidonic acidPGprostaglandinPGI2prostacyclinRPMsresident peritoneal macrophagesLPSlipopolysaccharideAEAarachidonoylethanolamide2-AG2-arachidonoylglycerolPG-Gglyceryl prostaglandinPG-EAethanolamide prostaglandinIP3inositol 1,4,5-trisphosphateERKextracellular signal-regulated kinasemIPSCsminiature inhibitory postsynaptic currentsEP receptorE series PG receptorMAPKmitogen-activated protein kinaseILinterleukinFP receptorF series PG receptorPPARδperoxisome proliferator-activated receptor-δsiRNAsmall interfering RNADAGdiacylglycerolPLphospholipase. 2The abbreviations used are:COXcyclooxygenase (prostaglandin G/H synthase)AAarachidonic acidPGprostaglandinPGI2prostacyclinRPMsresident peritoneal macrophagesLPSlipopolysaccharideAEAarachidonoylethanolamide2-AG2-arachidonoylglycerolPG-Gglyceryl prostaglandinPG-EAethanolamide prostaglandinIP3inositol 1,4,5-trisphosphateERKextracellular signal-regulated kinasemIPSCsminiature inhibitory postsynaptic currentsEP receptorE series PG receptorMAPKmitogen-activated protein kinaseILinterleukinFP receptorF series PG receptorPPARδperoxisome proliferator-activated receptor-δsiRNAsmall interfering RNADAGdiacylglycerolPLphospholipase. catalyze the committed step in the conversion of AA to PGs, thromboxane, and PGI2 and, in so doing, trigger the biosynthesis of an important family of lipid mediators (1Smith W.L. DeWitt D.L. Garavito R.M. Annu. Rev. Biochem. 2000; 69: 145-182Crossref PubMed Scopus (2394) Google Scholar, 2Hata A.N. Breyer R.M. Pharmacol. Ther. 2004; 103: 147-166Crossref PubMed Scopus (664) Google Scholar). Cyclooxygenase activity was first described in 1964 (3Bergstrom S. Danielsson H. Samuelsson B. Biochim. Biophys. Acta. 1964; 90: 207-210Crossref PubMed Scopus (10) Google Scholar), and COX-1 was purified in 1976 (4Miyamoto T. Ogino N. Yamamoto S. Hayaishi O. J. Biol. Chem. 1976; 251: 2629-2636Abstract Full Text PDF PubMed Google Scholar). These events occurred concomitantly with the realization that nonsteroidal anti-inflammatory drugs achieve their anti-inflammatory effects primarily by blocking the cyclooxygenase reaction (5Vane J.R. Nat. New Biol. 1971; 231: 232-235Crossref PubMed Scopus (7240) Google Scholar). The discovery of COX-2 generated important insights into inflammation, wound healing, reproduction, renal function, and vascular biology inter alia, leading to a pharmacological strategy for the treatment of inflammation with reduced gastrointestinal toxicity and providing a new target for the prevention of cancer (6Masferrer J.L. Zweifel B.S. Manning P.T. Hauser S.D. Leahy K.M. Smith W.G. Isakson P.C. Seibert K. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 3228-3232Crossref PubMed Scopus (1284) Google Scholar, 7Marnett L.J. DuBois R.N. Annu. Rev. Pharmacol. Toxicol. 2002; 42: 55-80Crossref PubMed Scopus (285) Google Scholar). Despite the rapid pace of these discoveries, our understanding of the physiological roles of the two COX enzymes is incomplete, especially with regard to potential non-redundant functions (8Smith W.L. Langenbach R. J. Clin. Investig. 2001; 107: 1491-1495Crossref PubMed Scopus (526) Google Scholar). cyclooxygenase (prostaglandin G/H synthase) arachidonic acid prostaglandin prostacyclin resident peritoneal macrophages lipopolysaccharide arachidonoylethanolamide 2-arachidonoylglycerol glyceryl prostaglandin ethanolamide prostaglandin inositol 1,4,5-trisphosphate extracellular signal-regulated kinase miniature inhibitory postsynaptic currents E series PG receptor mitogen-activated protein kinase interleukin F series PG receptor peroxisome proliferator-activated receptor-δ small interfering RNA diacylglycerol phospholipase. cyclooxygenase (prostaglandin G/H synthase) arachidonic acid prostaglandin prostacyclin resident peritoneal macrophages lipopolysaccharide arachidonoylethanolamide 2-arachidonoylglycerol glyceryl prostaglandin ethanolamide prostaglandin inositol 1,4,5-trisphosphate extracellular signal-regulated kinase miniature inhibitory postsynaptic currents E series PG receptor mitogen-activated protein kinase interleukin F series PG receptor peroxisome proliferator-activated receptor-δ small interfering RNA diacylglycerol phospholipase. Ptgs-1, which codes for COX-1, is transcribed constitutively into a 2.8-kb mRNA, whereas Ptgs-2 is an immediate-early gene that produces a 4-kb mRNA in response to a wide range of stimuli. COX-1 mRNA is relatively stable, whereas COX-2 mRNA turns over rapidly because of the presence of instability sequences in the 3′-untranslated region. Human COX-1 and COX-2 contain 576 and 580 amino acids, respectively, and are 60% identical in sequence (9Xie W. Chipman J.G. Robertson D.L. Erikson R.L. Simmons D.L. Proc. Natl. Acad. Sci. U. S. A. 1991; 88: 2692-2696Crossref PubMed Scopus (1677) Google Scholar, 10Kujubu D.A. Fletcher B.S. Varnum B.C. Lim R.W. Herschman H.R. J. Biol. Chem. 1991; 266: 12866-12872Abstract Full Text PDF PubMed Google Scholar, 11O'Banion M.K. Winn V.D. Young D.A. Proc. Natl. Acad. Sci. U. S. A. 1992; 89: 4888-4892Crossref PubMed Scopus (800) Google Scholar, 12DeWitt D.L. Smith W.L. Proc. Natl. Acad. Sci. U. S. A. 1988; 85: 1412-1416Crossref PubMed Scopus (537) Google Scholar). The major elements of the primary structures are comparable, so the domain structures are identical, and the three-dimensional structures are essentially superimposable. Both COX enzymes are located in the lumen of the endoplasmic reticulum and in the nuclear envelope (13Regier M.K. DeWitt D.L. Schindler M.S. Smith W.L. Arch. Biochem. Biophys. 1993; 301: 439-444Crossref PubMed Scopus (94) Google Scholar, 14Regier M.K. Otto J.C. DeWitt D.L. Smith W.L. Arch. Biochem. Biophys. 1995; 317: 457-463Crossref PubMed Scopus (26) Google Scholar). COX-1 and COX-2 catalyze the oxygenation of polyunsaturated fatty acids to hydroperoxy endoperoxides at the cyclooxygenase active site and the reduction of the hydroperoxide to an alcohol at the peroxidase active site (Fig. 1) (15Picot D. Loll P.J. Garavito R.M. Nature. 1994; 367: 243-249Crossref PubMed Scopus (1135) Google Scholar). Each protein uses a free radical mechanism in which an initial reaction with a hydroperoxide generates a higher oxidation state of the heme prosthetic group, which oxidizes an active-site tyrosine to activate the oxygenase (16Dietz R. Nastainczyk W. Ruf H.H. Eur. J. Biochem. 1988; 171: 321-328Crossref PubMed Scopus (194) Google Scholar, 17Rouzer C.A. Marnett L.J. Chem. Rev. 2003; 103: 2239-2304Crossref PubMed Scopus (195) Google Scholar, 18van der Donk W.A. Tsai A.L. Kulmacz R.J. Biochemistry. 2002; 41: 15451-15458Crossref PubMed Scopus (131) Google Scholar). COX-2 is more sensitive to hydroperoxide-dependent activation compared with COX-1 (∼10-fold), which may result in differential activation of the two enzymes in cells with low peroxide concentrations (19Kulmacz R.J. Wang L.H. J. Biol. Chem. 1995; 270: 24019-24023Abstract Full Text Full Text PDF PubMed Scopus (189) Google Scholar). Additional biochemical differences between the COX proteins are those related to the utilization of different polyunsaturated fatty acid substrates (20Laneuville O. Breuer D.K. Xu N. Huang Z.H. Gage D.A. Watson J.T. Lagarde M. DeWitt D.L. Smith W.L. J. Biol. Chem. 1995; 270: 19330-19336Abstract Full Text Full Text PDF PubMed Scopus (205) Google Scholar, 21Schneider C. Boeglin W.E. Yin H. Stec D.F. Voehler M. J. Am. Chem. Soc. 2006; 128: 720-721Crossref PubMed Scopus (25) Google Scholar) and differences in protein turnover (22Mbonye U.R. Wada M. Rieke C.J. Tang H.Y. Dewitt D.L. Smith W.L. J. Biol. Chem. 2006; 281: 35770-35778Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar). It is possible that the differential transcriptional responses to cell stimuli are the only physiologically relevant distinction between the COX enzymes. However, many of the cells that express COX-2 already express functional COX-1, so the net increase in PG production is only 2–3-fold even following dramatic increases in the levels of COX-2 (23Rouzer C.A. Marnett L.J. J. Biol. Chem. 2005; 280: 26690-26700Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar). COX-2 is expressed constitutively in specialized regions of the brain and kidney (24Kaufmann W.E. Worley P.F. Pegg J. Bremer M. Isakson P. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 2317-2321Crossref PubMed Scopus (564) Google Scholar, 25Harris R.C. McKanna J.A. Akai Y. Jacobson H.R. Dubois R.N. Breyer M.D. J. Clin. Investig. 1994; 94: 2504-2510Crossref PubMed Scopus (828) Google Scholar) and may represent the sole source of PGs in those areas. However, this situation is the exception rather than the rule with respect to tissue and cellular localization. Yu et al. (26Yu Y. Fan J. Hui Y. Rouzer C.A. Marnett L.J. Klein-Szanto A.J. FitzGerald G.A. Funk C.D. J. Biol. Chem. 2007; 282: 1498-1506Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar) recently tested the interchangeability of the two enzymes by knocking Ptgs-1 into the Ptgs-2 locus in mice. RPMs from these animals demonstrated inducibility of COX-1 protein in response to LPS treatment but were unable to produce PGs at low concentrations of AA, as anticipated by the differences in hydroperoxide activation described above. The Ptgs-1 knock-in partially restored the deficit in the major urinary PGI2 metabolite observed in Ptgs-2 knock-out animals, whereas the deficit in the major urinary PGE2 metabolite was completely restored. This suggests that there may be differences in coupling between the two oxygenases and downstream synthases. Deficiencies in reproductive and renal function observed in Ptgs-2-deficient mice were partially corrected or delayed, respectively, in Ptgs-1 knock-in mice. These mice will serve as an excellent resource with which to probe non-redundant functions of the two COX enzymes. A major structural difference between COX-1 and COX-2 is the size of their cyclooxygenase active sites (Fig. 2) (27Luong C. Miller A. Barnett J. Chow J. Ramesha C. Browner M.F. Nat. Struct. Biol. 1996; 3: 927-933Crossref PubMed Scopus (554) Google Scholar). The presence of a side pocket near the base of the active site of COX-2 makes its site 24% larger than that of COX-1. This side pocket was utilized accidentally in the development of the diarylheterocycle class of COX-2-selective inhibitors, which possess a sulfone or sulfonamide group that inserts into the side pocket of COX-2 (28Kurumbail R.G. Stevens A.M. Gierse J.K. McDonald J.J. Stegeman R.A. Pak J.Y. Gildehaus D. Miyashiro J.M. Penning T.D. Seibert K. Isakson P.C. Stallings W.C. Nature. 1996; 384: 644-648Crossref PubMed Scopus (1553) Google Scholar). 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Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). The ability of COX-2 to and to endoperoxides that are to or raises the possibility that this is of a COX-2-selective signaling of the biological effects of and is not but initial are in cells at to concentrations with a of is by the receptor B.C. Marnett L.J. Proc. Natl. Acad. Sci. U. S. A. 2004; PubMed Scopus Google Scholar). of extracellular but not the with an initial release of from by of from endoplasmic reticulum by of cells with the of protein kinase is observed with downstream of and transcriptional activation dependent on the response and downstream signaling in cells appear to be of to PGE2 B.C. Marnett L.J. Proc. Natl. Acad. Sci. U. S. A. 2004; PubMed Scopus Google Scholar). an increase in the of in with an of N. J. C. J. 2006; Scopus Google Scholar). This with the of its at a of the of the of but not increase the and increase the of but The PGs PGE2 and the of whereas has that the ability of and to increase the of is not to to PGs or binding to PG of the binding of to and expressed that it is at of than PGE2 at binding to of the B.C. Marnett L.J. Proc. Natl. Acad. Sci. U. S. A. 2004; PubMed Scopus Google Scholar). The of observed following treatment with is not by a receptor but is by an receptor and a The of these suggests that the of is by of or with novel and that and are in the downstream are with the COX-2 the of and are with the COX-2 it increases N. J. C. J. 2006; Scopus Google Scholar). The increase in by treatment is by an receptor and a that the increase is to of mediators produced by COX-2. in as by an of miniature postsynaptic currents N. J. C. J. 2007; PubMed Scopus Google Scholar). The increase in to as by and signaling and In to miniature postsynaptic currents in The inhibitory effects of are by receptor whereas the of are the of family and in by the of the common D. C. C. Biochem. J. PubMed Scopus Google Scholar). The COX-2 oxygenation a similar inhibitory at the cellular and levels transcriptional the The inhibitory effects of in or cells are by treatment with the COX-2 whereas the effects of are The effects of and are partially by the receptor but not by the the inhibitory effects of on may be partially by with the derivatives of are to and for the treatment of A. D.F. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar). has been the as for or its acid following or by binding the of tissue have the of of the receptor Y. D.F. C. D.F. Wang K. A. C. J. S. H. J. Pharmacol. Scholar). that a is between the receptor and a receptor of the and in nuclear cells increases the of the cells to by the of the cells to the is for the of a of following The activities may result from the of or with PG or of PG with of PG of these are of the class of for the activation of the nuclear receptor by of vascular cells with which of tissue M. Wang H. Y. J.M. N. T. J. 2007; PubMed Scopus Google Scholar). is a by cells that to The of activation is cells are with than are with The two major of AA and in vascular cells are and of but not activation by it that vascular cells into which and tissue activation is reduced by the COX-2-selective but not by the increases the production of tissue by The role of tissue in suggests that reduction in the levels of in the vascular may to the toxicity with COX-2 H. J.A. B. K. C. R. D. A. J.A. N. J. 2005; PubMed Scopus Google Scholar). are on the production of or in and have been in the and of mice following of A. J. A. R. D. J. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar). The levels of these compounds were higher to animals a of the gene for which rapidly to mice levels of and in the and small and was in were not in animals that not In was and in of from animals that treatment S. J. J.M. on the Scholar). have been of the production of in isolated RPMs and the cell (23Rouzer C.A. Marnett L.J. J. Biol. Chem. 2005; 280: 26690-26700Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar, Marnett L.J. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, C.A. S. Wang H. H. Marnett L.J. Biochem. J. 2006; PubMed Scopus (26) Google Scholar). that are following release of from by treatment with a of physiological and and The of that of PGs generated from AA and from RPMs and from (23Rouzer C.A. Marnett L.J. J. Biol. Chem. 2005; 280: 26690-26700Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar, C.A. S. Wang H. H. Marnett L.J. Biochem. J. 2006; PubMed Scopus (26) Google Scholar). of and PG biosynthesis that are produced at levels than PGs (23Rouzer C.A. Marnett L.J. J. Biol. Chem. 2005; 280: 26690-26700Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar, C.A. S. Wang H. H. Marnett L.J. Biochem. J. 2006; PubMed Scopus (26) Google Scholar). of this differential is to the of than AA by other may be important in the of addition of to rapid production of AA and PGs as as (23Rouzer C.A. Marnett L.J. J. Biol. Chem. 2005; 280: 26690-26700Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar). In the levels of PGs generated from are higher than those of is rapidly to AA in RPMs and to be the of COX-2 In of that COX-2 may be active only for a whereas COX-1 to be active for (23Rouzer C.A. Marnett L.J. J. Biol. Chem. 2005; 280: 26690-26700Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar). This the of oxygenation products in of PGs because AA is an excellent for COX-1 and whereas is a for COX-2. there may be major differences in the sites of release of AA and to the of COX-2 as as the of to the It will be interesting to similar in release and in other cell (e.g. and vascular of the of release of and the from which it is is suggests that is from of T. N. D. S. Biochem. J. PubMed Scopus Google Scholar, N. P. D. Nature. PubMed Scopus Google Scholar). are generated by or by is of the small that are are not selective and of and, in some fatty acid oxygenation T.D. Biochim. Biophys. Acta. PubMed Scopus Google Scholar). and J. are for in which may to the of and lipid is to the that are following cell C.A. P.T. Marnett L.J. Biochemistry. 2006; PubMed Scopus Google Scholar, C.A. P.T. Marnett L.J. Biochemistry. 2007; PubMed Scopus Google Scholar). it is possible to and to its turnover following or a of and lipid it be possible to the of lipids that to and to their following cell The discovery of an of COX that in tissue to the hypothesis that this is primarily for the of COX to the The anti-inflammatory of COX-2-selective this However, the more discovery of the toxicity of these clearly that COX-2 an of physiological T. S. FitzGerald G.A. J. Clin. Investig. 2006; PubMed Scopus Google Scholar). It is possible that the roles of COX-1 and COX-2 their differential of However, the with COX-1 knock-in mice that there are subtle differences in function that prevent from for the The of hydroperoxide activation of COX-2 compared with COX-1 may the for these However, the ability of COX-2 to neutral AA derivatives to an hypothesis as in AA from by is a for COX In a pathway is a selective for COX-2. oxygenation may to with a of physiological activities by of and their or nuclear lipid this function of COX-2 may a role in J. Nat. 2004; PubMed Scopus Google Scholar). of these of the biological activity of biosynthesis by intact and a role for COX-2 activity in in is to AA, which may be to of produces PGs, which are from those produced from AA of the of oxygenation in vivo a a understanding of the potential role of this pathway may to important insights into the function of COX-2 in and