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• W2918451382 abstract "Prostaglandin endoperoxide H synthases-1 and -2, commonly called cyclooxygenases-1 and -2 (COX-1 and -2), catalyze the committed step in prostaglandin biosynthesis—the conversion of arachidonic acid to prostaglandin endoperoxide H2. Both COX isoforms are sequence homodimers that function as conformational heterodimers having allosteric (Eallo) and catalytic (Ecat) subunits. At least in the case of COX-2, the enzyme becomes folded into a stable Eallo/Ecat pair. Some COX inhibitors (i.e. nonsteroidal anti-inflammatory drugs and coxibs) and common fatty acids (FAs) modulate Ecat activity by binding Eallo. However, the interactions and outcomes often differ between isoforms. For example, naproxen directly and completely inhibits COX-1 by binding Ecat but indirectly and incompletely inhibits COX-2 by binding Eallo. Additionally, COX-1 is allosterically inhibited up to 50% by common FAs like palmitic acid, whereas COX-2 is allosterically activated 2-fold by palmitic acid. FA binding to Eallo also affects responses to COX inhibitors. Thus, COXs are physiologically and pharmacologically regulated by the FA tone of the milieu in which each operates—COX-1 in the endoplasmic reticulum and COX-2 in the Golgi apparatus. Cross-talk between Eallo and Ecat involves a loop in Eallo immediately downstream of Arg-120. Mutational studies suggest that allosteric modulation requires a direct interaction between the carboxyl group of allosteric effectors and Arg-120 of Eallo; however, structural studies show some allosterically active FAs positioned in COX-2 in a conformation lacking an interaction with Arg-120. Thus, many details about the biological consequences of COX allosterism and how ligand binding to Eallo modulates Ecat remain to be resolved. Prostaglandin endoperoxide H synthases-1 and -2, commonly called cyclooxygenases-1 and -2 (COX-1 and -2), catalyze the committed step in prostaglandin biosynthesis—the conversion of arachidonic acid to prostaglandin endoperoxide H2. Both COX isoforms are sequence homodimers that function as conformational heterodimers having allosteric (Eallo) and catalytic (Ecat) subunits. At least in the case of COX-2, the enzyme becomes folded into a stable Eallo/Ecat pair. Some COX inhibitors (i.e. nonsteroidal anti-inflammatory drugs and coxibs) and common fatty acids (FAs) modulate Ecat activity by binding Eallo. However, the interactions and outcomes often differ between isoforms. For example, naproxen directly and completely inhibits COX-1 by binding Ecat but indirectly and incompletely inhibits COX-2 by binding Eallo. Additionally, COX-1 is allosterically inhibited up to 50% by common FAs like palmitic acid, whereas COX-2 is allosterically activated 2-fold by palmitic acid. FA binding to Eallo also affects responses to COX inhibitors. Thus, COXs are physiologically and pharmacologically regulated by the FA tone of the milieu in which each operates—COX-1 in the endoplasmic reticulum and COX-2 in the Golgi apparatus. Cross-talk between Eallo and Ecat involves a loop in Eallo immediately downstream of Arg-120. Mutational studies suggest that allosteric modulation requires a direct interaction between the carboxyl group of allosteric effectors and Arg-120 of Eallo; however, structural studies show some allosterically active FAs positioned in COX-2 in a conformation lacking an interaction with Arg-120. Thus, many details about the biological consequences of COX allosterism and how ligand binding to Eallo modulates Ecat remain to be resolved. The most recent detailed reviews of cyclooxygenase catalysis were published by Tsai and Kulmacz (1Tsai A.L. Kulmacz R.J. Prostaglandin H synthase: resolved and unresolved mechanistic issues.Arch. Biochem. Biophys. 2010; 493 (19728984): 103-12410.1016/j.abb.2009.08.019Crossref PubMed Scopus (78) Google Scholar) and Smith et al. (2Smith W.L. Urade Y. Jakobsson P.J. Enzymes of the cyclooxygenase pathways of prostanoid biosynthesis.Chem. Rev. 2011; 111 (21942677): 5821-586510.1021/cr2002992Crossref PubMed Scopus (350) Google Scholar). Prostaglandin endoperoxide H synthases (PGHSs) 3The abbreviations used are: PGHSprostaglandin endoperoxide H synthase2-AG2-arachidonoylglycerol1-AG1-arachidonoylglycerol13-Me-AA13-methylarachidonic acidAAarachidonic acidAEAanandamideCOXcyclooxygenaseDHAdocosahexaenoic acidDHLAdihomo-γ-linolenic acidDPAdocosapentaenoic acidEPAeicosapentaenoic acidFAfatty acidhuhumanMBDmembrane binding domainnsNSAIDsnonspecific nonsteroidal anti-inflammatory drugsovovinePApalmitic acidPGprostaglandinPOXperoxidaseERendoplasmic reticulum. efficiently convert the ω-6 polyunsaturated fatty acid (FA) arachidonic acid (5c,8c,11c,14c-eicosatetraenoic acid; AA), two O2 molecules, and two electrons to prostaglandin endoperoxide H2 (PGH2) in two steps: (a) a bis-oxygenase (“cyclooxygenase” (COX)) reaction to form prostaglandin endoperoxide G2 (PGG2), and (b) a peroxidase (POX) reaction that reduces PGG2 to PGH2 (Fig. 1). These reactions occur at separate but interconnected COX and POX active sites of the enzymes. AA utilized in the COX reaction is probably derived mainly through the actions of various phospholipase A2 forms (3Leslie C.C. Cytosolic phospholipase A2: physiological function and role in disease.J. Lipid Res. 2015; 56 (25838312): 1386-140210.1194/jlr.R057588Abstract Full Text Full Text PDF PubMed Scopus (237) Google Scholar, 4Murakami M. Yamamoto K. Miki Y. Murase R. Sato H. Taketomi Y. The roles of the secreted phospholipase A2 gene family in immunology.Adv. Immunol. 2016; 132 (27769509): 91-13410.1016/bs.ai.2016.05.001Crossref PubMed Scopus (47) Google Scholar). The physiological source(s) of the electrons used by the POX activity of PGHSs to form PGG2 is unknown. prostaglandin endoperoxide H synthase 2-arachidonoylglycerol 1-arachidonoylglycerol 13-methylarachidonic acid arachidonic acid anandamide cyclooxygenase docosahexaenoic acid dihomo-γ-linolenic acid docosapentaenoic acid eicosapentaenoic acid fatty acid human membrane binding domain nonspecific nonsteroidal anti-inflammatory drugs ovine palmitic acid prostaglandin peroxidase endoplasmic reticulum. The formation of PGH2 is typically shown as a COX reaction followed by a POX reaction (Fig. 1); however, the initiation of COX activity requires an initial oxidation of the heme group at the POX site by ambient H2O2, an alkyl hydroperoxide or nitric oxide (1Tsai A.L. Kulmacz R.J. Prostaglandin H synthase: resolved and unresolved mechanistic issues.Arch. Biochem. Biophys. 2010; 493 (19728984): 103-12410.1016/j.abb.2009.08.019Crossref PubMed Scopus (78) Google Scholar). Oxidation of the heme leads to generation of a heme radical cation in the POX active site and a tyrosyl radical on Tyr-385 in the COX active site. This tyrosyl radical abstracts the ω8 allylic hydrogen from AA bound in the COX site in the first step in COX catalysis. The first O2 insertion then occurs at C-11. Hydrogen abstraction from the ω8 position of dihomo-γ-linolenic acid (8c,11c,14c-eicosatrienoic acid; DHLA), the precursor of the “1 series” PGs, occurs with an isotope effect, which suggested that hydrogen abstraction is the rate-limiting step in COX catalysis (5Hamberg M. Samuelsson B. Oxygenation of unsaturated fatty acids by the vesicular gland of sheep.J. Biol. Chem. 1967; 242 (6070852): 5344-5354Abstract Full Text PDF PubMed Google Scholar). Recent evidence indicates that the first irreversible step is later in the complex reaction sequence when the hydrogen from a reduced Tyr-385 is transferred to generate PGG2 and regenerate the Tyr-385 radical (6Liu Y. Roth J.P. A revised mechanism for human cyclooxygenase-2.J. Biol. Chem. 2016; 291 (26565028): 948-95810.1074/jbc.M115.668038Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar). There are two PGHS isoforms: PGHS-1 and PGHS-2, also called COX-1 and COX-2. COX-1 has a narrow substrate specificity, preferentially oxygenating AA. COX-2 has a broader substrate specificity and can oxygenate several FAs more efficiently than does COX-1, including DHLA, eicosapentaenoic acid (EPA), and adrenic acid (22:4ω6) at 115, 45, and 57% of the rate of AA. One functional difference between COX-1 and COX-2 is the ability of COX-2 to efficiently oxygenate neutral derivatives of AA, such as 2-arachidonoylglycerol (2-AG) and anandamide (AEA). 2-AG and AEA have a wide tissue distribution and were the first endogenous ligands identified for the cannabinoid receptors (7Rouzer C.A. Marnett L.J. Non-redundant functions of cyclooxygenases: oxygenation of endocannabinoids.J. Biol. Chem. 2008; 283 (18250160): 8065-806910.1074/jbc.R800005200Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar). Marnett and co-workers showed that endocannabinoid oxygenation by COX utilizes the Tyr-385–based radical mechanism employed for AA. Their work is reviewed in Ref. 8Rouzer C.A. Marnett L.J. Endocannabinoid oxygenation by cyclooxygenases, lipoxygenases, and cytochromes P450: cross-talk between the eicosanoid and endocannabinoid signaling pathways.Chem. Rev. 2011; 111 (21923193): 5899-592110.1021/cr2002799Crossref PubMed Scopus (231) Google Scholar. COX-1 and COX-2 are both targets of common nonspecific nonsteroidal anti-inflammatory drugs (nsNSAIDs), including ibuprofen and naproxen (Fig. 1). Aspirin is a nsNSAID that unlike other inhibitors covalently and irreversibly modifies COXs by acetylating Ser-530 and interfering with AA access to the COX active site (9DeWitt D.L. el-Harith E.A. Kraemer S.A. Andrews M.J. Yao E.F. Armstrong R.L. Smith W.L. The aspirin and heme-binding sites of ovine and murine prostaglandin endoperoxide synthases.J. Biol. Chem. 1990; 265 (2108169): 5192-5198Abstract Full Text PDF PubMed Google Scholar10Lecomte M. Laneuville O. Ji C. DeWitt D.L. Smith W.L. Acetylation of human prostaglandin endoperoxide synthase-2 (cyclooxygenase-2) by aspirin.J. Biol. Chem. 1994; 269 (8175750): 13207-13215Abstract Full Text PDF PubMed Google Scholar, 11Loll P.J. Picot D. Garavito R.M. The structural basis of aspirin activity inferred from the crystal structure of inactivated prostaglandin H2 synthase.Nat. Struct. Biol. 1995; 2 (7552725): 637-64310.1038/nsb0895-637Crossref PubMed Scopus (462) Google Scholar, 12Rimon G. Sidhu R.S. Lauver D.A. Lee J.Y. Sharma N.P. Yuan C. Frieler R.A. Trievel R.C. Lucchesi B.R. Smith W.L. Coxibs interfere with the action of aspirin by binding tightly to one monomer of cyclooxygenase-1.Proc. Natl. Acad. Sci. U.S.A. 2010; 107 (19955429): 28-3310.1073/pnas.0909765106Crossref PubMed Scopus (147) Google Scholar, 13Dong L. Sharma N.P. Jurban B.J. Smith W.L. Pre-existent asymmetry in the human cyclooxygenase-2 sequence homodimer.J. Biol. Chem. 2013; 288 (23955344): 28641-2865510.1074/jbc.M113.505503Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar14Lucido M.J. Orlando B.J. Vecchio A.J. Malkowski M.G. Crystal structure of aspirin-acetylated human cyclooxygenase-2: insight into the formation of products with reversed stereochemistry.Biochemistry. 2016; 55 (26859324): 1226-123810.1021/acs.biochem.5b01378Crossref PubMed Scopus (109) Google Scholar). COX-2 “specific” inhibitors referred to as coxibs are more selective toward COX-2; however, some coxibs bind with high affinity to COX-1 and affect responses of COX-1 to nsNSAIDs and FAs. Most nsNSAIDs and coxibs are hydrophobic, many cause time-dependent COX inhibition, and each is metabolized at different rates. No one assay method provides a simple comparison of the specificities and potencies of COX inhibitors. A useful comparison based on in vitro whole-blood assays is described by Grosser et al. (15Grosser T. Fries S. FitzGerald G.A. Biological basis for the cardiovascular consequences of COX-2 inhibition: therapeutic challenges and opportunities.J. Clin. Invest. 2006; 116 (16395396): 4-15Crossref PubMed Scopus (835) Google Scholar). Each COX is associated with different biologies, but there is a level of functional complementarity (16Li X. Mazaleuskaya L.L. Yuan C. Ballantyne L.L. Meng H. Smith W.L. FitzGerald G.A. Funk C.D. Flipping the cyclooxygenase (Ptgs) genes reveals isoform-specific compensatory functions.J. Lipid Res. 2018; 59 (29180445): 89-10110.1194/jlr.M079996Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar, 17Li X. Mazaleuskaya L.L. Ballantyne L.L. Meng H. FitzGerald G.A. Funk C.D. Differential compensation of two cyclooxygenases in renal homeostasis is independent of prostaglandin-synthetic capacity under basal conditions.FASEB J. 2018; 32 (29676940): 5326-533710.1096/fj.201800252RCrossref PubMed Scopus (4) Google Scholar). Both COX isoforms are present on the luminal surface of the ER and associated inner membrane of the nuclear envelope (18Rollins T.E. Smith W.L. Subcellular localization of prostaglandin-forming cyclooxygenase in Swiss mouse 3T3 fibroblasts by electron microscopic immunocytochemistry.J. Biol. Chem. 1980; 255 (6768726): 4872-4875Abstract Full Text PDF PubMed Google Scholar, 19Otto J.C. Smith W.L. The orientation of prostaglandin endoperoxide synthases-1 and -2 in the endoplasmic reticulum.J. Biol. Chem. 1994; 269 (8051068): 19868-19875Abstract Full Text PDF PubMed Google Scholar20Spencer A.G. Woods J.W. Arakawa T. Singer I.I. Smith W.L. Subcellular localization of prostaglandin endoperoxide H synthases-1 and -2 by immunoelectron microscopy.J. Biol. Chem. 1998; 273 (9545330): 9886-989310.1074/jbc.273.16.9886Abstract Full Text Full Text PDF PubMed Scopus (295) Google Scholar). Importantly, COX-2 is also located in the Golgi apparatus where it is likely involved in PGE2 biosynthesis (21Yuan C. Smith W.L. A cyclooxygenase-2-dependent prostaglandin E2 biosynthetic system in the Golgi apparatus.J. Biol. Chem. 2015; 290 (25548276): 5606-562010.1074/jbc.M114.632463Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar). COX-2 is also associated with lipid droplets (22Accioly M.T. Pacheco P. Maya-Monteiro C.M. Carrossini N. Robbs B.K. Oliveira S.S. Kaufmann C. Morgado-Diaz J.A. Bozza P.T. Viola J.P. Lipid bodies are reservoirs of cyclooxygenase-2 and sites of prostaglandin-E2 synthesis in colon cancer cells.Cancer Res. 2008; 68 (18339853): 1732-174010.1158/0008-5472.CAN-07-1999Crossref PubMed Scopus (244) Google Scholar). Differences between the subcellular locations of COX-1 and COX-2 have consequences in terms of the availability of substrates and agents that modulate COX activities (e.g. hydroperoxides and FAs that are not substrates). COXs are sequence homodimers consisting of tightly associated monomers. Each monomer contains three domains: an N-terminal epidermal growth factor-like domain; a membrane-binding domain (MBD); and a globular C-terminal catalytic domain (Fig. 2) (23Picot D. Loll P.J. Garavito R.M. The X-ray crystal structure of the membrane protein prostaglandin H2 synthase-1.Nature. 1994; 367 (8121489): 243-24910.1038/367243a0Crossref PubMed Scopus (1148) Google Scholar). The heme group is located near the surface of the catalytic domain, where it serves as a “functional bridge” between the POX and COX active sites. The MBD is composed of four short amphipathic helices, with an opening in its center. The amphipathic helices serve to anchor the homodimer to the surface of the membrane through the side chains of hydrophobic amino acids that protrude into the bilayer (24Otto J.C. Smith W.L. Photolabeling of prostaglandin endoperoxide H synthase-1 with 3-trifluoro-3-(m-[125I]iodophenyl)diazirine as a probe of membrane association and the cyclooxygenase active site.J. Biol. Chem. 1996; 271 (8626626): 9906-991010.1074/jbc.271.17.9906Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar, 25Spencer A.G. Thuresson E. Otto J.C. Song I. Smith T. DeWitt D.L. Garavito R.M. Smith W.L. The membrane binding domains of prostaglandin endoperoxide H synthase-1 and -2: peptide mapping and mutational analysis.J. Biol. Chem. 1999; 274 (10551860): 32936-3294210.1074/jbc.274.46.32936Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar). FAs are envisioned to enter the COX active site through the opening within the MBD. Cytosolic (c) PLA2 translocating to the surface of Golgi apparatus and the ER and nuclear envelope, depending on the cytosolic Ca2+ concentration (3Leslie C.C. Cytosolic phospholipase A2: physiological function and role in disease.J. Lipid Res. 2015; 56 (25838312): 1386-140210.1194/jlr.R057588Abstract Full Text Full Text PDF PubMed Scopus (237) Google Scholar, 26Leslie C.C. Gangelhoff T.A. Gelb M.H. Localization and function of cytosolic phospholipase A2α at the Golgi.Biochimie. 2010; 92 (20226226): 620-62610.1016/j.biochi.2010.03.001Crossref PubMed Scopus (37) Google Scholar), is presumed to mobilize FA substrates that traverse the space between the monolayers of the bilayer entering methyl-end first into the pore formed by the MBD and from there into the COX active site. At the atomic level, the interactions that govern FA binding, specificity, and catalysis by COX-1 have been well established (27Bhattacharyya D.K. Lecomte M. Rieke C.J. Garavito M. Smith W.L. Involvement of arginine 120, glutamate 524, and tyrosine 355 in the binding of arachidonate and 2-phenylpropionic acid inhibitors to the cyclooxygenase active site of ovine prostaglandin endoperoxide H synthase-1.J. Biol. Chem. 1996; 271 (8567676): 2179-218410.1074/jbc.271.4.2179Abstract Full Text Full Text PDF PubMed Scopus (169) Google Scholar28Rieke C.J. Mulichak A.M. Garavito R.M. Smith W.L. The role of arginine 120 of human prostaglandin endoperoxide H synthase-2 in the interaction with fatty acid substrates and inhibitors.J. Biol. Chem. 1999; 274 (10358065): 17109-1711410.1074/jbc.274.24.17109Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar, 29Malkowski M.G. Ginell S.L. Smith W.L. Garavito R.M. The X-ray crystal structure of prostaglandin endoperoxide H synthase-1 complexed with arachidonic acid.Science. 2000; 289 (10988074): 1933-193710.1126/science.289.5486.1933Crossref PubMed Scopus (259) Google Scholar30Thuresson E.D. Malkowski M.G. Lakkides K.M. Rieke C.J. Mulichak A.M. Ginell S.L. Garavito R.M. Smith W.L. Mutational and X-ray crystallographic analysis of the interaction of dihomo-γ-linolenic acid with prostaglandin endoperoxide H synthases.J. Biol. Chem. 2001; 276 (11121413): 10358-1036510.1074/jbc.M009378200Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar), whereas the equivalent interactions for COX-2 have only recently come into focus (31Vecchio A.J. Simmons D.M. Malkowski M.G. Structural basis of fatty acid substrate binding to cyclooxygenase-2.J. Biol. Chem. 2010; 285 (20463020): 22152-2216310.1074/jbc.M110.119867Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar, 32Vecchio A.J. Orlando B.J. Nandagiri R. Malkowski M.G. Investigating substrate promiscuity in cyclooxygenase-2: the role of Arg-120 and residues lining the hydrophobic groove.J. Biol. Chem. 2012; 287 (22637474): 24619-2463010.1074/jbc.M112.372243Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar). In its catalytically productive conformation, AA is oriented in the COX channel of both COX-1 and COX-2 in an extended L-shaped conformation, with the carboxylate group located near the opening of the channel interacting with Arg-120 (Fig. 2). The ω-end of AA is located in a hydrophobic groove at the apex of the channel. In this orientation, C-13 of AA is optimally placed below Tyr-385, where the pro-S-hydrogen can be abstracted to initiate catalysis. The crystal structure of AA bound to COX-2 revealed AA in different conformations in the two monomers. The catalytically productive conformation of AA was observed in one monomer. The other monomer exhibited AA in a “nonproductive” pose, in which AA is bound inverted within the channel, with the carboxylate group stabilized by interactions with Tyr-385 and Ser-530 at the apex of the channel and the ω-end of AA directed toward the opening of the channel (31Vecchio A.J. Simmons D.M. Malkowski M.G. Structural basis of fatty acid substrate binding to cyclooxygenase-2.J. Biol. Chem. 2010; 285 (20463020): 22152-2216310.1074/jbc.M110.119867Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar, 33Kiefer J.R. Pawlitz J.L. Moreland K.T. Stegeman R.A. Hood W.F. Gierse J.K. Stevens A.M. Goodwin D.C. Rowlinson S.W. Marnett L.J. Stallings W.C. Kurumbail R.G. Structural insights into the stereochemistry of the cyclooxygenase reaction.Nature. 2000; 405 (10811226): 97-10110.1038/35011103Crossref PubMed Scopus (188) Google Scholar). Structure determinations have also characterized the binding of different FA substrates within the COX channel of COX-1 and COX-2 and provided insights into the molecular underpinnings responsible for the substrate selectivity observed for each isoform (30Thuresson E.D. Malkowski M.G. Lakkides K.M. Rieke C.J. Mulichak A.M. Ginell S.L. Garavito R.M. Smith W.L. Mutational and X-ray crystallographic analysis of the interaction of dihomo-γ-linolenic acid with prostaglandin endoperoxide H synthases.J. Biol. Chem. 2001; 276 (11121413): 10358-1036510.1074/jbc.M009378200Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar, 31Vecchio A.J. Simmons D.M. Malkowski M.G. Structural basis of fatty acid substrate binding to cyclooxygenase-2.J. Biol. Chem. 2010; 285 (20463020): 22152-2216310.1074/jbc.M110.119867Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar32Vecchio A.J. Orlando B.J. Nandagiri R. Malkowski M.G. Investigating substrate promiscuity in cyclooxygenase-2: the role of Arg-120 and residues lining the hydrophobic groove.J. Biol. Chem. 2012; 287 (22637474): 24619-2463010.1074/jbc.M112.372243Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar, 34Malkowski M.G. Thuresson E.D. Lakkides K.M. Rieke C.J. Micielli R. Smith W.L. Garavito R.M. Structure of eicosapentaenoic and linoleic acids in the cyclooxygenase site of prostaglandin endoperoxide H synthase-1.J. Biol. Chem. 2001; 276 (11477109): 37547-3755510.1074/jbc.M105982200Abstract Full Text Full Text PDF PubMed Scopus (110) Google Scholar). In general, these alternative FA substrates bind in extended L-shaped conformations, similar to that observed for AA, with their carboxylate groups located near Arg-120 and their ω-ends in the hydrophobic groove at the top of the channel. The resulting poses position C-13 (or C-11 in the case of linoleic acid and α-linolenic acid) below Tyr-385 for hydrogen abstraction, with the contacts and residues involved in the stabilization of the substrate within the channel highly conserved. Similar to that observed for AA, both nonproductive and productive poses are observed in each monomer for EPA bound in the COX channel of COX-2 (31Vecchio A.J. Simmons D.M. Malkowski M.G. Structural basis of fatty acid substrate binding to cyclooxygenase-2.J. Biol. Chem. 2010; 285 (20463020): 22152-2216310.1074/jbc.M110.119867Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar). There are subtle differences associated with the binding of different FA substrates to COX-1 and COX-2. With COX-2 there is not a functional requirement for a direct interaction between the substrate carboxylate group and Arg-120, and COX-2 has a larger COX channel volume. This conformational freedom is the major reason that COX-2 has a more promiscuous substrate preference than COX-1 (32Vecchio A.J. Orlando B.J. Nandagiri R. Malkowski M.G. Investigating substrate promiscuity in cyclooxygenase-2: the role of Arg-120 and residues lining the hydrophobic groove.J. Biol. Chem. 2012; 287 (22637474): 24619-2463010.1074/jbc.M112.372243Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar). In the case of COX-1, an interaction between the carboxylate end of the substrate and Arg-120 is required for binding and catalysis. With different substrates having different chain lengths and degrees of unsaturation, this leads to suboptimal alignments of C-13 and Tyr-385. As a result, there is inefficient hydrogen abstraction and oxygenation of these substrates (35Malkowski, M. G., (2017) in Encyclopedia of Inorganic and Bioinorganic Chemistry (Scott, R. A., ed) pp. 1–18, John Wiley & Sons Ltd., Chichester, UKGoogle Scholar). Conversely, binding of different FA substrates within the COX channel of COX-2 is driven by coordinated interactions between the FAs and multiple residues lining the channel, rather than by a single Arg-120 determinant (32Vecchio A.J. Orlando B.J. Nandagiri R. Malkowski M.G. Investigating substrate promiscuity in cyclooxygenase-2: the role of Arg-120 and residues lining the hydrophobic groove.J. Biol. Chem. 2012; 287 (22637474): 24619-2463010.1074/jbc.M112.372243Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar). Comparisons made between the conformations of AA and different FA substrates bound in the COX channel of COX-2 show significant differences in the positions of the carboxylate ends of these substrates, similar to that observed in COX-1. However, the lack of a requirement for binding to Arg-120 in COX-2 results in the proper insertion of the ω-end of the FA in the hydrophobic groove, which leads to optimal alignment of carbon 13 with Tyr-385. The X-ray crystal structure of COX-2 in complex with 1-AG revealed the molecular details of how endocannabinoid substrates bind within the COX channel (36Vecchio A.J. Malkowski M.G. The structural basis of endocannabinoid oxygenation by cyclooxygenase-2.J. Biol. Chem. 2011; 286 (21489986): 20736-2074510.1074/jbc.M111.230367Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar). (2-AG undergoes acyl migration in biological buffers resulting in the conversion of 2-AG to 1-AG.) 1-AG binds to both monomers of the dimer. In each monomer, the glycerol moiety is located near the opening of the channel with the ω-end of the acyl chain inserted into the hydrophobic groove. However, subtle differences in the conformations of 1-AG in each monomer were observed. In one monomer, the ω-end of 1-AG does not fully insert into the hydrophobic groove, resulting in the misalignment of carbon 13 for hydrogen abstraction. Conversely, the ω-end of 1-AG bound in the opposite monomer binds deep in the hydrophobic groove resulting in the optimal alignment of carbon 13 below Tyr-385 for hydrogen abstraction. This conformation mimics the productive pose of AA. Thus, 1-AG binds in a nonproductive conformation in one monomer and in a productive conformation in the other monomer, analogous to that observed for AA binding to COX-2. Movement of the side chain of Leu-531 near the opening of the channel provides the conformational flexibility required to accommodate the bulkier 2,3-dihydroxypropyl moiety and facilitate productive binding. COX-1 has been known to be a sequence homodimer since 1977 (37Van der Ouderaa F.J. Buytenhek M. Nugteren D.H. Van Dorp D.A. Purification and characterisation of prostaglandin endoperoxide synthetase from sheep vesicular glands.Biochim. Biophys. Acta. 1977; 487 (405045): 315-33110.1016/0005-2760(77)90008-XCrossref PubMed Scopus (324) Google Scholar). Until about 10 years ago, it was widely believed that each COX monomer comprising a dimer operated independently. This dogma was based on enzyme kinetics (38Swinney D.C. Mak A.Y. Barnett J. Ramesha C.S. Differential allosteric regulation of prostaglandin H synthase 1 and 2 by arachidonic acid.J. Biol. Chem. 1997; 272 (9139685): 12393-1239810.1074/jbc.272.19.12393Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar), measurements of the stoichiometry of heme binding (39Roth G.J. Machuga E.T. Strittmatter P. The heme-binding properties of prostaglandin synthetase from sheep vesicular gland.J. Biol. Chem. 1981; 256 (6792194): 10018-10022Abstract Full Text PDF PubMed Google Scholar), and aspirin acetylation (40Van Der Ouderaa F.J. Buytenhek M. Nugteren D.H. Van Dorp D.A. Acetylation of prostaglandin endoperoxide synthetase with acetylsalicylic acid.Eur. J. Biochem. 1980; 109 (6773769): 1-810.1111/j.1432-1033.1980.tb04760.xCrossref PubMed Scopus (135) Google Scholar). Additionally, and as noted above, structural studies with COX-1 and later COX-2 showed the enzymes to be composed of identical protein monomers. 4It is now known that COXs only crystallize in a reasonable amount of time in a symmetric form with both monomers occupied with a heme group and a COX ligand (56Sidhu R.S. Lee J.Y. Yuan C. Smith W.L. Comparison of cyclooxygenase-1 crystal structures: cross-talk between monomers comprising cyclooxygenase-1 homodimers.Biochemistry. 2010; 49 (20669977): 7069-707910.1021/bi1003298Crossref PubMed Scopus (101) Google Scholar). Evidence contradictory to the view that COX monomers function independently was first published in the mid 1980s. Kulmacz and Lands (41Kulmacz R.J. Lands W.E. Prostaglandin H synthase. Stoichiometry of heme cofactor.J. Biol. Chem. 1984; 259 (6427213): 6358-6363Abstract Full Text PDF PubMed Google Scholar) showed that there is one high-affinity site for heme per ovine (ov) COX-1 dimer and later that complete COX inhibition occurs at a ratio of one nsNSAID molecule per dimer (42Kulmacz R.J. Lands W.E. Stoichiometry and kinetics of the interaction of prostaglandin H synthase with anti-inflammatory agents.J. Biol. Chem. 1985; 260 (3930499): 12572-12578Abstract Full Text PDF PubMed Google Scholar). They suggested that the two COX-1 subunits are “distinct.” One early COX-2 structure showed AA positioned in different orientations in the two COX sites (33Kiefer J.R. Pawlitz J.L. Moreland K.T. Stegeman R.A. Hood W.F. Gierse J.K. Stevens A.M. Goodwin D.C. Rowlinson S.W. Marnett L.J. Stallings W.C. Kurumbail R.G. Structural insights into the stereochemistry of the cyclooxygenase reaction.Nature. 2000; 405 (10811226): 97-10110.1038/35011103Crossref PubMed Scopus (188) Google Scholar). 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