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A [[Cyclooxygenase]] is an enzyme that catalyzes the transformation of arachidonic acid into prostaglandins, prostacyclins, and thromboxanes.<ref name="Orlando">PMID:27710942</ref> Another name for cyclooxygenase is prostaglandin H2 synthase. <ref name="Smith">Smith, W. L and R. Langenbach (2001). "Why there are two cyclooxygenase isozymes." ''The Journal of Clinical Investigation'' 107(12):1491-1495.</ref> There are two names because there are two catalytic activities: cyclooxygenase and peroxidase. The abbreviation for cyclooxygenase and prostaglandin H2 synthase is COX and PGHS respectively and can be used interchangeably. There are two types of cyclooxygenases: COX-1 and COX-2. COX-1 is responsible for platelet aggregation and gastric acidity.<ref name="Orlando" /> COX-2 is involved in pathways that lead to inflammation (swelling), pain, and fever.<ref name="Orlando" />

Cyclooxygenases catalyzes arachidonic acid or other fatty acids into prostaglandin H2 (PGH2) and other molecules that can be used for signal transduction. Of the two catalytic activities, the cyclooxygenase reaction happens before the peroxidase reaction. However, the peroxidase activity activates the cyclooxygenase activity.<ref name="Picot">PMID:8121489</ref> “Two-electron reduction of a peroxide substrate results in the oxidation of the ferric heme to an oxo-ferryl porphyrin radical cation.”<ref name="Rouzer">PMID:18952571</ref> The most important catalytic residue is <scene name='80/800650/Tyrosine_385/1'>Tyrosine 385</scene>. It transfers an electron to the heme to create the radical on the Tyrosine <ref name="Rouzer" /> The Tyrosine then takes the pro-S hydrogen from carbon 13 of arachidonic acid to produce a radical on the arachidonic intermediate. <ref name="Lehninger">"Chapter 21: Lipid Biosynthesis." ''Lehninger Principles of Biochemistry'', by David L. Nelson et al., Basingstoke, 2017, pp. 824-825.</ref> Two oxygen molecules are inserted to cyclize the intermediate.<ref name="Lehninger" /> Tyrosine 385 is reduced from the “peroxyl radical to the hyperoxide to form PGG2.”<ref name="Rouzer" /> PGG2 is then reduced by the peroxidase activity to form PGH2.<ref name="Lehninger" />. The Tyrosine 385 radical is regenerated, so the cyclooxygenase activity does not need to be activated for every reaction.<ref name="Rouzer" />

There are many medical applications for the cyclooxygenase isozymes. COX-1 is responsible for platelet aggregation and gastric acidity.<ref name="Orlando" /> COX-2 is involved in pathways that lead to inflammation (swelling), pain, and fever.<ref name="Orlando" /> Inhibiting either or both of these enzymes can be beneficial. Inhibiting COX-1 for a brief period can reduce platelet aggregation, but if COX-1 is inhibited too long, gastric damage such as ulcers and bleeding can occur.<ref name="Orlando" /> Inhibitors that bind specifically to COX-1 or inhibitors that bind nonspecifically to the cyclooxygenases need to be small dosage and not for elongated periods of time. Inhibiting COX-2 can reduce swelling, pain, and fever.<ref name="Orlando" /> However, COX-2 is involved in both the initiation of inflammation and the resolution of inflammation, so it cannot be inhibited for long periods of time either, in the chance that the inflammation resolution will not occur.<ref name="Smith" /> Both isozymes are expressed in the female reproductive system.<ref name="Smith" /> A study on rats revealed that overexpression of the COX-2 enzyme increased the chance of tumor development during pregnancy and lactation in mammary glands.<ref name="Liu">PMID:11278747</ref> COX-2 is expressed when it is induced from a signal molecule while COX-1 is constitutively expressed.<ref name="Smith" /> Both isozymes can be expressed in the same cell, but COX-2 will be predominately active since it is inducible and COX-1 is always expressed.<ref name="Smith" />

[[Image:Peroxidase activity site.jpg|thumb|Figure 3: Peroxidase activity site. Image taken in Chimera from PDB file 5KIR.]]

Arachidonic acid has a higher kcat value of 27.0 ± 0.4 s-1 and a lower Km value of 5.14 ± 0.29 µM than EPA and DHA for the affinity to COX-2.<ref name="Vecchio" /> This means that arachidonic acid is the preferred substrate for COX-2 when compared with EPA and DHA fatty acids. The rate of the reaction can depend on the concentration of the substrate. However, the rate can be slowed or stopped with an inhibitor. <scene name='80/800650/Human_cox-2_bound_to_vioxx/3'>Rofecoxib</scene> and Celecoxib are two inhibitors that have selectivity towards COX-2.<ref name="Orlando" /> They differ from the nonsteroidal anti-inflammatory drugs (NSAIDs) because of their selectivity for COX-2.<ref name="Orlando" /> NSAIDs inhibit both COX-1 and COX-2.<ref name="Orlando" /> Rofecoxib, commonly known as Vioxx, has a 1000-fold selectivity for COX-2 over COX-1.<ref name="Chan">PMID:10411562</ref> It also has a 60-fold selectivity for COX-2 when compared to the selectivity of Celecoxib (Celebrex) for COX-2.<ref name="Orlando" /> The difference in the kinetics of Rofecoxib and Celecoxib is speculated to be from the binding kinetics and not the interaction between the inhibitor and the enzyme.<ref name="Orlando" /> The rate constant for the inhibition of COX-2 by Rofecoxib was experimentally determined to be 0.0036 ± 0.0024 µM-1s-1 for a two-step mechanism.<ref name="Chan" /> When bound to COX-2, Rofecoxib makes 42 contacts with the nearby residues where it binds.<ref name="Orlando" /> Celecoxib differs from Rofecoxib in structure by having a “pyrazole heterocycle and a sulfonamide moiety” whereas Rofecoxib has a “furanone heterocycle and a methyl sulfone moiety.”<ref name="Orlando" />