Arachidonic acid bound to the PTGS2 (COX-2) enzyme. Polar interactions between arachidonic acid (cyan) and Ser-530 and Tyr-385 residues are shown with yellow dashed lines. The substrate is stabilized by hydrophobic interactions. Mechanism of COX activation and catalysis. A hydroperoxide oxidizes the heme to a ferryl-oxo derivative that either is reduced in the first step of the peroxidase cycle or oxidizes 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. Both the peroxidase and PTGS activities are inactivated during catalysis by mechanism-based, first-order processes, which means that PGHS-2 peroxidase or PTGS activities fall to zero within 1–2 minutes, even in the presence of sufficient substrates. The conversion of arachidonic acid to PGG2 can be shown as a series of radical reactions analogous to polyunsaturated fatty acid autoxidation. 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<unk> . 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;<unk>  carbon-centered radicals are trapped during catalysis; 3) small amounts of oxidation products are formed due to the oxygen trapping of an allylic radical intermediate at positions 13 and 15. Another mechanism in which the 13-pro (S )-hydrogen is deprotonated and the carbanion is oxidized to a radical is theoretically possible. However, 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 it would eliminate fluoride to form a conjugated diene. The absence of<unk> -containing products derived from 10,10-difluoroarachidonic acid has been thought to indicate the importance of a C-10 carbocation in PGG2 synthesis. However, the cationic mechanism requires that<unk>  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.
Prostaglandin-endoperoxide synthase 2
Angiotensin-converting enzyme 2
Indoleamine 2,3-dioxygenase
Beta-secretase 1
Thromboxane receptor
Vitamin K epoxide reductase
Tropomyosin receptor kinase A
Phosphorylase kinase, alpha 1