page_title: Prostaglandin-endoperoxide synthase 2
section_title: Mechanism
hierarchical_section_title: Prostaglandin-endoperoxide synthase 2 / Mechanism
caption_attribution_description: English: Archidonic acid bound to COX-2
context_page_description: Prostaglandin-endoperoxide synthase 2, also known as cyclooxygenase-2 or COX-2, is an enzyme that in humans is encoded by the PTGS2 gene. In humans it is one of two cyclooxygenases. It is involved in the conversion of arachidonic acid to prostaglandin H2, an important precursor of prostacyclin, which is expressed in inflammation.
context_section_description: 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 endoperoxide. 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; 2) 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 endoperoxide-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 endoperoxide 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.
caption: Arachidonic acid bound to the PTGS2 (COX-2) enzyme. polar interactions between Archidonic Acid (cyan) and Ser-530 and Tyr-385 residues are shown with yellow dashed lines. The substrate is stabilized by hydrophobic interactions.[11]
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