Chemistry

Closer mechanistic consideration of the cyclooxygenase reaction and the peroxidase reaction of the COX

Closer mechanistic consideration of the cyclooxygenase reaction and the peroxidase reaction of the COX



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The mechanism described here is to be understood as a model that can be supported by many experimental findings but has not yet been proven in the final analysis:

In the first step of converting arachidonic acid to PGH2by the cyclooxygenase (COX) is formed by the formal addition of two oxygen molecules and an intramolecular carbocyclization PGG2. In the second step, the peroxidase reaction, the cyclic hydroperoxy endoperoxide becomes PGG2in a glutathione-dependent reaction to the endoperoxide PGH2reduced. These reaction steps should be considered mechanistically here with regard to the arachidonic acid. The mechanistic processes in cyclooxygenase such as the electron transfer between Tyr 385 and the heme group will be explained in more detail later.

The cyclooxygenase reaction is initiated by the transfer of an H atom (!) From position 13 of the arachidonic acid (1) to the COX. The unpaired electron of the resulting allyl radical 2 is delocalized over the carbon atoms 11 to 15. The addition of an oxygen molecule (diradical) to the C11 atom of the allyl radical2 leads to the peroxy radical 3. The subsequent intramolecular attack of the peroxy radical on the double bond between the atoms C8 and C9 and the one-electron shifts induced thereby generate the endoperoxide, the five-membered carbocycle and the allyl radical in intermediate stage 4. The unpaired electron of the allyl radical4 is delocalized over the carbon atoms 13 to 15. The addition of a second oxygen molecule to the C15 atom gives the peroxy radical 5. Recombination with the hydrogen atom initially transferred to the COX eventually turns the cyclic hydroperoxy endoperoxide into PGG2(6) formed.

In the following peroxidase reaction, also catalyzed by cyclooxygenase, the hydroperoxy group at C15 of the PGG2(6) into a hydroxy group in PGH2(7) converted. Glutathione (GSH) is used as a reducing equivalent / agent, which converts the two peroxy oxygen atoms in the -Iformal oxidation state through the transfer of two hydrogen atoms (or two electrons and two protons) to two oxygen atoms in the -II oxidation state the hydroxyl group and reduced in a water molecule. Glutathione (GSH) is simultaneously oxidized to glutathione disulfide (GSSG).