A model is proposed for the interaction of arachidonic acid with the heme associated with the cyclo-oxygenase enzyme which synthesizes prostaglandin endoperoxides. According to this concept, arachidonic acid attaches with its carboxylic acid residue to one ligand of the Fe++ in heme, then curls around the outside of the protoporphyrin to react with a molecule of oxygen associated with the ligand of the Fe++ on the other side of the protoporphyrin with addition of O2 at the C11 carbon, ring closure across C8-12, formation of the C9-11 endoperoxide and then addition of a second oxygen at C15 with an allylic shift of the double bond. This concept may resolve several experimental findings relating to the mechanism of prostaglandin synthesis and can account for much of the stereospecificity in the conversion of arachidonic acid to prostaglandin G2.
Bibliographical noteFunding Information:
We gratefully acknowledge the helpful comments of J.G. White, G.H.R. Rao, R. Borch, C. Smith and R. Lumry, the artwork of L. Richter and the support of USPHS grants HL-11880, AM-06317, HL-06314, CA-12607, CA-08832, CA-11996, GM-AM-22167, HL-20695, HL-16833, AM-16317 and a grant from the Leukemia Task Force. JMG is the recipient of an Established Investigatorship from the American Heart Association.
- Arachidonic Acid
- Fatty Acids