Aspirin inhibits the action of Prostaglandin Synthase (AKA Cyclooxygenase or COX). Prostaglandin Syntase catalyzes the conversion of Arachidonate in prostaglandin H2. Prostaglandin H2 is a precursor of thromboxane and other prostaglandins that mediates in the inflammation process, in pain and fever. Thromboxane participates in the coagulation mechanism facilitating platelet activation. Since Aspirin inhibits the activity of Prostaglandin Synthase, the production of Prostaglandin H2 and derivatives is decreased. It explains the antiinflamatory and anticoagulant effects of aspirin.
Aspirin acts as an irreversible inhibitor of Prostaglandin Synthase (Complete official name: Prostaglandin-endoperoxide Synthase, EC: 188.8.131.52). This enzyme, also know as Cycloxygenase (COX) is a key enzyme in the metabolism of Eicosanoids.
Eicosanoids are a kind of lipids that act as “local” hormones, since they act close to their site of formation. This group include prostaglandins, prostacyclines, thromboxanes and leukotriens. Eicosanoid lipids are derived from arachidonic acid, a 20 carbon polyunsaturated fatty acid (“eico” is the prefix that indicates 20, in the same way that “deca” means 10 and “penta” means 5).
Arachidonate is syntesized in the liver from linoleic acid (an essential fatty acid) and incorporated to phospholipids or diglycerides; they are transported then with the lipoproteins to extrahepatic tissues, where the phospholipids are incorporated to membranes.
The arachidonate in the membrane phospholipids is released by Phospholipase A2 , and once released it can follow two main metabolic pathways, the lineal pathway (lipoxygenase pathway) that produces leukotrienes, or the cyclic pathway (PG synthase or Ciclooxygenase pathway), that produces prostaglandins, prostacyclines and thromboxanes.
The Prostaglandin Synthase catalyzes the committed step in the cyclic pathway. This enzyme has two different activities: as a cyclooxygenase and as a peroxidase. The Cyclooxygenase activity has made this enzyme “popular” under the name of Cyclooxygenase or COX. Prostaglandin Synthase converts the arachidonate to Prostaglandin H2.There are two main kinds of Prostaglandin Synthase or COX isoenzymes: COX 1, constitutive (prostaglandin-endoperoxide Synthase 1, encoded in Chromosome 9), and COX 2, inducible (prostaglandin-endoperoxide Synthase 2, encoded in Chromosome 1). COX 1 is found in most mamalian cells, while COX2 is inducible as response to inflammation in macrophages and other cells found in inflammed tissues. (Some drugs like aspirin inhibit both types of Cycloxygenase, while other drugs are specific inhibitors of COX2)
The action of aspirin on prostaglandin Synthase is based in the transfer of the Acetyl group of Aspirin (recall Aspirin is Acetyl Salicylic acid) to an hydroxyl group of one amino acid in the active site of the enzyme. This is an esterification reaction, so the linkage that is formed is covalent. It means that the inhibition is irreversible.
For more information,
Search for aspirin in the FDA site http://www.fda.gov/
and/or review Eicosanoid metabolism in
ASPIRIN: THE PREQUEL
(About the History of Aspirin, BBC)
ASPIRIN: A SEQUEL
(Warning: Do not try it at home!)