Aspirin, Arachidonic Acid, and Prostaglandins

The word aspirin is derived from the prefix a- for acetyl + spir from the Latin name spirea for the meadowsweet plant. 

Recall from Chapter 2 that aspirin (acetylsalicylic acid) is a synthetic carboxylic acid, similar in structure to salicin, a naturally occurring compound isolated from willow bark, and salicylic add, found in meadowsweet. 

Both salicylic acid and sodium salicylate (its sodium salt) were widely used analgesics in the nineteenth cenmry, but both had undesirable side effects. Salicylic acid irritated the mucous membranes of the mouth and stomach, and sodium salicylate was too sweet for most patients. Aspirin, a synthetic compound, was first sold in 1899 after FeUx Hof nan, a German chemist at Bayer Company, developed a feasible commercial synthesis. Hof nan s work was motivated by personal reasons his father suffered from rheumatoid arthritis and was unable to tolerate the sweet taste of sodium salicylate. 

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Cascade of biosynthesis of prostaglandins from arachidonic acid and the role of aspirin (acetylsalicylic acid) in blocking biosynthesis and easing inflammation... 

In the 1960s, scientists discovered that aspirin acts by inhibiting cyclooxygenase (COX), a key enzyme in the conversion of arachidonic acid to prostaglandins (Section 19.5). With this discovery, it became clear why only one enantiomer of ibuprofen, naproxen, and ketoprofen is active Only the 5 enantiomer of each has the correct handedness to bind to COX and inhibit its activity. 

From phospholipid-bound arachidonic acid and other 20-carbon fatty acids, prostaglandins are synthesized in response to physiological triggers. Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit this conversion. 

In this bromoaspirin-inactivated structure, Ser , which lies along the wall of the tunnel, is bromoacetylated, and a molecule of salicylate is also bound in the tunnel. Deep in the tunnel, at the far end, lies Tyr, a catalytically important residue. Heme-dependent peroxidase activity is implicated in the formation of a proposed Tyr radical, which is required for cyclooxygenase activity. Aspirin and other NSAIDs block the synthesis of prostaglandins by filling and blocking the tunnel, preventing the migration of arachidonic acid to Tyr in the active site at the back of the tunnel. 

Aspirin sensitive asthma, affecting about 10% of all asthmatics, is a nonallergic response to aspirin and other agents that inhibit cyclooxygenase-1. Mechanistically, the most likely reasons are lack of bronchoprotective prostaglandin E2 and shunting of arachidonic acid into the leukotriene pathway. 

CYP5 synthesizes thromboxane A2, a fatty acid in the arachidonic acid cascade that causes platelet aggregation. Aspirin prevents platelet aggregation because it blocks the cyclooxygenases COX1 and COX2 which catalyze the initial step of the biotransformation of arachidonic acid to thromboxane and prostaglandins. 

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