How Aspirin Works

Aspirin ranks as one of the world's oldest pain relievers. One form of the drug can be found in willow leaves. It has been sold in tablet form since about the turn of the century. Aspirin belongs to a group of about 24 similar pharmacologic agents known collectively as the nonsteroidal anti-inflammatory drugs. Despite the long history and widespread application of these drugs, however, the biological mechanisms responsible for their physiologic effects have remained largely unknown. Only in recent decades have researchers begun to understand how aspirin works at the molecular level.

In 1971, Vane and his associates discovered that aspirin inhibits prostaglandin formation. Prostaglandins are a type of fatty acid. Their formation represents the first committed step in the prostanoid pathway of the arachidonate cascade. Through this cascade, vasoactive factors such as the thromboxanes and prostacyclin are formed. These different compounds have various physiological effects. Thromboxane A2, for example, acts as a potent vasoconstrictor and promoter of platelet aggregation. In contrast, prostacyclin is a vasodilator and inhibitor of platelet aggregation (2:1832).

Aspirin inhibits prostaglandin formation through its action on the enzyme, prostaglandin H2 synthase (PGHS). PGHS is a bifunctional, membrane-bound enzyme which occurs in platelets. It exhibits both peroxidase activity and, more importantly, cyclooxygenase activity.

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stinct active sites. The cyclooxygenase active site occurs in a narrow channel. This hydrophobic channel is about 25 + long. It runs from the membrane-binding motif to the center of the enzyme. The channel's lowest portion is comprised of (-helices A, B, C, and D. These helices offer a continuous pathway from the membrane to the cyclooxygenase active site (3:99-102). Prostaglandin H2 synthase's bifunctionality apparently did not result from the addition of a cyclooxygenase domain to a peroxidase enzyme. Instead, the cyclooxygenase active site evolved within the peroxidase's existing fold. During catalysis, the heme group at the peroxidase site is oxidized. It is then this intermediate which incites cyclooxygenase activity (7:12387-12392). The upper portion of the cyclooxygenase channel contains the residue, Tyr-385. It has been postulated that the formation of a free radical at this tyrosine residue facilitates prostaglandin G2 formation (3:99-102). In 1992, Shimokawa and Smith described how aspirin irreversibly inactivates PGHS-1 cyclooxygenase activity without substantially altering the enzyme's peroxidase activity. The researchers observed that this inhibition was associated with the selective acetylation of PGHS
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Some common words found in the essay are:
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Approximate Word count = 1678
Approximate Pages = 7 (250 words per page)

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