Nucleic Acids, Proteins, and Enzymes

Despite suffering from the “ague,” the Reverend Edward Stone went walking in the English countryside. Feverish, tired, with aching muscles and joints, he came across a willow tree. Although apparently unaware that many ancient healers used willow bark extracts to reduce fever, the clergyman knew of the tradition of natural remedies for various diseases. The willow reminded him of the bitter extracts from the bark of South American trees then being sold (at high prices) to treat fevers. Removing some willow bark, Stone sucked on it and found it did indeed taste bitter—and that it relieved his symptoms.

Later he gathered a pound of willow bark and ground it into a powder, which he gave to about 50 people who complained of pain; all said they felt better. Stone reported the results of this “clinical test” in a letter to the Royal Society, England’s most respected scientific body. Stone had discovered the main source of salicylic acid, the basis of the most widely used drug in the world. The date of his letter (which still exists) was April 25, 1763.

The chemical structure of salicylic acid (named for Salix, the willow genus) was worked out about 70 years later, and soon chemists could synthesize it in the laboratory. Although the compound alleviated pain, its acidity irritated the digestive system. In the late 1890s, the German chemical company Bayer synthesized a milder yet equally effective form, acetylsalicylic acid, which it marketed as aspirin. The new medicine’s success launched Bayer to world prominence as a pharmaceutical company, a position it maintains today.

In the 1960s and 1970s, aspirin use declined when two alternative medications, acetaminophen (Tylenol) and ibuprofen (Motrin and Advil), became widely available. But over this same time, clinical studies revealed a new use for aspirin: it is an effective anticoagulant, shown to prevent heart attacks and strokes caused by blood clots. Today many people take a daily low dose of aspirin as a preventive agent against clotting disorders.

Fever, joint pain, headache, blood clots. What do these symptoms have in common? They all are mediated by fatty acid products called prostaglandins and molecules derived from them. Salicylic acid blocks the synthesis of the primary prostaglandin. The biochemical mechanism by which aspirin works was described in 1971. As we will see, an understanding of this mechanism requires an understanding of protein and enzyme function—two subjects of this chapter.