Biosynthesis and Degradation of Nucleotides:- Excess Uric Acid Causes Gout
Long thought, erroneously, to be due to “high living,” gout is a disease of the joints caused by an elevated concentration of uric acid in the blood and tis sues. The joints become inflamed, painful, and arthritic, owing to the abnormal deposition of sodium urate crystals. The kidneys are also affected, as excess uric acid is deposited in the kidney tubules. Gout occurs pre dominantly in males. Its precise cause is not known, but it often involves an underexcretion of urate. A genetic deficiency of one or another enzyme of purine metabolism may also be a factor in some cases.
Gout is effectively treated by a combination of nutritional and drug therapies. Foods especially rich in nucleotides and nucleic acids, such as liver or glandular products, are withheld from the diet. Major alleviation of the symptoms is provided by the drug allopurinol (Fig. 1), which inhibits xanthine oxidase, the enzyme that catalyzes the conversion of purines to uric acid. Allopurinol is a substrate of xanthine oxidase, which converts allopurinol to oxypurinol (alloxanthine). Oxypurinol in activates the reduced form of the enzyme by remaining tightly bound in its active site. When xanthine oxidase is inhibited, the excreted products of purine metabolism are xanthine and hypoxanthine, which are more water soluble than uric acid and less likely to form crystalline deposits. Allopurinol was developed by Gertrude Elion and George Hitchings, who also developed acyclovir, used in treating people with AIDS, and other purine analogs used in cancer chemotherapy.
FIGURE 1 Allopurinol, an inhibitor of xanthine oxidase. Hypoxanthine is the normal substrate of xanthine oxidase. Only a slight alteration in the structure of hypoxanthine (shaded pink) yields the medically effective enzyme inhibitor allopurinol. At the active site, allopurinol is converted to oxypurinol, a strong competitive inhibitor that remains tightly bound to the reduced form of the enzyme.
