Excessive Uric Acid in Purine Degradation

Uric acid and its urate salts are very insoluble and can present difficulties in mammalian metabolism. Hyperuricemia is a condition characterized by chronic elevation of blood uric acid levels beyond normal levels. Also known as gout, it affects 3 people in 1000. High levels of urate leads to precipitation of sodium urate in the synovial fluid of joints. Precipitates can cause inflammation, arthritis, and/or severe degeneration of the joints.

Figure 22.9 shows that gout can be caused by abnormalities in three different enzymes in purine metabolism.

> PRPP synthetase - Defects in PRPP synthetase may render it insensitive to feedback inhibition by purine nucleotides. Thus, purine nucleotides are overproduced, leading to excessive uric acid synthesis and gout.

> PRPP amidotransferase - Defects in PRPP amidotransferase may render it insensitive to feedback inhibition by purine nucleotides, too, leading to the overproduction of purine nucleotides, excessive uric acid synthesis, and gout.

> Hypoxanthine-Guanine Phosphoribosyltransferase (HGPRT) - HGPRT is a salvage pathway enzyme for purine metabolism (another is specific for adenine). The relationship between a defect in this enzyme and gout is unclear, but it may be related to the fact that when HGPRT is active, it uses PRPP. The enzyme activity is not completely missing in gout patients, just at a low level. Complete absence of the enzymatic activity is associated with Lesch-Nyhan syndrome.

Gout can also be caused by defects in excreting uric acid (associated with the inability of the kidney tubules to secrete uric acid.

Cancer patients may experience gout as a result of chemotherapy, which generates many purines by nucleic acid degradation after cell death.

Allopurinol, which is similar to hypoxanthine (see here), is used to treat gout because it inhibits xanthine oxidase, leading to accumulation of hypoxanthine and xanthine, both of which are more soluble and more readily excreted than uric acid.

See also: Purine Degradation, Lesch-Nyhan Syndrome, Immunodeficiency and Defective Purine Catabolism

INTERNET LINK: Purine Metabolism