.
Purine bases are converted first into xanthine and then into urate for excretion. Xanthine oxidase catalyzes two steps in this process.
 |
Nucleotides are vital to a host of biochemical processes. It is not surprising, then, that disruption in nucleotide metabolism would have a variety of physiological effects.
Purine bases are converted first into xanthine and then into urate for excretion. Xanthine oxidase catalyzes two steps in this process.
Micrograph of sodium urate crystals. Joints and kidneys are damaged by these crystals in gout. [Courtesy of Dr. James McGuire.]
The nucleotides of a cell undergo continual turnover. Nucleotides are hydrolytically degraded to nucleosides by nucleotidases. The phosphorolytic cleavage of nucleosides to free bases and ribose 1-phosphate (or deoxyribose 1-phosphate) is catalyzed by nucleoside phosphorylases. Ribose 1-phosphate is isomerized by phosphoribomutase to ribose 5-phosphate, a substrate in the synthesis of PRPP. Some of the bases are reused to form nucleotides by salvage pathways. Others are degraded to products that are excreted (Figure 25.17). For example, AMP is degraded to the free base hypoxanthine through deamination and hydrolytic cleavage of the glycosidic bond. Xanthine oxidase, a molybdenum- and iron-containing flavoprotein, oxidizes hypoxanthine to xanthine and then to uric acid. Molecular oxygen, the oxidant in both reactions, is reduced to H2O2, which is decomposed to H2O and O2 by catalase. Uric acid loses a proton at physiological pH to form urate. In human beings, urate is the final product of purine degradation and is excreted in the urine. High serum levels of urate induce gout, a disease in which salts of urate crystallize and damage joints and kidneys (Figure 25.18). Allopurinol, an inhibitor of xanthine oxidase, is used to treat gout in some cases.
The average serum level of urate in humans is close to the solubility limit. In contrast, prosimians (such as lemurs) have tenfold lower levels. A striking increase in urate levels occurred in the evolution of primates. What is the selective advantage of a urate level so high that it teeters on the brink of gout in many people? It turns out that urate has a markedly beneficial action. Urate is a highly effective scavenger of reactive oxygen species. Indeed, urate is about as effective as ascorbate (vitamin C) as an antioxidant. The increased level of urate is humans compared with prosimians and other lower primates may contribute significantly to the longer life span of humans and to lowering the incidence of human cancer.
Mutations in genes that encode nucleotide biosynthetic enzymes can reduce levels of needed nucleotides and can lead to an accumulation of intermediates. A nearly total absence of hypoxanthine-guanine phosphoribosyltransferase has unexpected and devastating consequences. The most striking expression of this inborn error of metabolism, called the Lesch-Nyhan syndrome, is compulsive self-destructive behavior. At age 2 or 3, children with this disease begin to bite their fingers and lips and will chew them off if unrestrained. These children also behave aggressively toward others. Mental deficiency and spasticity are other characteristics of the Lesch-Nyhan syndrome. Elevated levels of urate in the serum lead to the formation of kidney stones early in life, followed by the symptoms of gout years later. The disease is inherited as a sex-linked recessive disorder.
The biochemical consequences of the virtual absence of hypoxanthine-guanine phosphoribosyl transferase are an elevated concentration of PRPP, a marked increase in the rate of purine biosynthesis by the de novo pathway, and an overproduction of urate. The relation between the absence of the transferase and the bizarre neurologic signs is an enigma. Specific cells in the brain may be dependent on the salvage pathway for the synthesis of IMP and GMP. Indeed, transporters of the neurotransmitter dopamine are present at lower levels in affected individuals. Alternatively, cells may be damaged by the accumulation of intermediates to abnormal levels. The Lesch-Nyhan syndrome demonstrates that the salvage pathway for the synthesis of IMP and GMP is not gratuitous. Moreover, the LeschNyhan syndrome reveals that abnormal behavior such as self-mutilation and extreme hostility can be caused by the absence of a single enzyme. Psychiatry will no doubt benefit from the unraveling of the molecular basis of such mental disorders.
