32.6 Disruptions in Nucleotide Metabolism Can Cause Pathological Conditions

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. As already discussed, some of the bases are reused to form nucleotides by salvage pathways. Others are degraded to products that are excreted (Figure 32.12). A deficiency of an enzyme can disrupt these pathways, leading to a pathological condition.

Figure 32.12: Purine catabolism. Purine bases are converted, first, into xanthine and, then, into urate for excretion. Xanthine oxidase catalyzes two steps in this process.

!clinic! CLINICAL INSIGHT: The Loss of Adenosine Deaminase Activity Results in Severe Combined Immunodeficiency

The pathway for the degradation of AMP includes an extra step relative to that of the other nucleotides. First, the phosphoryl group is removed by a nucleotidase to yield the nucleoside adenosine (Figure 32.12). In the extra step, adenosine is deaminated by adenosine deaminase to form inosine. Finally, the ribose is removed by nucleoside phosphorylase, generating hypoxanthine and ribose 1-phosphate.

A deficiency in adenosine deaminase activity is associated with some forms of severe combined immunodeficiency (SCID), an immunological disorder. Persons with the disorder have acute recurring infections, often leading to death at an early age. SCID is characterized by a loss of T cells, which are crucial to the immune response. Although the biochemical basis of the disorder has not been clearly established, a lack of adenosine deaminase results in an increase of 50 to 100 times the normal level of dATP, which inhibits ribonucleotide reductase and, consequently, DNA synthesis. SCID is often called the “bubble boy disease” because some early treatments included complete isolation of the patient from the environment. The current treatment is bone-marrow transplantation. Adenosine deaminase deficiency was the first genetic disease to be treated by gene therapy.

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DID YOU KNOW?

Uric acid is a component of urine. When exposed to chlorine, the chemical commonly used to disinfect swimming pools, uric acid generates cyanogen chloride and trichloramine. Both chemicals are toxic. Trichloramine in particular reduces lung function and causes itchy eyes and runny noses. Urea also results in trichloramine synthesis. While sweat introduces some uric acid, more than 90% comes from urine. So please, practice proper pool etiquette.

!clinic! CLINICAL INSIGHT: Gout Is Induced by High Serum Levels of Urate

After the production of hypoxanthine in the degradation of AMP, xanthine oxidase 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 (Figure 32.12). In human beings, urate is the final product of purine degradation and is excreted in the urine.

High serum levels of urate (hyperuricemia) induce the painful joint disease gout. In this disease, the sodium salt of urate crystallizes in the fluid and lining of the joints (Figure 32.13). The small joint at the base of the big toe is a common site for sodium urate buildup, although the salt accumulates at other joints also. Painful inflammation results when cells of the immune system engulf the sodium urate crystals. The kidneys, too, may be damaged by the deposition of urate crystals. Gout is a common medical problem, affecting 1% of the population of Western countries. It is nine times as common in men as in women.

Figure 32.13: Gout. (A) Gout, “the king of diseases and the disease of kings,” has been recognized as a malady since antiquity. Gout was believed to result from excessive food and drink consumption, excesses available only to the rich. Because of the pain in his inflamed leg, the corpulent musician feels as if he is being tortured by the devil. (B) Micrograph of sodium urate crystals. The accumulation of these crystals damages joints and kidneys.

The administration of allopurinol, an analog of hypoxanthine, is one treatment for gout. The mechanism of action of allopurinol is interesting: it acts first as a substrate and then as an inhibitor of xanthine oxidase. The oxidase hydroxylates allopurinol to alloxanthine (oxipurinol), which then remains tightly bound to the active site. We see here another example of suicide inhibition.

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The synthesis of urate from hypoxanthine and xanthine decreases soon after the administration of allopurinol. The serum concentrations of hypoxanthine and xanthine rise, and that of urate drops.

The average serum level of urate in human beings is close to the solubility limit and is higher than levels found in other primates. What is the selective advantage of a urate level so high that it teeters on the brink of gout in many people? Urate turns out to have a markedly beneficial action: it 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 in human beings may protect against reactive oxygen species that are implicated in a host of pathological conditions.

!clinic! CLINICAL INSIGHT: Lesch–Nyhan Syndrome Is a Dramatic Consequence of Mutations in a Salvage-Pathway Enzyme

Mutations in genes that encode enzymes for nucleotide synthesis can reduce levels of needed nucleotides and can lead to an accumulation of intermediates. A nearly total absence of hypoxanthine-guanine phosphoribosyltransferase, an enzyme in the salvage pathway for guanylate and inosinate, 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 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 an X-linked recessive disorder and predominantly affects males.

What is the connection between the absence of HGPRT activity and the behavioral characteristic of Lesch–Nyhan syndrome? The answer is not clear, but it is possible to speculate. The brain has limited capacity for de novo purine synthesis. Consequently, lack of HGPRT results in a deficiency of purine nucleotides. ATP and ADP, formed from inosinate, are especially important in the brain as signal molecules. These nucleotides bind to and activate G-protein coupled receptors that regulate the dopamine secreting neurons. Thus, the lack of hypoxanthine-guanine phosphoribosyltransferase results in an imbalance of key neurotransmitters. Moreover, the guanosine nucleotides required for G-protein function may also be in short supply. The Lesch–Nyhan syndrome demonstrates that the salvage pathway for the synthesis of IMP and GMP is not of minor importance. Moreover, the Lesch–Nyhan 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.

!clinic! CLINICAL INSIGHT: Folic Acid Deficiency Promotes Birth Defects Such As Spina Bifida

Spina bifida is one of a class of birth defects characterized by the incomplete or incorrect formation of the neural tube early in development. In the United States, the prevalence of neural-tube defects is approximately 1 case per 1000 births. A variety of studies have demonstrated that the prevalence of neural-tube defects is reduced by as much as 70% when women take folic acid as a dietary supplement before and during the first trimester of pregnancy. One hypothesis is that more folate derivatives are needed for the synthesis of DNA precursors when cell division is frequent and substantial amounts of DNA must be synthesized.

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