BIOCHEMISTRY - L. Stryer - 1984

VOLUME 2

PART III. BIOSYNTHESIS OF MACROMOLECULAR PRECURSORS

CHAPTER 22. BIOSYNTHESIS OF NUCLEOTIDES

22.21. Birds and Terrestrial Reptiles Excrete Uric Acid Instead of Urea to Conserve Water

In terrestrial reptiles and birds, urea is not the end product of amino Nitrogen METABOLISM. Instead, these animals synthesize Purines from excess amino nitrogen and then degrade them to uric acid. This alternative pathway for disposing of amino nitrogen serves a vital function: it conserves Water. Because of its extremely low solubility at acidic pH values, uric acid is used to excrete amino nitrogen; the pK_a of the most acidic group of uric acid is 5.4.

The acidic urine of birds and terrestrial reptiles is a suspension of uric acid crystals. These crystals are excreted with a minimal amount of water. In contrast, The excretion of an equivalent amount of highly soluble urea would entail a large loss of water.

22.22. Degradation of Pyrimidines

The degradation of thymine (Fig. 22.30) serves as an example of pyrimidine breakdown. Thymine is degraded to β-aminoisobutyrate, which undergoes metabolic reactions similar to those of standard Amino Acids. Transamination removes the amino group to form methylmalonate semialdehyde, which is then converted into methylmalonyl-CoA. The conversion of methylmalonyl-CoA into succinyl-CoA, which allows this compound to enter The Citric Acid Cycle, has already been discussed (Section 18.11).

Class="center">Fig. 22.30. Degradation of thymine

22.23. Excess Production of Uric Acid Causes Gout

Gout is a disease that affects the joints, leading to Arthritis. The primary biochemical manifestation of gout is an elevated level of uric acid in the Blood serum. Joint inflammation is caused by the precipitation of sodium urate crystals. Deposition of urate crystals in the Kidneys can also cause renal disease. Gout most commonly affects adult males. A vivid description of an acute attack of gout can be found in the writings of the outstanding seventeenth-century English physician Thomas Sydenham, who himself suffered from the disease: 'The victim goes to bed and sleeps in good health. About two o'clock in the morning, he is awakened by a severe pain in the great toe; more rarely in the heel, ankle, or instep. The pain is like that of a dislocation, and yet the parts feel as if cold water were poured over them. Then follow chills and shivers, and a little fever. The pain, which was at first moderate, becomes more intense. With its intensity, the chills and shivers increase. After a time, the pain reaches its maximum, and insinuates itself among the small bones and ligaments of the tarsus and metatarsus. Now it is a gnawing pain, now it is a pressure and tightening. So exquisite and lively is the feeling of the part affected, that it cannot bear the weight of the bedclothes, nor the jar of a person walking in the room. The night is passed in torture, sleeplessness, turning of the part affected, and perpetual change of posture; the tossing about of the body being as incessant as the pain of the tortured joint, and being worse as the fit comes on.'

The underlying biochemical defects in most cases of gout remain elusive. In all probability, gout is the result of various inborn errors of metabolism, whose common manifestation is the overproduction of urate. Some patients with this anomaly have a partial deficiency of hypoxanthine-guanine phosphoribosyltransferase, the enzyme that catalyzes the salvage synthesis of IMP and GMP:

A deficiency of this enzyme leads to decreased salvage synthesis of GMP and IMP and an increased concentration of PRPP. As a result, There is a marked acceleration of de novo Purine Biosynthesis. Some gout patients exhibit abnormally high activity of phosphoribosyl pyrophosphate synthetase. In these patients, the Allosteric Regulation of this enzyme is impaired. Consequently, an excess of PRPP is produced, which in turn accelerates purine synthesis.

Allopurinol is an analog of hypoxanthine in which the N-7 and C-8 atoms are interchanged. It is used to treat gout. The MECHANISM OF ACTION of allopurinol is highly interesting: it initially acts as a substrate for xanthine oxidase and subsequently as its inhibitor. This enzyme hydroxylates allopurinol to alloxanthine, which remains tightly bound to the Active Site. Upon binding alloxanthine, the molybdenum atom of xanthine oxidase remains in the +4 oxidation state rather than returning to the +6 oxidation state, as occurs during the normal catalytic cycle. The Mechanism of action of allopurinol is an example of suicide inhibition, where an enzyme converts a compound into a potent inhibitor that immediately inactivates the enzyme itself.

Shortly after the administration of allopurinol, the synthesis of uric acid from hypoxanthine and xanthine decreases. Following allopurinol administration, the concentrations of hypoxanthine and xanthine in the blood serum rise, while the concentration of uric acid falls. The formation of uric acid stones is almost completely prevented by allopurinol; the condition of patients with arthritis also improves somewhat. In addition, the overall rate of purine biosynthesis is reduced. The inhibitory effect of allopurinol depends on its reaction with PRPP to form a ribonucleotide. Consequently, the concentration of PRPP, the rate-limiting substrate for de novo purine synthesis, is decreased. Furthermore, allopurinol ribonucleotide inhibits the conversion of PRPP into phosphoribosylamine catalyzed by amidophosphoribosyltransferase.

22.24. Lesch-Nyhan Syndrome: Self-Mutilation, Mental Retardation, and Excess Production of Uric Acid

The near-complete absence of hypoxanthine-guanine phosphoribosyltransferase has devastating consequences. The most striking manifestation of this inborn error of metabolism, known as Lesch-Nyhan syndrome, is the patients' compulsion for self-mutilation. At the age of 2 or 3, affected children begin to bite their fingers and Lips. This self-destructive behavior is so severe that patients must be protected from themselves, for example, by wrapping their hands in gauze bandages. In addition, they exhibit increased aggressiveness toward others, suffer from mental retardation, and experience spasticity. Elevated serum uric acid levels lead to stone formation in the first years of life, and symptoms of gout appear a few years later. The disease is inherited as a sex-linked recessive trait.

The biochemical consequence of the near-complete absence of hypoxanthine-guanine phosphoribosyltransferase is the overproduction of uric acid and an elevated concentration of PRPP. In addition, The rate of de novo purine biosynthesis is substantially increased. The Link Between the absence of the transferase and the bizarre neurological symptoms remains a mystery. It is possible that the Brain is highly dependent on the salvage pathway for IMP and GMP synthesis.

Normally, The activity of hypoxanthine-guanine phosphoribosyltransferase in the brain is higher than in any other tissue. Conversely, the activity of amidotransferase, which catalyzes the committed step of de novo biosynthesis, is relatively low in the brain. Allopurinol effectively reduces uric acid synthesis in Lesch-Nyhan syndrome. However, it has no effect on the rate of de novo purine synthesis and is unable to alleviate the neurological symptoms of the disease. In patients with Lesch-Nyhan syndrome, allopurinol is not converted into its ribonucleotide because they lack hypoxanthine-guanine phosphoribosyltransferase. Consequently, the administration of allopurinol does not lower the concentration of PRPP in these patients, and de novo purine synthesis is not suppressed.

The biochemical mechanism of Lesch-Nyhan syndrome demonstrates that the salvage pathway for IMP and GMP synthesis is not a luxury. It clearly plays an extremely important, though not yet fully understood, role. Furthermore, the relationship between the de novo and Salvage Pathways of purine synthesis remains to be elucidated. Finally, Lesch-Nyhan syndrome shows that abnormal behavior, such as self-mutilation and extreme aggressiveness, can result from the absence of a single enzyme. This discovery was an important contribution to the subsequent development of psychiatry.