BIOCHEMISTRY: A TEXTBOOK FOR MEDICAL UNIVERSITIES - E. S. Severin - 2004

CHAPTER 10. NUCLEOTIDE METABOLISM

IV. Disorders of Purine Nucleotide Metabolism

Urates are significantly more soluble than uric acid. For instance, in urine with a pH of 5.0, where uric acid is undissociated, its solubility is 10 times lower than in urine with a pH of 7.0, where the majority of uric acid exists as salts. The pH of urine depends on dietary composition, but it is typically slightly acidic, which is why most Urinary Tract stones consist of uric acid crystals.

A. Hyperuricemia and Gout

When the concentration of uric acid in Blood Plasma exceeds the normal range, hyperuricemia occurs. Hyperuricemia can lead to gout—a condition characterized by the deposition of uric acid and urate crystals in articular Cartilage, the synovial membrane, and subcutaneous tissue, forming gouty nodules, or tophi. Characteristic Features of gout include recurrent attacks of acute joint inflammation (most frequently in small joints), known as acute gouty Arthritis. The disease may progress to chronic gouty arthritis.

Because leukocytes phagocytose urate crystals, the inflammation is triggered by the destruction of leukocyte lysosomal membranes by uric acid crystals. The released lysosomal Enzymes enter the Cytosol and destroy Cells, while the products of cellular Catabolism provoke inflammation.

The total pool of serum urates normally amounts to ~ 1.2 g in men and 0.6 g in women. In gout without tophi formation (i.e., gouty nodules where sodium urate and uric acid accumulate), The amount of urates increases to 2–4 g, and in patients with severe forms of the disease accompanied by the proliferation of tophi, it can reach 30 g.

Gout is a widespread disease affecting 0.3 to 1.7% of the population across various countries. Furthermore, because the serum urate pool in men is twice as large as in women, men develop the disease 20 times more frequently than women.

As a rule, gout is genetically determined and runs in families. It is caused by functional abnormalities in PRPP synthetase or salvage pathway enzymes: hypoxanthine-guanine or adenine phosphoribosyltransferases.

Other characteristic manifestations of gout include nephropathy, which involves The formation of urate stones in the urinary tract.

Polymorphic Variants of PRPP Synthetase

The activity of PRPP synthetase, which catalyzes PRPP formation, is strictly controlled by purine NUCLEOTIDES. Mutations in the PRPP synthetase Gene have led to The Emergence of polymorphic Variants of the enzyme characterized by an abnormal response to normal regulatory factors: the concentrations of ribose-5-phosphate and purine nucleotides. Typically, enzyme superactivation is observed. Purine nucleotides are synthesized at a rate nearly independent of cellular needs. This results in the inhibition of Salvage Pathways, enhanced catabolism of excess nucleotides, increased uric acid production, hyperuricemia, and gout (Table 10-1).

Class="center">Table 10-1. Hyperuricemia Caused by Defects in Purine Nucleotide METABOLISM Enzymes

In approximately 40% of patients with one of the forms of Glycogen storage disease—Von Gierke's disease (glucose-6-phosphatase deficiency)—gout is a comorbid condition. The reduced ability of the Liver to secrete glucose into the blood increases the utilization of glucose-6-phosphate in the Pentose Phosphate Pathway. Large amounts of ribose-5-phosphate are produced, which can stimulate excessive synthesis and, consequently, Catabolism of Purine nucleotides.

B. Deficiency of Purine Nucleotide Salvage Pathway Enzymes. Lesch-Nyhan Syndrome

In A number of cases, hyperuricemia, excessive urinary purine excretion, and gout are caused by impairments in the Purine Base Salvage pathway enzymes (Table 10-1). Hypoxanthine-guanine phosphoribosyltransferase catalyzes The conversion of guanine and hypoxanthine into their respective nucleotides (Fig. 10-7). Polymorphic variants of hypoxanthine-guanine phosphoribosyltransferase with reduced enzymatic activity have been identified, which:

✵ reduce the reuse of purine bases, causing them to be converted into uric acid;

✵ increase de novo purine nucleotide synthesis due to poor utilization of PRPP in salvage reactions and an increase in its intracellular concentration. Adenylic and guanylic nucleotides are produced in quantities exceeding cellular requirements, which promotes enhanced catabolism.

Lesch-Nyhan syndrome is a severe form of hyperuricemia that is inherited as an X-linked recessive trait and manifests exclusively in males.

The disease is caused by a complete lack of hypoxanthine-guanine phosphoribosyltransferase activity and is accompanied by hyperuricemia, with uric acid levels ranging from 9 to 12 mg/dL, which exceeds urate solubility at normal plasma pH. Uric acid excretion in patients with Lesch-Nyhan syndrome exceeds 600 mg/day and requires at least 2700 mL of urine to eliminate this amount of product.

Children with this pathology develop tophi, urinary tract urate stones, and severe neurological abnormalities at an early age, accompanied by speech disorders, cerebral palsy, intellectual disability, and self-mutilating behavior (biting of Lips, Tongue, and fingers).

In the first months of life, neurological disorders are not yet apparent, but pink and orange stains caused by the presence of uric acid crystals in the urine are noticeable on diapers. If left untreated, patients die before the age of 10 due to renal failure.

Complete loss of adenine phosphoribosyltransferase activity is not as dramatic as the absence of hypoxanthine-guanine phosphoribosyltransferase; nevertheless, impaired adenine salvage in this condition also leads to hyperuricemia and urolithiasis, characterized by the formation of 2,8-dihydroxyadenine crystals.

V. Treatment of Hyperuricemia

The primary medication used to treat hyperuricemia is allopurinol, a structural analog of hypoxanthine (Fig. 10-11).

Fig. 10-11. Structures of allopurinol and hypoxanthine.

Allopurinol exerts a dual effect on purine nucleotide metabolism:

✵ it inhibits xanthine oxidase, halting purine catabolism at the hypoxanthine stage, the solubility of which is nearly 10 times higher than that of uric acid. The drug's inhibitory effect on the enzyme is due to the fact that it is first oxidized into hydroxypurinol, much like hypoxanthine, but subsequently remains tightly bound to the enzyme's Active Site, thereby causing its inactivation;

✵ on the other hand, acting as a pseudosubstrate, allopurinol can be converted into a nucleotide via the salvage pathway and inhibit PRPP synthetase and amidophosphoribosyltransferase, thereby suppressing de novo purine synthesis.

When children with Lesch-Nyhan syndrome are treated with allopurinol, The Development of pathological joint and Kidney changes caused by uric acid overproduction can be prevented; however, the drug does not cure behavioral abnormalities or neurological and psychiatric disorders.

G. Hypouricemia

Hypouricemia and increased excretion of hypoxanthine and xanthine can result from xanthine oxidase deficiency caused by structural mutations in the gene encoding this enzyme, or as a consequence of liver damage.