Textbook - BIOLOGICAL CHEMISTRY - Gubsky Yu.I. - 2000

Chapter IV. MOLECULAR MECHANISMS OF HEREDITY AND THE EXPRESSION OF GENETIC INFORMATION

CHAPTER 19. BIOSYNTHESIS OF NUCLEOTIDES

19.4. CATABOLISM OF NUCLEOTIDES

The source of free purine and pyrimidine NUCLEOTIDES is The breakdown of the body's own Nucleic Acids by hydrolytic Enzymes (DNases and RNases), as well as the de novo Biosynthesis of Nucleotides occurring in Tissues. Free nucleotides that are not utilized in nucleic acid synthesis undergo degradation to yield the End products of nitrogen (nucleic acid) METABOLISM.

Class="center">

Pathway of purine nucleotide conversion to uric acid.

Degradation of purine nucleotides

The Catabolism of Purine nucleotides (AMP and GMP) involves the following reactions:

- removal of the phosphate group to yield the nucleosides adenosine and guanosine (catalyzed by 5'-nucleotidase);

- deamination (at the adenosine level by adenosine deaminase, or at the guanine level by guanine deaminase);

- Cleavage of the D-ribose pentose residue from the nucleosides (catalyzed by nucleosidase) or removal of The pentose phosphate moiety as a whole (catalyzed by phosphorylases);

- subsequent catabolism of hypoxanthine (derived from AMP) or xanthine (derived from GMP) to produce the end product, uric acid (2,6,8-trioxypurine):

The oxidation of hypoxanthine to xanthine, and of xanthine to uric acid, is catalyzed by the enzyme xanthine oxidase:

Xanthine oxidase is an FAD-dependent flavoprotein that also contains iron and molybdenum ions. In xanthine oxidase reactions, molecular oxygen O₂ serves as the electron acceptor and is reduced to hydrogen peroxide:

Hereditary disorders of uric acid metabolism

Uric acid is poorly soluble in Water. The solubility limit of sodium urate—the molecular form in which uric acid exists in Blood Plasma—is 7 mg/dL (70 mg/L), which represents the upper limit of the normal concentration of this compound in the blood (30-70 mg/L). It is believed that the Biological Significance of maintaining a considerable level of urates in The Human Body lies in their high antioxidant activity, acting as scavengers of cytotoxic, chemically reactive oxygen radicals (L. Stryer, 1995).

Gout

The solubility of urates in the human body is maintained by their binding to Blood Plasma Proteins; however, even a slight elevation in blood uric acid levels—known as hyperuricemia—leads to the precipitation of urate crystals in tissues, clinically manifesting as The Development of gout.

Gout is a condition primarily characterized by severe pain resulting from the deposition of urate crystals in joint cavities and the subsequent inflammatory response. To reduce hyperuricemia in gout patients, the drug Allopurinol is prescribed; its MECHANISM OF ACTION involves the irreversible inhibition of xanthine oxidase. The administration of this drug significantly lowers blood uric acid levels, thereby helping to alleviate the Clinical symptoms of the disease.

Fig. 19.6. Ivan Ya. Horbaczewski (1854–1942), Ukrainian biochemist. Professor of Medical Chemistry at the Czech University, professor and rector of the Ukrainian University in Prague and Vienna. He was the first to synthesize uric acid and discovered the enzyme xanthine oxidase.

Lesch-Nyhan syndrome

This disease is an X-linked inherited form of hyperuricemia that develops in childhood (in boys) and, In addition to symptoms characteristic of gout, also manifests with severe neuropsychiatric disorders.

The BIOCHEMICAL BASIS OF this enzymopathy is a genetic defect in the synthesis of hypoxanthine-guanine phosphoribosyltransferase, an enzyme responsible for the reutilization of free hypoxanthine and guanine in metabolic pathways (the salvage pathway). Due to this enzyme deficiency, an abnormal accumulation of hypoxanthine and guanine occurs in the body, which are converted into uric acid, thereby causing hyperuricemia.

Degradation of Pyrimidine Nucleotides

The Initial Stages of pyrimidine nucleotide catabolism, much like those of purine nucleotides, involve the removal of ribose phosphate followed by the oxidation of the resulting Pyrimidines.

The catabolism of nitrogenous bases (uracil, cytosine, thymine) involves the cleavage of the pyrimidine rings to yield Amino Acid Derivatives—β-Alanine and β-aminoisobutyrate—as end products. In turn, β-alanine is degraded into carbon dioxide and ammonia, whereas β-aminoisobutyrate can be metabolized similarly to other branched-chain Amino Acids, ultimately forming succinyl-CoA.

Pathway of pyrimidine nitrogenous base catabolism.