Various genetic defects in PRPP synthetase (reaction ➀, Figure 1) present clinically as gout. Each defect—for example, an elevated Vmax , increased affinity for ribose 5-phosphate, or resistance to feedback inhibition—results in overproduction and overexcretion of purine catabolites. When serum urate levels exceed the solubility limit, sodium urate crystalizes in soft tissues and joints where it causes an inflammatory reaction, gouty arthritis. However, most cases of gout reflect abnormalities in renal handling of uric acid.

Fig1. Purine biosynthesis from ribose 5-phosphate and ATP. See the text for explanations. ( P , PO3 2– or PO2–.)

While purine deficiency states are rare in human subjects, there are numerous genetic disorders of purine catabolism. Hyperuricemias may be differentiated based on whether patients excrete normal or excessive quantities of total urates. Some hyperuricemias reflect specific enzyme defects. Others are secondary to diseases such as cancer or psoriasis that enhance tissue turnover.

Lesch-Nyhan Syndrome

The Lesch-Nyhan syndrome, an overproduction hyperuricemia characterized by frequent episodes of uric acid lithiasis and a bizarre syndrome of self-mutilation, reflects a defect in hypoxanthine-guanine phosphoribosyl transferase, an enzyme of purine salvage (Figure 2). The accompanying rise in intracellular PRPP results in purine overproduction. Mutations that decrease or abolish hypoxanthine-guanine phosphoribosyltransferase activity include deletions, frame shift mutations, base substitutions, and aberrant mRNA splicing.

Fig2. Phosphoribosylation of adenine, hypoxanthine, and guanine to form AMP, IMP, and GMP, respectively.

von Gierke Disease

Purine overproduction and hyperuricemia in von Gierke disease (glucose-6-phosphatase deficiency) occurs secondary to enhanced generation of the PRPP precursor ribose 5-phosphate. An associated lactic acidosis elevates the renal threshold for urate, elevating total body urates.

Hypouricemia

Hypouricemia and increased excretion of hypoxanthine and xanthine are associated with a deficiency in xanthine oxidase, EC 1.17.3.2 (Figure 3) due to a genetic defect or to severe liver damage. Patients with a severe enzyme deficiency may exhibit xanthinuria and xanthine lithiasis.

Adenosine Deaminase & Purine Nucleoside Phosphorylase Deficiency

Adenosine deaminase deficiency (Figure 3) is associated with an immunodeficiency disease in which both thymus-derived lymphocytes (T cells) and bone marrow derived lymphocytes (B cells) are sparse and dysfunctional. Patients suffer from severe immunodeficiency. In the absence of enzyme replacement or bone marrow transplantation, infants often succumb to fatal infections. Defective activity of purine nucleoside phosphorylase (EC 2.4.2.1) is associated with a severe deficiency of T cells, but apparently nor mal B-cell function. Immune dysfunctions appear to result from accumulation of dGTP and dATP, which inhibit ribonucleotide reductase and thereby deplete cells of DNA precursors. Table 1 summarizes known disorders of purine metabolism.

Fig2. Formation of uric acid from purine nucleo sides by way of the purine bases hypoxanthine, xanthine, and guanine. Purine deoxyribonucleosides are degraded by the same catabolic pathway and enzymes, all o which exist in the mucosa o the mammalian gastrointestinal tract.

Table1. Metabolic Disorders of Purine & Pyrimidine Matabolism

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مواضيع ذات صلة

DNA Contains Four Distinct Deoxynucleotides

Overproduction of Pyrimidine Catabolites

Biochemical Characteristics and Biological Function of Cardiac Natriuretic Peptides

The Deoxyribonucleosides of Uracil & Cytosine are Salvaged

Biosynthesis of Pyrimidine Nucleotides

Hepatic Purine Biosynthesis is Stringently Regulated

Inosine Monophosphate (IMP) is Synthesized From Amphibolic Intermediates

DNA & RNA are Polynucleotides

Synthetic Nucleotide Analogs are Used in Chemotherapy

Chemistry of Purines, Pyrimidines, Nucleosides, & Nucleotides

Disorders of Bilirubin Metabolism

Catabolism of HEME Produces Bilirubin