Gout as a disorder of purine metabolism
Gout is a disease associated with impaired catabolism of purine nucleotides and increased production of uric acid. Uric acid is a poorly soluble end product normally excreted by the kidneys and partially through the intestine. When in excess, sodium urate crystals form, depositing in joints, ligaments, and soft tissues, leading to the formation of gouty nodules — tophi. Clinically, this manifests as joint inflammation (gouty arthritis) and the development of urolithiasis.
The upper limit of the normal blood uric acid concentration is 0.15–0.47 mmol/L. A state of persistently elevated concentration is termed hyperuricemia (important not to confuse with hyperazotemia and urea).
Purine nucleotide catabolism
The degradation of AMP and GMP converges on the formation of xanthine, which is oxidized to uric acid. General reaction logic: phosphate cleavage → deamination → ribose-1-phosphate cleavage.
AMP degradation pathway:
- 5′-nucleotidase cleaves the phosphate, forming adenosine;
- adenosine deaminase deaminates adenosine to inosine;
- purine nucleoside phosphorylase cleaves ribose-1-phosphate, forming hypoxanthine;
- xanthine oxidase oxidizes hypoxanthine to xanthine, and then to uric acid with the formation of H₂O₂.
GMP degradation pathway:
- 5′-nucleotidase → guanosine;
- purine nucleoside phosphorylase → guanine;
- guanase deaminates guanine to xanthine;
- xanthine oxidase oxidizes xanthine to uric acid.
Regulation of purine synthesis and causes of hyperuricemia
The source of elevated uric acid is the excessive synthesis of AMP and GMP. The key reaction of purine synthesis de novo is the conversion of ribose-5-phosphate into 5-phosphoribosyl-1-diphosphate (PRPP) mediated by PRPP synthetase. This enzyme is inhibited by the end products AMP and GMP (as well as ATP and GTP) via negative feedback.
Two variants of primary PRPP synthetase defects are known:
- increased initial enzyme activity;
- loss of sensitivity to inhibition by purine nucleotides.
In both cases, the synthesis of AMP and GMP increases, followed by an increase in uric acid production.
Salvage pathway and the HGPRT enzyme
In parallel with de novo synthesis operates the salvage pathway of purine bases. The enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRT) transfers the phosphoribosyl moiety from PRPP to hypoxanthine and guanine, returning them to the nucleotide pool as IMP and GMP. Thus, hypoxanthine is diverted from oxidation into uric acid.
When HGPRT activity decreases, hypoxanthine is not salvaged and is directed by xanthine oxidase to form uric acid, leading to hyperuricemia.
Lesch–Nyhan syndrome
Complete loss of HGPRT activity leads to a severe form of hyperuricemia — Lesch–Nyhan syndrome. The inheritance pattern is X-linked recessive, so males are predominantly affected.
Clinical features:
- early (in the first months of life) onset of neurological and psychiatric disorders, self-mutilation;
- orange-pink urate crystal stains on diapers;
- early urinary tract involvement.
The severity of neurological manifestations is explained by the fact that the purine salvage pathway is particularly active in nervous tissue, where de novo synthesis is limited.
Principles of gout treatment. Allopurinol
The therapeutic strategy includes two main directions:
- diet with reduced intake of foods rich in nucleoproteins (meat, organ meats, legumes) — decreasing purine intake;
- pharmacological suppression of uric acid formation — inhibition of xanthine oxidase.
Allopurinol is a structural analogue of hypoxanthine. Xanthine oxidase itself oxidizes allopurinol to oxypurinol (alloxanthine), which tightly binds to the active site of the enzyme and irreversibly blocks it. As a result, purine catabolism stops at the stage of hypoxanthine and xanthine, without reaching uric acid.
Accumulating hypoxanthine is approximately 10 times more soluble in biological fluids than uric acid and is freely excreted in the urine without forming crystals.
Key points
- Gout is caused by hyperuricemia and the deposition of urate crystals in tissues with the formation of tophi.
- The end product of AMP and GMP catabolism is uric acid; the key enzyme is xanthine oxidase.
- The normal blood uric acid level is 0.15–0.47 mmol/L.
- PRPP synthetase regulates de novo purine synthesis and is inhibited by AMP and GMP; its defects lead to hyperuricemia.
- HGPRT ensures the salvage of hypoxanthine and guanine; a decrease in its activity enhances uric acid production.
- Complete HGPRT deficiency causes Lesch–Nyhan syndrome with neurological disorders in males.
- Allopurinol, via its metabolite oxypurinol, irreversibly inhibits xanthine oxidase.
- Accumulating hypoxanthine is highly soluble and easily excreted in the urine.