Gout as a disorder of purine nucleotide metabolism
Gout is a disease associated with alterations in purine nucleotide catabolism leading to increased production of uric acid. Uric acid is a poorly soluble end product of purine metabolism, normally excreted from the body in the urine and through the intestines.
In excess, uric acid forms urate crystals that deposit in articular cartilage, ligaments, and soft tissues, leading to the formation of gouty nodules (tophi). This is accompanied by joint inflammation (gouty arthritis) and the development of urolithiasis. The condition of elevated blood uric acid levels is called hyperuricemia (normal range: 0.15–0.47 mmol/L).
Purine nucleotide catabolism
The breakdown of purine nucleotides AMP and GMP ultimately leads to the formation of xanthine, which is oxidized into uric acid.
Pathway of AMP degradation:
- 5'-Nucleotidase cleaves off the phosphate group to form adenosine;
- adenosine deaminase deaminates adenosine to inosine;
- purine nucleoside phosphorylase cleaves ribose-1-phosphate, forming hypoxanthine;
- xanthine oxidase oxidizes hypoxanthine to xanthine with the production of hydrogen peroxide;
- xanthine oxidase also converts xanthine into uric acid.
Pathway of GMP degradation:
- nucleotidase cleaves off the phosphate to form guanosine;
- purine nucleoside phosphorylase cleaves off the ribose to form guanine;
- guanase deaminates guanine to xanthine;
- xanthine is oxidized by xanthine oxidase to uric acid.
Purine nucleotide synthesis and its regulation
Uric acid levels rise when the synthesis of AMP and GMP is enhanced. The key initiating reaction is the conversion of ribose-5-phosphate into 5-phosphoribosyl-1-pyrophosphate (PRPP) by the enzyme PRPP synthetase.
Normally, the enzyme is inhibited by the end products of the pathway — ATP and GTP — via feedback inhibition. Two types of defects are possible:
- increased (constitutively high) activity of PRPP synthetase;
- loss of the enzyme's sensitivity to inhibition by ATP and GTP.
In both cases, purine nucleotide synthesis increases, and consequently, so does the concentration of uric acid.
Purine salvage pathway and Lesch-Nyhan syndrome
There is a so-called purine salvage pathway. The key enzyme is hypoxanthine-guanine phosphoribosyltransferase (HGPRT). It converts hypoxanthine into IMP and guanine into GMP, using PRPP as a phosphoribose donor. Thus, hypoxanthine avoids degradation into uric acid and is returned to the nucleotide pool.
When HGPRT activity decreases, hypoxanthine and guanine are not salvaged but are instead oxidized to uric acid, leading to hyperuricemia. Complete loss of HGPRT activity causes a severe hereditary form of hyperuricemia known as Lesch-Nyhan syndrome. The disease is X-linked and manifests with marked hyperuricemia, joint damage, nephrolithiasis, neurological symptoms (spasticity, choreoathetosis), and characteristic self-mutilating behavior.
Treatment of gout: allopurinol
The primary pharmacological target in gout is xanthine oxidase. The drug allopurinol is a structural analog of hypoxanthine and acts as a competitive inhibitor of xanthine oxidase.
Principles of therapy:
- allopurinol blocks the conversion of hypoxanthine to xanthine and of xanthine to uric acid;
- as a result, more soluble precursors — hypoxanthine and xanthine — accumulate in the blood and are more easily excreted by the kidneys;
- blood uric acid levels decrease, and urate deposition ceases;
- an essential component of treatment is dietary restriction of purine-rich foods (meat, organ meats, legumes, alcohol).
Key points
- Gout is caused by hyperuricemia and the tissue deposition of urates with tophi formation.
- The end product of purine catabolism is uric acid, which is poorly soluble in water.
- The key enzyme for the oxidation of hypoxanthine and xanthine is xanthine oxidase.
- The initiating reaction of purine synthesis is catalyzed by PRPP synthetase, which is inhibited by ATP and GTP.
- Defects in PRPP synthetase (increased activity or loss of inhibition) enhance purine synthesis.
- The enzyme HGPRT provides the purine salvage pathway; its defect leads to hyperuricemia.
- Complete loss of HGPRT activity causes Lesch-Nyhan syndrome.
- Allopurinol is a competitive inhibitor of xanthine oxidase and the basis of pathogenetic therapy for gout.