Reaction catalyzed by Xanthine oxidase

Allopurinol, (the inhibitor of xanthine oxidase), is used in the treatment of Gout. More recently, febuxostat, a novel nonpurine analog inhibitor of xanthine oxidase, has been used. Which of the following reactions is catalyzed by xanthine oxidase?

A. Hypoxanthine to Xanthine

B. Xanthine to Hypoxanthine

C. Hypoxanthine to uric acid

D. Inosine to hypoxanthine

E. Adenosine to Inosine.

The correct answer is- A, Conversion of hypoxanthine to xanthine.

Basic concept

Gout is a metabolic disease most often affecting middle-aged to elderly men and postmenopausal women. It is the result of an increased body pool of urate with hyperuricemia, typically characterized by episodic acute and chronic arthritis, due to deposition of ‘Mono Sodium Urate crystals’ in joints and connective tissues with the risk for deposition in kidney interstitium or uric acid nephrolithiasis.

Acute arthritis is initially monarticular and often involves the first metatarsophalangeal joint. Symptoms include acute pain, tenderness, warmth, redness, and swelling.

Diagnosis requires identification of crystals in synovial fluid. Treatment of acute attacks is with anti-inflammatory drugs. The frequency of attacks can be reduced by regular use of NSAIDs (non steroidal anti inflammatory drugs), colchicine, or both and by treating hyperuricemia with allopurinol or uricosuric drugs.

Allopurinol, which inhibits urate synthesis, is the most commonly prescribed hypouricemic therapy. It is especially helpful in treating patients who repeatedly pass uric acid or Calcium oxalate stones or who have severe renal dysfunction. Uric acid stones or gravel may dissolve during allopurinol treatment.

Allopurinol acts by inhibiting Xanthine oxidase, the enzyme involved in the conversion of hypoxanthine to xanthine and then onwards conversion of xanthine to uric acid (figure). Allopurinol acts by suicidal inhibition.

Purine degradation

Figure- AMP is degraded to the free base hypoxanthine through deamination and hydrolytic cleavage of the glycosidic bond. Xanthine oxidase, a molybdenum- and iron-containing flavoprotein, oxidizes hypoxanthine to xanthine and then to uric acid. Molecular oxygen, the oxidant in both reactions, is reduced to H2O2, which is decomposed to H2O and O2 by catalase. Uric acid loses a proton at physiological pH to form urate. In human beings, urate is the final product of purine degradation and is excreted in the urine. H

As regards other options

B. Xanthine to Hypoxanthine– Conversion is not possible. Hypoxanthine is irreversibly converted to xanthine.

C. Hypoxanthine to uric acid- The direct conversion is  not possible (figure). It is a two step process. Hypoxanthine is first converted to xanthine, and then xanthine is converted to uric acid.

D. Inosine to hypoxanthine– Inosine is a nucleoside, whereas hypoxanthine is a modified purine base. Inosine is converted to hypoxanthine by the action of nucleoside phosphorylase; the enzyme requires phosphate for its action. Ribose, the sugar is removed in the phosphorylated form (figure)

E. Adenosine to Inosine conversion takes place with the help of Adenosine deaminase enzyme (figure).

 

 

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