Question

Azathioprine is an immunosuppressant drug used in kidney transplants. In vivo, azathioprine is metabolized to the hypoxanthine analog 6-mercaptopurine, which is then converted into 6-mercaptopurine ribose monophosphate, the active form of the drug. 6-Mercaptopurine ribose monophosphate also inhibits de novo purine synthesis, reducing uric acid levels in the blood and urine. However, when administered to Lesch–Nyhan patients, there was no effect on uric acid levels. Explain why this is the case.

Answer 1

Lesch-Nyhan syndrome is associated with deficiency of hypoxanthine-guanine phosphoribosyltransferase (HGPRT).

HGPRT catalyzes

Hypoxanthine + PRPP IMP +PPi

Guanine + PRPP GMP +PPi

PRPPis phosphoribosyl pyrophosphate.

Lack of HGPRT leads to accumulation of PRPP which then promotes purine production and degradation into uric acid.

This is why Lesch-Nyhan patients have excess uric acid in their urine.

Azathioprine, an analog of hypoxanthine, would not have any effect of purine metabolism in Lesch-Nyhan patients because the patients already have excess purine production and degradation due to PRPP accumulation (not by hypoxanthine).

Azathiprine affects hypoxanthine levels not PRPP.