Allopurinol reduces uric acid production by inhibiting xanthine oxidase. In a patient with Lesch-Nyhan syndrome on allopurinol, what secondary metabolic effect would be expected regarding PRPP and purine de novo synthesis?

• A Decreased de novo purine synthesis because salvage pathway is restored
• B Increased de novo purine synthesis because hypoxanthine accumulates and is not salvaged due to absent HGPRT, leaving PRPP unrequenced ✓
• C No change in PRPP utilisation because allopurinol acts downstream of de novo synthesis
• D Decreased PRPP availability because allopurinol is phosphoribosylated, consuming PRPP

Explanation

In Lesch-Nyhan syndrome, HGPRT (hypoxanthine-guanine phosphoribosyltransferase) is absent; the salvage pathway cannot recycle hypoxanthine/guanine back to IMP/GMP. With allopurinol blocking xanthine oxidase, hypoxanthine and xanthine accumulate instead of uric acid. Without functional HGPRT, hypoxanthine cannot consume PRPP (5-phosphoribosyl-1-pyrophosphate) via salvage; surplus PRPP drives increased de novo purine synthesis, partially counteracting allopurinol. This is why allopurinol controls hyperuricaemia but does not correct the neurological features in Lesch-Nyhan syndrome.

Reference: Harper's Illustrated Biochemistry, 32nd ed.

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