In Lesch-Nyhan syndrome, hypoxanthine-guanine phosphoribosyltransferase (HGPRT) deficiency causes purine overproduction. The key mechanism linking HGPRT deficiency to increased de novo purine synthesis is:

• A Loss of feedback inhibition of xanthine oxidase by IMP and GMP
• B Constitutive activation of adenylosuccinate synthetase in the absence of AMP feedback
• C Accumulation of hypoxanthine that allosterically activates the first step of de novo synthesis
• D Elevated PRPP levels due to reduced consumption by the salvage pathway, driving amidophosphoribosyltransferase ✓

Explanation

HGPRT normally salvages hypoxanthine and guanine back to IMP and GMP, consuming PRPP in the process. When HGPRT is absent, PRPP accumulates because it is not being used by the salvage pathway. Elevated PRPP levels allosterically activate amidophosphoribosyltransferase (PPAT), the rate-limiting enzyme of de novo purine synthesis, causing massive purine overproduction. Additionally, reduced IMP/GMP levels relieve feedback inhibition on PPAT, compounding the problem.

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

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.