Mechanism of purine overproduction in genetic defects of purine metabolism

Abstract

A number of defects of purine metabolism are associated with hyperuricemia and/or other indicators of increased purine synthesis, whereas in another group of mutations purine production in vivo is normal. In the former group, elevated purine synthesis has been correlated with increased intracellular phosphoribosyl-pyrophosphate (PRPP) concentrations in hypoxanthine phosphoribo-syltransferase (HPRT) deficiency (Lesch-Nyhan syndrome) and PRPP synthetase overactivity, whereas in purine nucleoside phosphorylase (PNP) deficiency normal PRPP concentrations have been reported despite increased purine synthesis. We have re-evaluated PRPP metabolism in PNP-deficient fibroblasts and demonstrated that the rate of PRPP synthesis is normal but the steady-state concentration is significantly elevated. The association of increased purine synthesis with increased PRPP levels was confirmed in HPRT deficiency and PRPP synthetase overactivity, and normal values for both parameters were found in adenine phosphoribosyl-transferase and adenosine deaminase deficiencies. All the mutants studied thus conform to the rule that elevated PRPP levels are correlated with increased purine synthesis, and a causal relationship is suggested. Supported by the Academy of Finland, Sigrid Juselius Foundation, NIH (18197), and VA Medical Research Service.