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INHIBITION OF PURINE NUCLEOTIDE BIOSYNTHESIS BY AMMONIA: A POTENTIAL MECHANISM FOR PHYSICAL AND MENTAL RETARDATION IN CHRONIC HYPERAMMONEMIA

Enzyme deficiencies of the urea cycle and certain other inborn errors are associated with protein intolerance, hyperammonemia and retardation in both mental and physical development. We have studied the effect of ammonia on purine nucleotide biosynthesis to explore a possible mechanism that would relate chronic hyper-ammonemia to mental and physical retardation. Purine nucleotide biosynthesis in rat liver minces or homogenate was measured by following the incorporation of 14C-Formate into total cellular purines (de novo) or 14C-purine base into soluble nucleotides (salvage). Addition of 10-20mM NH4Cl resulted in a 30-50% reduction in purine biosynthesis in both assays. The content of 5-phosphoribosyl-1-pyrophosphate (PRPP), an important intermediate in purine nucleotide biosynthesis was decreased 35-50% in liver homogenates incubated with 20mM NH4Cl. Substitution of 5mM carbamyl phosphate (CP) for NH4Cl resulted in a marked reduction of purine nucleotide biosynthesis both de novo (70% decrease) and from preformed bases (25-35% decrease). It is proposed that ammonia stimulates the production of CP by the mitochondrial CP synthetase, which in turn would stimulate de novo pyrimidine synthesis and result in a reduced tissue content of PRPP available for purine nucleotide biosynthesis. This work was supported in part by NIH grant #GM 07004).