Effects of nicotinic acid on human fibroblast purine biosynthesis

In fibroblasts derived from normal individuals and from patients with the Lesch—Nyhan syndrome (severe hypoxanthine—guanine phosphoribosyltransferase deficiency), the pyridine nucleotide precursor nicotinic acid has been demonstrated to inhibit de novo purine synthesis as measured by the accumulation of α-N-formylglycinamide ribonucleotide. The inhibition of purine synthesis occurs at concentrations of nicotinic acid which significantly diminish intracellular concentrations of 5-phosphoribosyl 1-pyrophosphate (PP-ribose-P), a substrate in the first unique and likely rate-limiting reaction in de novo purine synthesis, the PP-ribose-P amidotransferase reaction. Since pyridine nucleotides do not themselves inhibit this reaction, these results support the hypothesis that the rate of purine synthesis is determined at least in part by the intracellular PP-ribose-P concentration.