Biochemical Bases of Accelerated Purine Biosynthesis de Novo in Human Fibroblasts Lacking Hypoxanthine-Guanine Phosphoribosyltransferase

Abstract

Fibroblasts cultured from patients completely deficient in hypoxanthine-guanine phosphoribosyltransferase activity were studied to determine the biochemical bases of the increased rate of purine biosynthesis de novo observed in such patients. Enzyme-deficient fibroblasts had accelerated rates of this pathway and elevated levels of 5-phosphoribosyl 1-pyrophosphate, although the rate of synthesis of this compound was not increased. These cells were sensitive to feedback inhibition of purine synthesis by nucleotides of adenine and 6-methylmercaptopurine ribonucleoside, but the rate of purine synthesis was increased by hypoxanthine and guanine. The concentrations of purine ribonucleotides in mutant cells were normal. The catabolism of inosinate synthesized de novo was increased in enzyme-deficient fibroblasts.