Purine and Pyrimidine Nucleotide Concentrations in Cells with Decreased Hypoxanthine-Guanine-Phosphoribosyltransferase (HGPRT) Activity

Abstract

Severe and partial deficiency of the enzyme Hypoxanthineguanine-phosphoribosyl-transferase (HGPRT) (EC.2.4.2.8.) is associated with accelerated rates of purine biosynthesis de novo, both in vivo (1,2,3) and in cultured skin fibroblasts (4,5) and lymphoblasts (6) from patients with these diseases. Although the biochemical basis for this accelerated de novo purine biosynthesis has been attributed to elevated intracellular levels of phosphoribosylpyrophosphate (PP-ribose-P) both in fibroblasts (4) and lymphoblasts (6,7) recent in vitro experiments with the enzyme amidophosphoribosyltransferase (EC.2.4.2.14) have re-emphasised the potential regulatory role of purine ribonucleotides as feedback inhibitors at this first, and presumed rate limiting step in the de novo pathway ; the activity and physical properties of the enzyme being controlled by a critical interaction of PP-ribose-P and purine ribonucleotides (8). In an effort to investigate the role of purine ribonucleotides in the regulation of de novo purine biosynthesis in living human cells deficient in HGPRT, intracellular ribonucleotide concentrations have been measured in HGPRT⁻ human lymphoblasts, fibroblasts and erythrocytes and in appropriate HGPRT⁺ controls.