Regulation of enzymes of purine metabolism in intact tumor cells

Abstract

Studies have been made of the regulation of individual enzymes of purine ribonucleotide metabolism in intact Ehrlich ascites tumor cells incubated in vitro. Amidophosphoribosyltransferase, the first enzyme of the pathway of purine biosynthesis de novo, was not inhibited in cells that contained elevated concentrations of purine ribonucleotides, whereas phosphoribosyl pyrophosphate (PRPP) synthetase activity was inhibited under the same conditions. However, the rate of PRPP synthesis was found to be greater in the presence of purine bases than in their absence. The major factor responsible for inhibition of purine biosynthesis de novo when cells were incubated with purine bases was lowered concentrations of PRPP. Ribonucleotide synthesis from purine bases was limited by availability of PRPP, and was inhibited when cells contained elevated concentrations of purine nucleotides. The apparent activities of adenylate deaminase and inosinate dehydrogenase were inhibited by high intracellular concentrations of GTP, and the activities of guanylate synthetase and adenylosuccinate synthetase were limited by concentrations of glutamine and aspartate, respectively. When cells were incubated with deoxyglucose or dinitrophenol, rates of adenylate deamination and inosinate dephosphorylation increased greatly. However, these processes did not appear to be regulated by concentrations of ATP. It is concluded that endproduct inhibition of enzymes by purine ribonucleotides is not an important mode of regulation of purine metabolism in intact tumor cells.