Regulation of Mammalian Deoxyribonucleotide Biosynthesis by Nucleotides as Activators and Inhibitors

Abstract

The effects of several nucleoside triphosphates as activators and inhibitors of the enzymic reduction of ribonucleoside diphosphates to deoxynucleotides was studied. The enzyme was a partially purified preparation of the ribonucleotide reductase system from the Novikoff ascites rat tumor, with dithioerythritol used as a model reducing agent. The reduction of cytidine diphosphate and uridine diphosphate to the corresponding deoxyribonucleotides required activation of the enzyme by adenosine triphosphate; reduction of guanosine diphosphate required activation by low concentrations of deoxythymidine triphosphate with ATP giving further stimulation; and reduction of ADP required activation by low concentrations of dGTP or dTTP. Reduction of CDP and UDP was inhibited by dTTP, dUTP, dGTP, and dATP; reduction of GDP was inhibited by dGTP and dATP; and reduction of ADP was inhibited by dATP. Only slight inhibition by dCTP was seen. The results are interpreted in terms of metabolic control of the biosynthesis of deoxynucleotides by these nucleoside triphosphates serving as regulatory effectors.