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Effects of Deoxyadenosine Triphosphate and 9-ß-D-Arabinofuranosyladenine 5'-Triphosphate on Human Ribonucleotide Reductase from Molt-4F Cells and the Concept of "Self-Potentiation"¹

Department of Pharmacology, School of Medicine, University of North Carolina, Chapel Hill, North Carolina 27514

Deoxyadenosine triphosphate (dATP) acted as a noncompetitive inhibitor with respect to the specific nucleoside triphosphate activator for the reduction of all four common ribonucleoside diphosphates catalyzed by the reductase derived from human Molt-4F (T-type lymphoblast) cells. The inhibition constant of dATP for different ribonucleotide reduction reactions was different, indicating that the binding of the nucleoside triphosphate activator or substrate could modify the binding affinity of dATP to the enzyme. dATP also acted as a noncompetitive inhibitor with respect to cytidine diphosphate (CDP) for reductase-catalyzed CDP reduction. 9-ß-D-Arabinofuranosyladenine 5'-triphosphate acted as a competitive inhibitor with respect to either adenosine triphosphate or guanosine triphosphate for CDP or for adenosine diphosphate reduction, respectively. The inhibition constant was 15 µM for CDP reduction and 4 µM for adenosine diphosphate reduction. 1-ß-D-Arabinofuranosyladenine 5'-triphosphate could not substitute for adenosine triphosphate or guanosine triphosphate as the activator for CDP or adenosine diphosphate reduction, respectively. The effects of 9-ß-D-arabinofuranosylcytosine 5'-triphosphate and 5-iodo-2'-deoxyuridine 5'-triphosphate on ribonucleotide reductase were also included for comparison. The "self-potentiation" mechanism of the action of 9-ß-D-arabinofuranosyladenine and 5-iodo-2'-deoxyuridine is discussed.

¹ This work was supported by USPHS Project Grant CA-27449 from the National Cancer Institute, NIH. This is Paper 5 in a series on human ribonucleotide reductase from Molt-4F cells.

² Present address: Biochemistry Department, Southern Research Institute, 2000 Ninth Avenue South, Birmingham, Ala. 35205.

³ An American Leukemia Society Scholar. To whom requests for reprint should be addressed.

Received 2/ 4/80. Accepted 7/ 9/80.

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