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Phosphorylation of 3-Deazaguanosine by Nicotinamide Riboside Kinase in Chinese Hamster Ovary Cells¹

Department of Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030 [P. P. S., M-T. T., C. D. S]; and the Nucleic Acid Research Institute, ICN Plaza, Costa Mesa, California 92626 [R. K. R.]

The growth inhibitory activity of 3-deazaguanosine toward a mutant line (TG^R-3) of Chinese hamster ovary cells deficient in hypoxanthineguanine phosphoribosyltransferase (EC 2.4.2.8) was substantially reversed by the simultaneous addition of nicotinamide riboside. The activities of most other ribonucleoside analogues tested were unaffected. The formation of cellular 3-deazaGMP and 3-deazaGTP from the ribonucleoside analogue, as measured by high-pressure liquid chromatography, was inhibited by the presence of nicotinamide riboside. The inhibition was dependent on concentration of 3-deazaguanosine and could also be demonstrated by following the metabolism of 3-deazaguanosine, labeled with ¹⁴C in the ribose moiety, to [¹⁴C]3-deazaGTP. In the presence of 100 µM nicotinamide riboside formation of the labeled triphosphate derivative of 3-deazaguanosine was undetectable.

A 3-deazaguanosine phosphorylating activity was separated from other cellular kinases by DEAE-cellulose chromatography. Contaminating purine nucleoside phosphorylase (EC 2.4.2.1) was subsequently removed by sucrose density gradient centrifugation. The resulting enzyme preparation demonstrated the greatest activities with nicotinamide riboside and 3-deazaguanosine and, in addition, could also phosphorylate tiazofurin and guanosine to lesser, but significant, degrees.

These and other observations suggest that 3-deazaguanosine, and perhaps other agents such as tiazofurin, may, at least in part, be phosphorylated by a nicotinamide ribonucleoside kinase in these cells. If so, it is possible that the activity of this agent in other types of cells in vivo could be dependent upon the presence of this enzyme and that it could be influenced by cellular concentrations of the natural pyridine nucleoside.

¹ Supported by American Cancer Society Grant CH-283.

² To whom requests for reprints should be addressed.

Received 6/ 2/89. Revised 8/28/89. Accepted 9/ 5/89.

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