L- and D-enantiomers of 2',3'-dideoxycytidine 5'-triphosphate analogs as substrates for human DNA polymerases. Implications for the mechanism of toxicity.
5'-Triphosphates of beta-D and beta-L-enantiomers of 2',3'-dideoxycytidine (ddC), 2',3'-dideoxy-5-fluorocytidine (FddC), 1,3-dioxolane-cytidine (OddC), and 1,3-dioxolane-5-fluorocytidine (FOddC) were evaluated as inhibitors and substrates for human DNA polymerases alpha, beta, gamma, delta, and epsilon. L-ddCTP was not a substrate or inhibitor for any DNA polymerase studied; L-FddCTP was not an inhibitor or substrate for replicative DNA polymerases and was a less potent inhibitor of DNA polymerases gamma and beta than its D-enantiomer by 2 orders of magnitude. In contrast, all L-dioxolane analogs were potent inhibitors and chain terminators for all cellular DNA polymerases studied. The Ki values of their 5'-triphosphates for DNA polymerase gamma were found to be in the following order: D-ddC < D-FddC L-OddC D-FOddC < L-FOddC << L-FddC. The Ki values of L-OddCTP for the reactions catalyzed by DNA polymerases alpha, delta, epsilon, beta, and gamma were 6.0, 1.9, 0.4, 3.0, and 0.014 microM, respectively, and those of L-FOddCTP were 6.5, 1.9, 0.7, 19, and 0.06 microM, respectively. The Km values for incorporation of L-OddCTP into the standing points of primer extension were also evaluated and determined to be 1.3, 3.5, 1.5, 2.8, and 0.7 microM for DNA polymerases alpha, delta, epsilon, beta, and gamma, respectively. The incorporation of dioxolane analogs into DNA by replicative DNA polymerases could explain their potent cellular toxicity.[1]References
- L- and D-enantiomers of 2',3'-dideoxycytidine 5'-triphosphate analogs as substrates for human DNA polymerases. Implications for the mechanism of toxicity. Kukhanova, M., Liu, S.H., Mozzherin, D., Lin, T.S., Chu, C.K., Cheng, Y.C. J. Biol. Chem. (1995) [Pubmed]
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