L- and D-enantiomers of 2',3'-dideoxycytidine 5'-triphosphate analogs as substrates for human DNA polymerases. Implications for the mechanism of toxicity

• Published in: The Journal of biological chemistry 1995-09, Vol.270 (39), p.23055-23059
• Main Authors: Kukhanova, M, Liu, S H, Mozzherin, D, Lin, T S, Chu, C K, Cheng, Y C
• Format: Article
• Language: English
• Subjects: Base Sequence; Deoxycytosine Nucleotides - metabolism; Deoxycytosine Nucleotides - pharmacology; Dideoxynucleotides; DNA Polymerase I - metabolism; DNA Polymerase II - metabolism; DNA Polymerase III - metabolism; DNA Primers; DNA-Directed DNA Polymerase - metabolism; Enzyme Inhibitors - metabolism; Humans; Kinetics; Molecular Sequence Data; Nucleic Acid Synthesis Inhibitors; Stereoisomerism; Structure-Activity Relationship; Substrate Specificity
• ISSN: 0021-9258
• DOI: 10.1074/jbc.270.39.23055

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