Low enantioselectivities of human deoxycytidine kinase and human deoxyguanosine kinase with respect to 2 '-deoxyadenosine, 2 '-deoxyguanosine and their analogs

The antiviral activity of L-nucleoside analogs depends in part on the enant ioselectivity of nucleoside kinases which catalyse their monophosphorylatio n. The substrate properties of human recombinant deoxycytidine kinase (dCK) and human recombinant deoxyguanosine kinase (dGK) with respect to L-adenos ine and L-guanosine analogs, in the presence of saturating amounts of ATP a nd relatively high concentrations of substrates, demonstrated a marked lack of enantioselectivity of both these enzymes. Human dCK catalysed the phosp horylation of D- and L-enantiomers of beta-dA, beta-araA, and beta-dG with enantioselectivities favoring the unnatural enantiomer for the adenosine de rivatives and the natural enantiomer for 2'-deoxyguanosine. No other tested L-adenosine or L-guanosine analog was a substrate of dCK. Similarly, D- an d L-enantiomers of beta-dA, beta-araA, and beta-dG were substrates of human dGK but with different enantioselectivities compared to dCK, especially co ncerning beta-dA. The present results indicate that human dCK and dGK have similar properties including substrate properties, relaxed enantioselectivi ties, and possibly catalytic cycles. (C) Societe francaise de biochimie et biologie moleculaire/Editions scientifiques et medicales Elsevier SAS.