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-Deoxycytidine Kinase:
Relevance for the Activation of 
-L-Deoxycytidine Analogs
as Antineoplastic and Antiviral Agents
Istituto di Genetica Biochimica ed Evoluzionistica, Consiglio
Nazionale delle Ricerche, I-27100 Pavia, Italy (A.V., F.F., G.P.,
S.S.),
Laboratoire de Chimie BioOrganique UMR CNRS-USTL 5625, Université Montpellier II, France (G.G., J.-L.I.).
I.Co.C.E.A.,
CNR, 101 I-40129 Bologna, Italy (M.C., A.G.)
We demonstrate that human 2
-deoxycytidine kinase (dCK) is a
nonenantioselective enzyme because it phosphorylates
-D-2-deoxycytidine (D-dCyd), the natural
substrate, and -L-2-deoxycytidine (L-dCyd), its enantiomer, with the same efficiency. Kinetic studies showed that
L-dCyd is a competitive inhibitor of the phosphorylation of
D-dCyd with a Ki
value of 0.12 µM, which is lower than the
Km value for
D-dCyd (1.2 µM). Chemical
modifications of either the base or the pentose ring strongly decrease
the inhibitory potency of L-dCyd.
L-dCyd is resistant to cytidine deaminase and competes
in cell cultures with the natural D-dCyd as substrate for dCK, thus reducing the incorporation of exogenous
[3H]dCyd into DNA. L-dCyd had no effect
on the pool of dTTP deriving from the salvage or from the de
novo synthesis, does not inhibit short term RNA and protein
syntheses, and shows little or no cytotoxicity. Our results indicate a
catalytic similarity between human dCK and herpetic thymidine kinases,
enzymes that also lack stereospecificity. This functional analogy
underlines the potential role of dCK as activator of
L-deoxycytidine analogs as antiviral and
antineoplastic agents and lends support to the hypothesis that
herpesvirus thymidine kinase might have evolved from a captured
cellular dCK gene, developing the ability to phosphorylate thymidine
and retaining that to phosphorylate deoxycytidine.
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