A comparison of the enantioselectivities of human deoxycytidine kinase and human cytidine deaminase∗

Add time:08/02/2019    Source:sciencedirect.com

The stereoselectivities of recombinant human deoxycytidine kinase (EC 2. 7.1.74) (dCK) and of recombinant human cytidine deaminase (EC 3.5.4.5) (CDA) were investigated with respect to a series of cytidine analogs, most of them having the unnatural l-stereochemistry. The enantioselectivity of dCK was always low and generally favored the l-enantiomers in the case of β-2′,3′-dideoxycytidine (β-ddC), 5-fluoro-β-2′,3′-dideoxycytidine (β-FddC) and β-cytidine (β-riboC). Concerning β-2′-deoxycytidine, dCK showed a preference for the d-enantiomer. All other examined β-l-cytidine analogs, [1-β-l-lyxofuranosyl cytosine (β-l-lyxoC), 1-β-l-xylofuranosyl cytosine (β-l-xyloC), and 5-fluoro-1-β-l-xylofuranosyl cytosine (β-l-Fxylo C)], were substrates of dCK regardless of the nature of the pentose. None of the studied α-l-anomers (α-l-riboC, α-l-araC, α-l-lyxoC, or α-l-xyloC) was a substrate of dCK. Contrasting with the relaxed enantioselectivity of dCK, CDA had a strict requirement for d-cytidine analogs since none of the already listed β-l- or α-l analogs was a substrate or an inhibitor of the enzyme. The conjunction of the preceding stereochemical properties of dCK and CDA confers to l-cytidine analogs important potentialities in antiviral and anticancer therapies.

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