title: A comparison of the enantioselectivities of human deoxycytidine kinase and human cytidine deaminase.
abstract: 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 beta-2',3'-dideoxycytidine (beta-ddC), 5-fluoro-beta-2',3'-dideoxycytidine (beta-FddC) and beta-cytidine (beta-riboC). Concerning beta-2'-deoxycytidine, dCK showed a preference for the D-enantiomer. All other examined beta-L-cytidine analogs, [1-beta-L-lyxofuranosyl cytosine (beta-L-lyxoC), l-beta-L-xylofuranosyl cytosine (beta-L-xyloC), and 5-fluoro-1-beta-L-xylofuranosyl cytosine (beta-L-Fxylo C)], were substrates of dCK regardless of the nature of the pentose. None of the studied alpha-L-anomers (alpha-L-riboC, alpha-L-araC, alpha-L-lyxoC, or alpha-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 beta-L- or alpha-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.
authors.affiliation: Laboratoire de Chimie Bioorganique, UMR 5625 du CNRS, Université Montpellier II, France.
authors.forename: M
authors.initials: M
authors.lastname: Shafiee
authors.forename: J F
authors.initials: JF
authors.lastname: Griffon
authors.forename: G
authors.initials: G
authors.lastname: Gosselin
authors.forename: A
authors.initials: A
authors.lastname: Cambi
authors.forename: S
authors.initials: S
authors.lastname: Vincenzetti
authors.forename: A
authors.initials: A
authors.lastname: Vita
authors.forename: S
authors.initials: S
authors.lastname: Eriksson
authors.forename: J L
authors.initials: JL
authors.lastname: Imbach
authors.forename: G
authors.initials: G
authors.lastname: Maury
mesh_terms: D000998:Antiviral Agents / Q000378:metabolism*; D003562:Cytidine / Q000378:metabolism*; D003564:Cytidine Deaminase / Q000378:metabolism*; D003842:Deoxycytidine Kinase / Q000378:metabolism*; D006801:Humans; D011994:Recombinant Proteins; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000998:Antiviral Agents; D011994:Recombinant Proteins; D003562:Cytidine; D003842:Deoxycytidine Kinase; D003564:Cytidine Deaminase