Human cytidine deaminase: A biochemical characterization of its naturally occurring variants.

Human cytidine deaminase is an enzyme of the pyrimidine salvage pathways that metabolizes severalcytosine nucleoside analogs used as prodrugs in chemotherapy. We carried out a characterization ofthe cytidine deaminase 79A>C and 208G>A Single Nucleotide Polymorphisms, in order to highlight theirfunctional role and provide data that could help fine-tune the chemotherapic use of cytosine nucleosidesin patients carrying the above mentioned SNPs. The 79A>C SNP results in a K27Q change in a proteinregion not involved in the catalytic event. The 208G>A SNP produces an alanine to threonine substitution(A70T) within the conserved catalytic domain. Q27 variant is endowed with a greater catalytic efficiencytoward the natural substrates and the antileukemic agent cytarabine (Ara-C), when compared to K27variant. Molecular modeling, protein stability experiments and site-directed mutagenesis suggest thatK27 variant may have an increased stability with respect to Q27 due to an ionic interaction between alysine residue at position 27 and a glutamate residue at position 24. The T70 variant has a lower catalyticefficiency toward the analyzed substrates when compared to the A70 variant, suggesting that patientscarrying the 208G>A SNP may have a greater exposure to cytosine based pro drugs, with possible toxicityconsequences.