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.

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

CARPI, FRANCESCO MARTINO;PUCCIARELLI, Stefania;POLZONETTI, Valeria;POLIDORI, Paolo;COSTANZI, Stefano;VINCENZETTI, Silvia
2014

Abstract

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.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11581/290383
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