Cytidine deaminases catalyze the conversion of N ( S , O ) 4 -substituted pyrimidine nucleosides
![Thumbnail](/bitstream/handle/123456789/115162/sciadv.ade4361.pdf.jpg?sequence=3&isAllowed=y)
View/ Open
Date
2023Author
Urbelienė, Nina
Tiškus, Matas
Tamulaitienė, Giedrė
Gasparavičiūtė, Renata
Lapinskaitė, Ringailė
Jauniškis, Vykintas
Sūdžius, Jurgis
Meškienė, Rita
Tauraitė, Daiva
Skrodenytė, Emilija
Urbelis, Gintaras
Vaitekūnas, Justas
Meškys, Rolandas
Metadata
Show full item recordAbstract
Cytidine deaminases (CDAs) catalyze the hydrolytic deamination of cytidine and 2′-deoxycytidine to uridine and 2′-deoxyuridine. Here, we report that prokaryotic homo-tetrameric CDAs catalyze the nucleophilic substitution at the fourth position of N4-acyl-cytidines, N4-alkyl-cytidines, and N4-alkyloxycarbonyl-cytidines, and S4-alkylth-io-uridines and O4-alkyl-uridines, converting them to uridine and corresponding amide, amine, carbamate, thiol, or alcohol as leaving groups. The x-ray structure of a metagenomic CDA_F14 and the molecular modeling of the CDAs used in this study show a relationship between the bulkiness of a leaving group and the volume of the binding pocket, which is partly determined by the flexible β3α3 loop of CDAs. We propose that CDAs that are active toward a wide range of substrates participate in salvage and/or catabolism of variously modified pyrim-idine nucleosides. This identified promiscuity of CDAs expands the knowledge about the cellular turnover of cytidine derivatives, including the pharmacokinetics of pyrimidine-based prodrugs.