Title Cytidine deaminases catalyze the conversion of N ( S , O ) 4 -substituted pyrimidine nucleosides /
Authors 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
DOI 10.1126/sciadv.ade4361
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Is Part of Science advances.. New York : American Association for the Advancement of Science (AAAS). 2023, vol. 9, iss. 5, art. no. eade4361, p. 1-13.. eISSN 2375-2548
Keywords [eng] Cytidine deaminases ; CDA ; nucleosides ; pyrimidine nucleosides
Abstract [eng] 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.
Published New York : American Association for the Advancement of Science (AAAS)
Type Journal article
Language English
Publication date 2023
CC license CC license description