Hydrolytic deamination of 5,6-dihydrocytosine in a protic medium: a theoretical study.
The mechanism for the deamination reaction of 5,6-dihydrocytosine with H(2)O in a protic medium was investigated by DFT calculations at the B3LYP/6-311G(d,p) level of theory as a model reaction for the deamination reaction of 5,6-saturated cytosine derivatives. Two pathways were found. Pathway dhA, which can explain the deamination in a protic medium at acidic pH, and pathway dhBt, more representative of the reaction in a protic medium at neutral pH. Pathway dhA is a two-step mechanism initiated by the nucleophilic addition of a water molecule to carbon C4 of N3-protonated 5,6-dihydrocytosine with the assistance of a second water molecule, followed by elimination of an ammonium cation to form 5,6-dihydrouracil. The nucleophilic addition is rate-determining with an activation free energy of 116.0 kJ/mol in aqueous solution. Pathway dhBt is a four-step mechanism which starts with the water-assisted tautomerization of 5,6-dihydrocytosine to form the imino tautomer. This intermediate undergoes nucleophilic addition of water to carbon C4, which after protonation eliminates an ammonium cation, as in pathway dhA. The nucleophilic addition is again rate-determining, with an activation free energy of 113.3 kJ/mol in aqueous solution. The latter value is about 25 kJ/mol lower than its counterpart for cytosine, in agreement with the experimental observation that 5,6-saturated cytosine derivatives exhibit a much shorter lifetime in aqueous solution than their unsaturated counterparts. The evaluation of reactivity indices derived from conceptual DFT leads to the conclusion that this lower activation free energy can be attributed to a larger local electrophilic power of carbon C4 in 5,6-saturated derivatives.
Labet
Vanessa
V
Laboratoire Lésions des Acides Nucléiques, INAC/SCIB-UMR-E no. 3 CEA-UJF, CEA Grenoble, 17 rue des Martyrs, F-38 054 Grenoble cedex 9, France. val28@cornell.edu
Morell
Christophe
C
Douki
Thierry
T
Cadet
Jean
J
Eriksson
Leif A
LA
Grand
André
A
D003198:Computer Simulation; D003596:Cytosine / Q000737:chemistry*; D003641:Deamination; D004579:Electron Transport; D006868:Hydrolysis; D008958:Models, Molecular; D015394:Molecular Structure; D055672:Static Electricity; D013816:Thermodynamics
D003596:Cytosine