Mechanism of nitric oxide induced deamination of cytosine

Phys Chem Chem Phys. 2009 Apr 14;11(14):2379-86. doi: 10.1039/b818669c. Epub 2009 Feb 12.

Abstract

A five-step mechanism is proposed for the NO -induced deamination of cytosine. It has been investigated using DFT calculations, including both explicit water molecules and a bulk solvent model to mimic an aqueous environment. According to this mechanism, cytosine first undergoes tautomerization with the assistance of a water molecule from the bulk. A NO(+) cation produced by the autooxidation of NO is subsequently added to the exocyclic imino group of the cytosine imine tautomer. The resulting adduct is able to undergo a tautomerization step with the participation of a water molecule to produce a cytosine in which a -N(2)OH group is attached to carbon C4. Protonation of the oxygen of the latter gives a water molecule which dissociates instantaneously, leading to a pyrimidinic diazonium cation. This constitutes the rate-determining step of the mechanism with an activation free energy of 92.6 kJ mol(-1). The last step, which is highly exergonic, represents the driving force of the reaction. It is the substitution of the -N(2)(+) terminal group by a water molecule which simultaneously allows the transfer of one of the two hydrogens to the bulk. Thus, the two products of the reaction consist of a nitrogen molecule and the enol tautomer of uracil in equilibrium with the keto form.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Catalysis
  • Cytosine / chemistry*
  • Deamination / drug effects
  • Hydrogen-Ion Concentration
  • Isomerism
  • Nitric Oxide / chemistry*
  • Nitric Oxide / pharmacology*
  • Quantum Theory
  • Thermodynamics
  • Water / chemistry

Substances

  • Water
  • Nitric Oxide
  • Cytosine