Conformation and Proton Configuration of Pyrimidine Deoxynucleoside Oxidation Damage Products in Water

Abstract

Emerging data strongly suggest that the oxidation of DNA bases can contribute to genomic instability. Structural changes to DNA, induced by base oxidation, may reduce the fidelity of DNA replication and interfere with sequence-specific DNA-protein interactions. We have examined the structures of a series of pyrimidine deoxynucleoside oxidation damage products in aqueous solution. The modified nucleosides studied include the deoxynucleoside derivatives of 5-hydroxyuracil, 5-hydroxycytosine, 5-(hydroxymethyl)uracil, 5-(hydroxymethyl)cytosine, 5-formyluracil, and 5-formylcytosine. The influence of base oxidation on ionization constants, sugar conformation, and tautomeric configuration has been determined on the basis of UV, proton, and nitrogen NMR spectra of the (15)N-enriched derivatives. The potential biological consequences of the structural perturbations resulting from base oxidation are discussed.

Thymine DNA Glycosylase Can Rapidly Excise 5-Formylcytosine and 5-Carboxylcytosine

“…The carboxyl group is deprotonated at neutral pH, and the m of Ϫ0.10 for COO Ϫ would indicate an electron-donating effect. However, the COO Ϫ substituent lowers the N3 pK a of cytosine (⌬pK a ϭ Ϫ0.3) (28,40), due likely to stabilization of COO Ϫ by NH 2 (Fig. 1B), indicating an electron-withdrawing effect.…”

Two-dimensional IR spectroscopy of the anti-HIV agent KP1212 reveals protonated and neutral tautomers that influence pH-dependent mutagenicity

“…The pK a1 at 7.0 corresponds to protonation of KP1212, and is significantly higher than that of dC (pK a = 4.3 at N3 atom) (19). This value could be even higher as pK a s of some nucleosides have been found to increase when converted to nucleotides (23). The presence of the 1,703-cm −1 mode suggests that protonated KP1212 is in the keto form because a similar high-frequency C=O stretch has been observed for protonated cytidine 5′-monophosphate (CMP) (Fig.…”

Base-pairing properties of the oxidized cytosine derivative, 5-hydroxy uracil

“…At the 2 nd and 4 th positions, the keto form is more stable and would be the predominant form, as the electron donating -OH group would make the imino hydrogen (at the N3 position) less acidic. The pKa of the hydroxyl group at the 5 th position is determined to be 7.68 [20], and therefore, under physiological conditions, the ionized form of 5-OHU would also be present in cells.…”