A reevaluation of the ambident reactivity of the guanine moiety towards hydroxyl radicals.
ABSTRACT Radically different: Contrary to previous proposals, the main reaction of the HO(*) radical with guanosine or 2'-deoxyguanosine is the hydrogen abstraction from the NH(2) moiety to give a guanyl radical. This radical, characterized by a broad band in the visible region (around 610 nm), undergoes tautomerization to the most stable isomer.
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ABSTRACT: The transport of charge through the DNA base-pair stack offers a route to carry out redox chemistry at a distance. Here we describe characteristics of this chemistry that have been elucidated and how this chemistry may be utilized within the cell. The shallow distance dependence associated with these redox reactions permits DNA-mediated signaling over long molecular distances in the genome and facilitates the activation of redox-sensitive transcription factors globally in response to oxidative stress. The long-range funneling of oxidative damage to sites of low oxidation potential in the genome also may provide a means of protection within the cell. Furthermore, the sensitivity of DNA charge transport to perturbations in base-pair stacking, as may arise with base lesions and mismatches, may be used as a route to scan the genome for damage as a first step in DNA repair. Thus, the ability of double-helical DNA in mediating redox chemistry at a distance provides a natural mechanism for redox sensing and signaling in the genome.Journal of the American Chemical Society 01/2010; 132(3):891-905. · 10.68 Impact Factor
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ABSTRACT: Dopamine is known to be an efficient antioxidant and to protect neurocytes from oxidative stress by scavenging free radicals. In this work, we have carried out a systematic quantum chemistry and computational kinetics study on the reactivity of dopamine toward hydroxyl (•OH) and hydroperoxyl (•OOH) free radicals in aqueous and lipidic simulated biological environments, within the density functional theory framework. Rate constants and branching ratios for the different paths contributing to the overall reaction, at 298 K, are reported. For the reactivity of dopamine toward hydroxyl radicals, in water at physiological pH, the main mechanism of the reaction is proposed to be the sequential electron proton transfer (SEPT), whereas in the lipidic environment, hydrogen atom transfer (HAT) and radical adduct formation (RAF) pathways contribute almost equally to the total reaction rate. In both environments, dopamine reacts with hydroxyl radicals at a rate that is diffusion-controlled. Reaction with the hydroperoxyl radical is much slower and occurs only by abstraction of any of the phenolic hydrogens. The overall rate coefficients are predicted to be 2.23 × 10(5) and 8.16 × 10(5) M(-1) s(-1), in aqueous and lipidic environment, respectively, which makes dopamine a very good •OOH, and presumably •OOR, radical scavenger.The Journal of Physical Chemistry B 09/2011; 115(42):12234-46. · 3.61 Impact Factor
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ABSTRACT: One electron oxidation of neutral sugar radicals has recently been suggested to lead to important intermediates in the DNA damage process culminating in DNA strand breaks. In this work, we investigate sugar radicals in a DNA model system to understand the energetics of sugar radical formation and oxidation. The geometries of neutral sugar radicals C(1')(•), C(2')(•), C(3')(•), C(4')(•), and C(5')(•) of 2'-deoxyguanosine (dG) and 2'-deoxythymidine (dT) were optimized in the gas phase and in solution using the B3LYP and ωB97x functionals and 6-31++G(d) basis set. Their corresponding cations (C(1')(+), C(2')(+), C(3')(+), C(4')(+), and C(5')(+)) were generated by removing an electron (one-electron oxidation) from the neutral sugar radicals, and their geometries were also optimized using the same methods and basis set. The calculation predicts the relative stabilities of the neutral sugar radicals in the order C(1')(•) > C(4')(•) > C(5')(•) > C(3')(•) > C(2')(•), respectively. Of the neutral sugar radicals, C(1')(•) has the lowest vertical ionization potential (IP(vert)), ca. 6.33 eV in the gas phase and 4.71 eV in solution. C(2')(•) has the highest IP(vert), ca. 8.02 eV, in the gas phase, and the resultant C(2') cation is predicted to undergo a barrierless hydride transfer from the C(1') site to produce the C(1') cation. One electron oxidation of C(2')(•) in dG is predicted to result in a low lying triplet state consisting of G(+•) and C(2')(•). The 5',8-cyclo-2'-deoxyguanosin-7-yl radical formed by intramolecular bonding between C(5')(•) and C(8) of guanine transfers spin density from C(5') site to guanine, and this structure has IP(vert) 6.25 and 5.48 eV in the gas phase and in solution.The Journal of Physical Chemistry B 07/2012; 116(31):9409-16. · 3.61 Impact Factor