Reactions of 5-methylcytosine cation radicals in DNA and model systems: Thermal deprotonation from the 5-methyl group vs. excited state deprotonation from sugar (original) (raw)
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Structural Chemistry, 2012
The cation radicals of DNA constituents generated by the ionizing radiation initiate the alteration of the bases, which is one main type of cytotoxic DNA lesions. These cation radical spices are known for their role in producing nucleic acid strand break, and it is important to identify the cation radical formation at particular atomic site in these molecules so that the major pathway for the nucleic acid damage may be trapped. In the present study, we explored theoretically energetic, structural, and electronic properties of the possible radicals formed via proton atom abstraction at various sites of sugar part of deoxycytidine cation radical by employing density functional theory at B3LYP/6-311??G (d,p) level. The computation revealed 0.0-22.6 kcal/mol energy disparity in these radicals. Radical-centered carbon increases the extent of bonding with its adjacent atoms. This tendency should be important in predicting the reactivity of sugar-based radicals. Based on DFT calculations, sugar radicals of deoxycytidine have following stability order:
Deamination features of 5-hydroxymethylcytosine, a radical and enzymatic DNA oxidation product
Journal of molecular modeling, 2014
The 5-methylcytosine derivative 5-hydroxymethylcytosine (5hmCyt), which is generated via enzymatic oxidation, is sometimes referred to as the sixth nucleobase due to its widespread presence in the DNA of brain and embryonic stem cells. In this study, we used density functional based methods and reactivity indices from conceptual DFT to explore the mechanism and key features of the hydrolytic deamination of 5hmCyt. The data obtained are used to compare and contrast this deamination reaction with those of other cytosine derivatives. The deamination process for 5hmCyt is similar to the corresponding processes for other unsaturated derivatives in that the amino form is the reactive one and water addition is the rate-limiting step. However, several differences due to the rotameric asymmetry of the current system are also noted.
Oxidative damage to 5-methylcytosine in DNA
Nucleic Acids Research, 1995
Exposure of pyrimidines of DNA to ionizing radiation under aerobic conditions or oxidizing agents results in attack on the 5,6 double bond of the pyrimidine ring or on the exocyclic 5-methyl group. The primary product of oxidation of the 5,6 double bond of thymine is thymine glycol, while oxidation of the 5-methyl group yields 5-hydroxymethyluracil. Oxidation of the 5,6 double bond of cytosine yields cytosine glycol, which decomposes to 5-hydroxycytosine, 5-hydroxyuracil and uracil glycol, all of which are repaired in DNA by Escherichia coliendonuclease Ill. We now describe the products of oxidation of 5-methylcytosine in DNA.
Nucleic Acids Research, 2007
The carbonate radical anion is a biologically important one-electron oxidant that can directly abstract an electron from guanine, the most easily oxidizable DNA base. Oxidation of the 5'-d(CCTACGCTACC) sequence by photochemically generated CO 3 À radicals in low steady-state concentrations relevant to biological processes results in the formation of spiroiminodihydantoin diastereomers and a previously unknown lesion. The latter was excised from the oxidized oligonucleotides by enzymatic digestion with nuclease P1 and alkaline phosphatase and identified by LC-MS/MS as an unusual intrastrand cross-link between guanine and thymine. In order to further characterize the structure of this lesion, 5'-d(GpCpT) was exposed to CO 3 À radicals, and the cyclic nature of the 5'-d(G Ã pCpT Ã) cross-link in which the guanine C8-atom is bound to the thymine N3-atom was confirmed by LC-MS/MS, 1D and 2D NMR studies. The effect of bridging C bases on the cross-link formation was studied in the series of 5'-d(GpC n pT) and 5'-d(TpC n pG) sequences with n = 0, 1, 2 and 3. Formation of the G Ã-T Ã cross-links is most efficient in the case of 5'-d(GpCpT). Cross-link formation (n = 0) was also observed in doublestranded DNA molecules derived from the selfcomplementary 5'-d(TTACGTACGTAA) sequence following exposure to CO 3 À radicals and enzymatic excision of the 5'-d(G Ã pT Ã) product.
• H Atom and • OH Radical Reactions with 5-Methylcytosine
The Journal of Physical Chemistry A, 2007
The reactions between either a hydrogen atom or a hydroxyl radical and 5-methylcytosine (5-MeCyt) are studied by using the hybrid kinetic energy meta-GGA functional MPW1B95. • H atom and • OH radical addition to positions C5 and C6 of 5-MeCyt, or • OH radical induced H-abstraction from the C5 methyl group, are explored. All systems are optimized in bulk solvent. The data presented show that the barriers to reaction are very low: ca. 7 kcal/mol for the • H atom additions and 1 kcal/mol for the reactions involving the • OH radical. Thermodynamically, the two C6 radical adducts and the • H-abstraction product are the most stable ones. The proton hyperfine coupling constants (HFCC), computed at the IEFPCM/MPW1B95/6-311++G(2d,2p) level, agree well with B3LYP results and available experimental and theoretical data on related thymine and cytosine radicals.
Direct Formation of the C5′-Radical in the Sugar–Phosphate Backbone of DNA by High-Energy Radiation
The Journal of Physical Chemistry B, 2012
Neutral sugar radicals formed in DNA sugar− phosphate backbone are well-established as precursors of biologically important damage such as DNA strand scission and cross-linking. In this work, we present electron spin resonance (ESR) evidence showing that the sugar radical at C5′ (C5′ • ) is one of the most abundant (ca. 30%) sugar radicals formed by γand Ar ion-beam irradiated hydrated DNA samples. Taking dimethyl phosphate as a model of sugar−phosphate backbone, ESR and theoretical (DFT) studies of γ-irradiated dimethyl phosphate were carried out. CH 3 OP(O 2 − )OCH 2 • is formed via deprotonation from the methyl group of directly ionized dimethyl phosphate at 77 K. The formation of CH 3 OP(O 2 − )OCH 2 • is independent of dimethyl phosphate concentration (neat or in aqueous solution) or pH. ESR spectra of C5′ • found in DNA and of CH 3 OP(O 2 − )OCH 2 • do not show an observable β-phosphorus hyperfine coupling (HFC). Furthermore, C5′ • found in DNA does not show a significant C4′-H β-proton HFC. Applying the DFT/B3LYP/6-31G(d) method, a study of conformational dependence of the phosphorus HFC in CH 3 OP(O 2 − )OCH 2 • shows that in its minimum energy conformation, CH 3 OP(O 2 −
Tetrahedron, 2000
AbstractÐIn order to understand the heterolytic cleavage of 4 H -DNA radical 1 and the regioselective attack of nucleophiles at the intermediate DNA radical cation 3, the chemistry of model radical 8 was studied. It turned out that the heterolytic cleavage in water is favored over homolysis because of the effective solvation of the ions 9 and 10. The regioselectivity of the nucleophilic attack at radical cation 10 can be explained with the valence bond con®guration mixing (VBCM) model. q Scheme 1. General overview of the reaction pathways of C4 H -DNA radical and of its model system 8.
Radiation Research, 2003
In this study, the effects of high-LET radiation on DNA were investigated and compared with the effects of ␥ radiation. Hydrated DNA samples at 77 K were irradiated with argon-ion beams (36 Ar or 40 Ar beam at energies between 60 and 100 MeV/nucleon). The individual free radicals formed were identified and their yields were investigated by electron spin resonance spectroscopy. Argon-ion irradiation resulted in lower yields of base ion radicals and higher yields of neutral radicals than ␥ irradiation. A hitherto unknown species was assigned to the radical formed by CO bond rupture at the deoxyribose C3, resulting in a sugar carbon-centered radical. A previously characterized phosphorus-centered radical was also found. The formation of each of these species was accompanied by an immediate strand break. G values, k values, and analyses for the individual yields of neutral radicals and ion radical composition for argon-ion-irradiated hydrated DNA are reported and compared to those found previously for ␥irradiated DNA. The lower G values and k values for ion radicals and the higher fraction of neutral radicals found for argon-ion-irradiated DNA are attributed to differences in track structure inherent in the two radiations.