The effects of oxidation and protonation on the N-glycosidic bond stability of 8-oxo-2′-deoxyguanosine: DFT study

Zheng, Yan; Yang, Xue; Yan, Guo

doi:10.1016/j.theochem.2008.03.014

Cited by 14 publications

(18 citation statements)

References 38 publications

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“…Our goal was to compute the p K a values of the protonated nucleosides as well as the activation energies and rate constants of the process represented in Scheme so that their half-lives can be determined. Optimized geometries for reactants and their transition states were in agreement with structures previously reported. ,, In particular, in agreement with the literature data, , the minimum energy structure of dG and 8-Oxo-dG was in the anti conformation, whereas that of 8-Me-dG was measured in the syn conformation (Figure ). Evidently, S -cdG and ddcdG are locked in the anti orientation (Figure ).…”

Section: Resultssupporting

confidence: 90%

“…Optimized geometries for reactants and their transition states were in agreement with structures previously reported. 19,33,34 In particular, in agreement with the literature data, 35,36 the minimum energy structure of dG and 8-Oxo-dG was in the anti conformation, whereas that of 8-Me-dG was measured in the syn conformation (Figure 9). Evidently, S -cdG and ddcdG are locked in the anti orientation (Figure 9).…”

Section: Resultssupporting

confidence: 89%

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Stability of N-Glycosidic Bond of (5′S)-8,5′-Cyclo-2′-deoxyguanosine

Das

Samaraweera

Morton

et al. 2012

Chem. Res. Toxicol.

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8,5′-Cyclopurine deoxynucleosides are unique tandem lesions containing an additional covalent bond between the base and the sugar. These mutagenic and genotoxic lesions are repaired only by nucleotide excision repair. The N-glycosidic (or C1′-N9) bond of 2′-deoxyguanosine (dG) derivatives is usually susceptible to acid hydrolysis, but even after cleavage of this bond of the cyclopurine lesions, the base would remain attached to the sugar. Here, the stability of the N-glycosidic bond and the products formed by formic acid hydrolysis of (5′S)-8,5′-cyclo-2′-deoxyguanosine (S-cdG) were investigated. For comparison, the stability of the N-glycosidic bond of 8,5′-cyclo-2′,5′-dideoxyguanosine (ddcdG), 8-methyl-2′-deoxyguanosine (8-Me-dG), 7,8-dihydro-8-oxo-2′-deoxyguanosine (8-Oxo-dG), and dG was also studied. In various acid conditions, S-cdG and ddcdG exhibited similar stability to hydrolysis. Likewise, 8-Me-dG and dG showed comparable stability, but the half lives of the cyclic dG lesions were at least 5-fold higher than dG or 8-Me-dG. NMR studies were carried out to investigate the products formed after the cleavage of the C1′-N9 bond. 2-Deoxyribose generated α and β anomers of deoxyribopyranose and deoxyribopyranose oligomers following acid treatment. S-cdG gave α and β deoxyribopyranose linked guanine as the major products, but α and β anomers of deoxyribofuranose linked guanine and other products were also detected. The N-glycosidic bond of 8-Oxo-dG was found exceptionally stable in acid. Computational studies determined that both the protonation of the N7 atom and the rate constant in the bond breaking step control the overall kinetics of hydrolysis, but both varied for the molecules studied indicating a delicate balance between the two steps. Nevertheless, the computational approach successfully predicted the trend observed experimentally. For 8-Oxo-dG, the low pKa of O8 and N3 prevented appreciable protonation, making the free energy for N-glycosidic bond cleavage in the subsequent step very high.

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Section: Resultssupporting

confidence: 90%

Section: Resultssupporting

confidence: 89%

Stability of N-Glycosidic Bond of (5′S)-8,5′-Cyclo-2′-deoxyguanosine

Das

Samaraweera

Morton

et al. 2012

Chem. Res. Toxicol.

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“…Despite these studies providing critical information about the intrinsic effects of the nucleophile, nucleobase activation, and the environment on the structure and energetics of stationary points along the DNA deglycosylation pathway, the effect of DNA damage on the reaction barrier and mechanism remains unclear. Indeed, to the best of our knowledge, while the deglycosylation pathway has been considered for select DNA nucleobases that are excised by DNA glycosylases, including uracil, − ,, 8-oxoguanine, ,− 8-oxoadenine, and oxidized thymine, ,, no study to date has compared the deglycosylation of a semicomprehensive list of damaged DNA nucleotides to their corresponding natural (undamaged) counterparts.…”

Section: Introductionmentioning

confidence: 99%

Glycosidic Bond Cleavage in DNA Nucleosides: Effect of Nucleobase Damage and Activation on the Mechanism and Barrier

2015

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Although DNA damage can have a variety of deleterious effects on cells (e.g., senescence, death, and rapid growth), the base excision repair (BER) pathway combats the effects by removing several types of damaged DNA. Since the first BER step involves cleavage of the bond between the damaged nucleobase and the DNA sugar-phosphate backbone, we have used density functional theory to compare the intrinsic stability of the glycosidic bond in a number of common DNA oxidation, deamination, and alkylation products to the corresponding natural nucleosides. Our calculations predict that the dissociative (SN1) and associative (SN2) pathways are nearly isoenergetic, with the dissociative pathway only slightly favored on the Gibbs reaction surface for all canonical and damaged nucleosides, which suggests that DNA damage does not affect the inherently most favorable deglycosylation pathway. More importantly, with the exception of thymine glycol, all DNA lesions exhibit reduced glycosidic bond stability relative to the undamaged nucleosides. Furthermore, the trend in the magnitude of the deglycosylation barrier reduction directly correlates with the relative nucleobase acidity (at N9 for purines or N1 for pyrimidines), which thereby provides a computationally efficient, qualitative measure of the glycosidic bond stability in DNA damage. The effect of nucleobase activation (protonation) at different sites predicts that the positions leading to the largest reductions in the deglycosylation barrier are typically used by DNA glycosylases to facilitate base excision. Finally, deaza purine derivatives are found to have greater glycosidic bond stability than the canonical counterparts, which suggests that alterations to excision rates measured using these derivatives to probe DNA glycosylase function must be interpreted in reference to the inherent differences in the nucleoside reactivity. Combined with previous studies of the deglycosylation of DNA nucleosides, the current study provides a greater fundamental understanding about the reactivity of the glycosidic bond in damaged DNA, which has direct implications to the function of critical DNA repair enzymes.

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“…Furthermore, the effects of different nucleophiles (i.e., amine, proline, or water), ,, mechanisms (i.e., S N 1 versus S N 2), ,, and damaged (e.g., 8-oxoguanine and thymine glycol) ,,, or activated (i.e., via hydrogen bonding, protonation, or π–π interactions) , DNA nucleobases were considered. These works were augmented by other contributions in the literature that used small models to investigate the impact of nucleobase oxidation − and/or activation (i.e., protonation or metal ions) − on DNA deglycosylation, as well as larger protein–DNA models to focus on specific enzymes (i.e., DNA glycosylases). − …”

Section: Introductionmentioning

confidence: 99%

Hydrolytic Glycosidic Bond Cleavage in RNA Nucleosides: Effects of the 2′-Hydroxy Group and Acid–Base Catalysis

2016

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Despite the inherent stability of glycosidic linkages in nucleic acids that connect the nucleobases to sugar-phosphate backbones, cleavage of these bonds is often essential for organism survival. The current study uses DFT (B3LYP) to provide a fundamental understanding of the hydrolytic deglycosylation of the natural RNA nucleosides (A, C, G, and U), offers a comparison to DNA hydrolysis, and examines the effects of acid, base, or simultaneous acid-base catalysis on RNA deglycosylation. By initially examining HCOO···HO mediated deglycosylation, the barriers for RNA hydrolysis were determined to be 30-38 kJ mol higher than the corresponding DNA barriers, indicating that the 2'-OH group stabilizes the glycosidic bond. Although the presence of HCOO as the base (i.e., to activate the water nucleophile) reduces the barrier for uncatalyzed RNA hydrolysis (i.e., unactivated HO nucleophile) by ∼15-20 kJ mol, the extreme of base catalysis as modeled using a fully deprotonated water molecule (i.e., OH nucleophile) decreases the uncatalyzed barriers by up to 65 kJ mol. Acid catalysis was subsequently examined by selectively protonating the hydrogen-bond acceptor sites of the RNA nucleobases, which results in an up to ∼80 kJ mol barrier reduction relative to the corresponding uncatalyzed pathway. Interestingly, the nucleobase proton acceptor sites that result in the greatest barrier reductions match sites typically targeted in enzyme-catalyzed reactions. Nevertheless, simultaneous acid and base catalysis is the most beneficial way to enhance the reactivity of the glycosidic bonds in RNA, with the individual effects of each catalytic approach being weakened, additive, or synergistic depending on the strength of the base (i.e., degree of water nucleophile activation), the nucleobase, and the hydrogen-bonding acceptor site on the nucleobase. Together, the current contribution provides a greater understanding of the reactivity of the glycosidic bond in natural RNA nucleosides, and has fundamental implications for the function of RNA-targeting enzymes.

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The effects of oxidation and protonation on the N-glycosidic bond stability of 8-oxo-2′-deoxyguanosine: DFT study

Cited by 14 publications

References 38 publications

Stability of N-Glycosidic Bond of (5′S)-8,5′-Cyclo-2′-deoxyguanosine

Stability of N-Glycosidic Bond of (5′S)-8,5′-Cyclo-2′-deoxyguanosine

Glycosidic Bond Cleavage in DNA Nucleosides: Effect of Nucleobase Damage and Activation on the Mechanism and Barrier

Hydrolytic Glycosidic Bond Cleavage in RNA Nucleosides: Effects of the 2′-Hydroxy Group and Acid–Base Catalysis

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