Journal
CHEMICAL RESEARCH IN TOXICOLOGY
Volume 15, Issue 8, Pages 1023-1035Publisher
AMER CHEMICAL SOC
DOI: 10.1021/tx010146r
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Funding
- NCI NIH HHS [CA 85779] Funding Source: Medline
- NICHD NIH HHS [HD 36385] Funding Source: Medline
- NIGMS NIH HHS [GM 41336] Funding Source: Medline
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8-Oxoguanine is a mutagenic oxidative damage product of guanine that has been the subject of many experimental studies. Despite numerous references to this damaged base, its precise configuration or population of configurations in equilibrium are unknown, as it can be drawn in over 100 potential neutral and ionized tautomeric forms. The structural uncertainty surrounding 8-oxoguanine complicates mechanistic studies of its mutagenicity and capacity to be recognized for repair. Experimental measurements on the tautomeric equilibria and pK(a) values of 8-oxoguanine are complicated by its insolubility in water. Therefore, we used first principles quantum mechanics (density functional theory, B3LYP, in combination with the Poisson-Boltzmann continuum-solvation model) to investigate the relative stabilities and site-specific pKa values of various neutral and ionized tautomers of 8-oxoguanine. We show that the major tautomer of neutral 8-oxoguanine in aqueous solution is the 6,8-diketo form 2, and that 8-oxoguanine has increased acidity at N1 relative to guanine. Our calculations on 2'-deoxyguanosine-3',5'-bisphosphate and its 8-oxo analogue support the accepted conclusion that repulsion between the 08 of 8-oxoguanine and O5' of the backbone sugar promote 8-oxoguanine: adenine pairings in the syn:anti conformation. Further, we show that the N7 proton of 8-oxoguanine is difficult to remove either through tautomerization or ionization, consistent with its involvement as an important landmark in distinguishing guanine from 8-oxoguanine. The possibility of additional structural landmarks that distinguish 8-oxoguanine from guanine, and a possible mechanism for glycosylase removal of 8-oxoguanine are discussed.
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