First Principles Calculations of the Tautomers and pKa Values of 8-Oxoguanine: Implications for Mutagenicity and Repair

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• 作者：Yun Hee Jang ; William A. Goddard ; III ; Katherine T. Noyes ; Lawrence C. Sowers ; Sungu Hwang ; and Doo Soo Chung
• 刊名：Chemical Research in Toxicology
• 出版年：2002
• 出版时间：August 2002
• 年：2002
• 卷：15
• 期：8
• 页码：1023 - 1035
• 全文大小：343K
• 年卷期：v.15,no.8(August 2002)
• ISSN：1520-5010

文摘

8-Oxoguanine is a mutagenic oxidative damage product of guanine that has been the subjectof many experimental studies. Despite numerous references to this damaged base, its preciseconfiguration or population of configurations in equilibrium are unknown, as it can be drawnin over 100 potential neutral and ionized tautomeric forms. The structural uncertaintysurrounding 8-oxoguanine complicates mechanistic studies of its mutagenicity and capacityto be recognized for repair. Experimental measurements on the tautomeric equilibria and pK_avalues of 8-oxoguanine are complicated by its insolubility in water. Therefore, we used firstprinciples quantum mechanics (density functional theory, B3LYP, in combination with thePoisson-Boltzmann continuum-solvation model) to investigate the relative stabilities and site-specific pK_a values of various neutral and ionized tautomers of 8-oxoguanine. We show thatthe major tautomer of neutral 8-oxoguanine in aqueous solution is the 6,8-diketo form 2, andthat 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 thatrepulsion between the O8 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 of8-oxoguanine is difficult to remove either through tautomerization or ionization, consistentwith 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.