Jia Lei, Shafirovich Vladimir, Shapiro Robert, Geacintov Nicholas E, Broyde Suse
Department of Chemistry, New York University, New York, New York 10003, USA.
Biochemistry. 2005 Apr 26;44(16):6043-51. doi: 10.1021/bi0473657.
Reactive oxygen species present in the cell generate DNA damage. One of the major oxidation products of guanine in DNA, 8-oxo-7,8-dihydroguanine, formed by loss of two electrons, is among the most extensively studied base lesions. The further removal of two electrons from this product can yield spiroiminodihydantoin (Sp) R and S stereoisomers. Both in vitro and in vivo experiments have shown that the Sp stereoisomers are highly mutagenic, causing G --> T and G --> C transversions. Hence, they are of interest as examples of endogenous DNA damage that may initiate cancer. To interpret the mutagenic properties of the Sp lesions, an understanding of their structural properties is needed. To elucidate these structural effects, we have carried out computational investigations at the level of the Sp-modified base and nucleoside. At the base level, quantum mechanical geometry optimization studies have revealed exact mirror image symmetry of the R and S stereoisomers, with a near-perpendicular geometry of the two rings. At the nucleoside level, an extensive survey of the potential energy surface by molecular mechanics calculations using AMBER has provided three-dimensional potential energy maps. These maps reveal that the range and flexibility of the glycosidic torsion angles are significantly more restricted in both stereoisomeric adducts than in unmodified 2'-deoxyguanosine. The structural and energetic results suggest that the unusual geometric, steric, and hydrogen bonding properties of these lesions underlie their mutagenicity. In addition, stereoisomer-specific differences indicate the possibility that their processing by cellular replication and repair enzymes may be differentially affected by their absolute configuration.
细胞中存在的活性氧会导致DNA损伤。DNA中鸟嘌呤的主要氧化产物之一，8-氧代-7,8-二氢鸟嘌呤，是通过失去两个电子形成的，是研究最为广泛的碱基损伤之一。该产物进一步失去两个电子可产生螺环亚氨基二氢尿嘧啶（Sp）的R和S立体异构体。体外和体内实验均表明，Sp立体异构体具有高度致突变性，可导致G→T和G→C颠换。因此，它们作为可能引发癌症的内源性DNA损伤的例子备受关注。为了解释Sp损伤的致突变特性，需要了解其结构特性。为了阐明这些结构效应，我们在Sp修饰的碱基和核苷水平上进行了计算研究。在碱基水平上，量子力学几何优化研究揭示了R和S立体异构体的精确镜像对称性，两个环近乎垂直。在核苷水平上，使用AMBER通过分子力学计算对势能面进行的广泛研究提供了三维势能图。这些图表明，与未修饰的2'-脱氧鸟苷相比，两种立体异构加合物中糖苷扭转角的范围和灵活性受到的限制要大得多。结构和能量结果表明，这些损伤异常的几何、空间和氢键性质是其致突变性的基础。此外，立体异构体特异性差异表明，细胞复制和修复酶对它们的处理可能会因其绝对构型而受到不同影响。
