Department of Chemistry, Center in Molecular Toxicology, Vanderbilt University, Nashville, Tennessee 37235, USA.
Environ Mol Mutagen. 2010 Jul;51(6):625-34. doi: 10.1002/em.20599.
Trans-4-Hydroxynonenal (HNE) is a peroxidation product of omega-6 polyunsaturated fatty acids. Michael addition of HNE to deoxyguanosine yields four diastereomeric 1,N(2)-dG adducts. The adduct of (6S,8R,11S) stereochemistry forms interstrand N(2)-dG:N(2)-dG cross-links in the 5'-CpG-3' sequence. It has been compared with the (6R,8S,11R) adduct, incorporated into 5'-d(GCTAGCXAGTCC)-3' . 5'-d(GGACTCGCTAGC)-3', containing the 5'-CpG-3' sequence (X = HNE-dG). Both adducts rearrange in DNA to N(2)-dG aldehydes. These aldehydes exist in equilibrium with diastereomeric cyclic hemiacetals, in which the latter predominate at equilibrium. These cyclic hemiacetals mask the aldehydes, explaining why DNA cross-linking is slow compared to related 1,N(2)-dG adducts formed by acrolein and crotonaldehyde. Both the (6S,8R,11S) and (6R,8S,11R) cyclic hemiacetals are located within the minor groove. However, the (6S,8R,11S) cyclic hemiacetal orients in the 5'-direction, while the (6R,8S,11R) cyclic hemiacetal orients in the 3'-direction. The conformations of the diastereomeric N(2)-dG aldehydes, which are the reactive species involved in DNA cross-link formation, have been calculated using molecular mechanics methods. The (6S,8R,11S) aldehyde orients in the 5'-direction, while the (6R,8S,11R) aldehyde orients in the 3'-direction. This suggests a kinetic basis to explain, in part, why the (6S,8R,11S) HNE adduct forms interchain cross-links in the 5'-CpG-3' sequence, whereas (6R,8S,11R) HNE adduct does not. The presence of these cross-links in vivo is anticipated to interfere with DNA replication and transcription, thereby contributing to the etiology of human disease.
反式-4-羟壬烯醛（HNE）是 ω-6 多不饱和脂肪酸的过氧化产物。HNE 与脱氧鸟苷的迈克尔加成生成四种非对映异构的 1，N（2）-dG 加合物。具有（6S，8R，11S）立体化学的加合物在 5'-CpG-3'序列中形成链间 N（2）-dG：N（2）-dG 交联。它已与（6R，8S，11R）加合物进行了比较，后者掺入 5'-d（GCTAGCXAGTCC）-3'。5'-d（GGACTCGCTAGC）-3'，含有 5'-CpG-3'序列（X = HNE-dG）。两种加合物在 DNA 中重排为 N（2）-dG 醛。这些醛在平衡中与非对映环状半缩醛相互转化，后者在平衡中占主导地位。这些环状半缩醛掩盖了醛，这解释了为什么与丙烯醛和巴豆醛形成的相关 1，N（2）-dG 加合物相比，DNA 交联速度较慢。（6S，8R，11S）和（6R，8S，11R）环状半缩醛都位于小沟内。然而，（6S，8R，11S）环状半缩醛定向于 5'-方向，而（6R，8S，11R）环状半缩醛定向于 3'-方向。参与 DNA 交联形成的反应性物质的非对映异构 N（2）-dG 醛的构象已使用分子力学方法进行了计算。（6S，8R，11S）醛定向于 5'-方向，而（6R，8S，11R）醛定向于 3'-方向。这为部分解释为什么（6S，8R，11S）HNE 加合物在 5'-CpG-3'序列中形成链间交联，而（6R，8S，11R）HNE 加合物则不形成交联提供了动力学依据。预计这些交联在体内的存在会干扰 DNA 复制和转录，从而导致人类疾病的发生。
