Determination of the Nucleic Acid Adducts Structure at the Nucleoside/Nucleotide Level by NMR Spectroscopy

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• 作者：Martin Dra膷铆nsk媒 ; Radek Pohl
• 刊名：Chemical Research in Toxicology
• 出版年：2015
• 出版时间：February 16, 2015
• 年：2015
• 卷：28
• 期：2
• 页码：155-165
• 全文大小：415K
• ISSN：1520-5010

文摘

All living organisms are exposed to xenobiotics from the environment. The exposure can lead to the formation of covalent adducts of xenobiotics or their metabolites with nucleic acids (NAs). The knowledge of NA adduct structure provides valuable information on the mechanism of carcinogenesis on a molecular level. While NMR spectroscopy is extremely successful in structural analysis of many classes of molecules ranging from small inorganic and organic molecules to large biomacromolecules, the structural analysis of NA adducts by NMR spectroscopy is accompanied by some challenges. First, the structural diversity of the adducts is very large; the electrophilic species generated from the metabolism of xenobiotics can attack various atoms of the nucleobases, and new rings are frequently formed. The second challenge in the DNA adducts structure determination is the low sensitivity of NMR spectroscopy and low amount of the adducts isolated from in vivo experiments. Recent developments of NMR hardware and experimental methods have led, however, to unprecedented sensitivity. This contribution reviews NMR techniques that are commonly applied in the determination of nucleic acid adducts structure at the nucleoside/nucleotide level. These NMR techniques and the large structural heterogeneity of NA adducts are demonstrated on recent examples (mostly published after 2000) of NA adducts structure determined by NMR. Most of the examples report 2鈥?deoxyribonucles(t)ide derivatives, but RNA adducts are also briefly discussed. The influence of the formation of NA adducts on nucleoside conformation (particularly syn/anti orientation of the base) is also demonstrated on recent examples.