Peroxy radical oxidation of thymidine.
Peroxy radical oxidation of thymidine.
复制标题
胸苷的过氧自由基氧化。
DOI：
10.1021/tx960154l
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发表时间：
1997
期刊：
影响因子：
--
通讯作者：
Termini,J
中科院分区：
文献类型：
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作者：
Martini,M;Termini,J
过氧自由基（ROO·）是DNA损伤产生中涉及的活性氧物种中的独特之处，因为它具有极长的半衰期（秒级），并且预计在其反应中相对于其他自由基中间体具有相对更大的化学选择性。然而，还没有关于ROO·与碱基、核苷或DNA反应的产物研究出现，因此无法对它可能参与DNA碱基损伤和致突变过程做出有意义的预测。我们在这里报告的反应产物形成的过氧自由基与胸苷，一个主要目标的氧化碱基损伤。ROO·与胸腺嘧啶反应，主要产生5-Me氧化产物。高致突变性5-（氢过氧甲基）-2 '-脱氧尿苷、5-甲酰基-2'-脱氧尿苷和5-（羟甲基）-2 '-脱氧尿苷通过过氧自由基氧化产生。相比之下，5-Me氧化产物是·OH氧化胸苷的次要产物，其通过添加到5，6双键而产生主要饱和衍生物。本文提出了一个合理的机制方案，用于过氧自由基对胸苷的碱性氧化产物的形成。如游离碱释放所示，还发现脱氧核糖部分的攻击导致氧化脱嘧啶。导致单链和双链断裂的磷酸二酯骨架裂解也被过氧自由基催化，如使用质粒切口测定所证明的。
The peroxy radical (ROO•) is unique among reactive oxygen species implicated in the production of DNA damage in that it possesses an extremely long half-life (order of seconds) and is predicted to have a relatively greater chemical selectivity in its reactions relative to other radical intermediates. Yet no product studies of the reactions of ROO•with bases, nucleosides, or DNA have appeared, and thus no meaningful predictions can be made regarding its potential involvement in the production of DNA base damage and the mutagenic process. We report here on the reaction products formed by peroxy radical with thymidine, a major target of oxidative base damage. ROO•reacts with thymine to yield predominantly 5-Me oxidation products. The highly mutagenic 5-(hydroperoxymethyl)-2‘-deoxyuridine, 5-formyl-2‘-deoxyuridine, and 5-(hydroxymethyl)-2‘-deoxyuridine are produced by peroxy radical oxidation. In contrast, 5-Me oxidation products are minor products of thymidine oxidation by•OH, which yields predominantly saturated derivatives via addition to the 5,6 double bond. A plausible mechanistic scheme for the formation of the base oxidation products of thymidine by peroxy radicals is presented. Attack at the deoxyribose moiety resulting in oxidative depyrimidination is also found to occur, as indicated by free base release. Phosphodiester backbone cleavage resulting in single and double strand breaks is also catalyzed by peroxy radical, as demonstrated using a plasmid nicking assay.