Nucleotides function as endogenous chemical sensors for oxidative stress signaling.
Nucleotides function as endogenous chemical sensors for oxidative stress signaling.
复制标题
DOI：
10.3164/jcbn.11-003fr
复制
发表时间：
2011-01
影响因子：
2.4
通讯作者：
Akaike T
中科院分区：
文献类型：
--
作者：
Ihara H;Sawa T;Nakabeppu Y;Akaike T
在培养的细胞和组织中，活性氮氧化物和活性氧产生氧化和硝化的核苷酸，包括8-氧鸟嘌呤和8-硝基鸟嘌呤衍生物，如8-硝基鸟苷3‘，5’-环单磷酸。DNA和RNA中的8-氧鸟嘌呤和8-硝基鸟嘌呤具有潜在的致突变性，前者也可诱导细胞死亡。8-硝基鸟苷3‘，5’-环单磷酸是一种重要的硝化鸟嘌呤核苷酸，是一种新的第二信使。令人惊讶的是，在表达诱导型一氧化氮合酶的细胞中，8-硝基鸟苷3‘，5’-环一磷酸的生成量高于3‘，5’-环磷酸鸟苷的生成量。更重要的是，8-硝基鸟苷3‘，5’-环一磷酸是亲电性的，通过3‘，5’-环一磷酸加合作用与蛋白质的巯基反应生成一种新的翻译后修饰(称为S鸟苷)。例如，8-硝基鸟苷3‘，5’-环一磷酸诱导的Kelch样ECH相关蛋白1的S鸟苷化导致了核因子-E2相关因子的激活和抗氧化酶的诱导。因此，8-硝基鸟苷3‘，5’-环一磷酸可以保护细胞免受氧化应激相关的细胞毒性。因此，尽管通过氧化和硝化应激产生的化学修饰核苷酸被简单地视为内源性诱变剂，但储存在细胞内的内源核苷酸本身可能作为活性氮氧化物和氧物种的传感机制来诱导细胞对氧化应激的适应性反应。
Oxidized and nitrated nucleotides including 8-oxogunanine and 8-nitroguanine derivatives such as 8-nitroguanosine 3',5'-cyclic monophosphate were generated by reactive nitrogen oxides and reactive oxygen species in cultured cells and in tissues. 8-oxoguanine and 8-nitroguanine in DNA and RNA are potentially mutagenic, and the former also induces cell death. Some derivative, 8-nitroguanosine 3',5'-cyclic monophosphate a major nitrated guanine nucleotide, was identified as a novel second messenger. Surprisingly, the amount of 8-nitroguanosine 3',5'-cyclic monophosphate generated was found to be higher than that of guanosine 3',5'-cyclic monophosphate in cells expressing inducible nitric oxide synthase. More important, 8-nitroguanosine 3',5'-cyclic monophosphate is electrophilic and reacted efficiently with sulfhydryls of proteins to produce a novel posttranslational modification (named S-guanylation) via guanosine 3',5'-cyclic monophosphate adduction. For example, 8-nitroguanosine 3',5'-cyclic monophosphate-induced S-guanylation of Kelch-like ECH-associated protein 1 led to NF-E2-related factor activation and induction of antioxidant enzymes. 8-nitroguanosine 3',5'-cyclic monophosphate may thus protect cells against oxidative stress-related cytotoxicity. Therefore, although chemically modified nucleotides produced via oxidative and nitrative stress are regarded simply as endogenous mutagens, the endogenous nucleotides stored in cells per se may serve functionally as a sensing mechanism for reactive nitrogen oxides and oxygen species to induce cellular adaptive responses to oxidative stress.