Metabolic fate of oxidized guanine ribonucleotides in mammalian cells
Metabolic fate of oxidized guanine ribonucleotides in mammalian cells
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DOI：
10.1021/bi982361l
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发表时间：
1999-03-23
期刊：
影响因子：
2.9
通讯作者：
Sekiguchi, M
中科院分区：
文献类型：
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作者：
Hayakawa, H;Hofer, A;Sekiguchi, M
含有8-氧-7,8-二氢鸟嘌呤-（8-氧鸟嘌呤-）的核苷酸是由细胞正常代谢过程中产生的氧自由基在细胞核苷酸池中产生的。我们研究了含8-氧鸟嘌呤的核糖核苷酸在哺乳动物细胞中的相互转化和代谢命运。(1) 8-OxoGTP不仅可以通过GTP的直接氧化产生，也可以通过核苷酸二磷酸激酶对8-oxoGDP的磷酸化产生，由此形成的8-OxoGTP可以作为RNA聚合酶II的底物诱导转录错误。(2) MTH1蛋白携带固有的8-oxo-dGTPase活性，具有将8-oxoGTP水解为8-oxoGMP的潜力，从而防止8-oxo鸟嘌呤错掺入RNA。降解产物8-OxoGMP不能再利用，因为鸟苷酸激酶对8-OxoGMP没有活性，而鸟苷酸激酶有可能使GMP和dGMP磷酸化。(3)核糖核苷酸还原酶能催化四种天然存在的二磷酸核糖核苷的还原，但不能将含8-氧鸟嘌呤的核糖核苷酸转化为脱氧核糖核苷酸。这一步骤似乎起到了看门人的作用，以防止氧化核糖核苷酸合成DNA的诱变底物的形成。
8-Oxo-7,8-dihydroguanine- (8-oxoguanine-) containing nucleotides are generated in the cellular nucleotide pool by the action of oxygen radicals produced during normal cellular metabolism. We examined the interconversion and metabolic fate of 8-oxoguanine-containing ribonucleotides in mammalian cells. (1) 8-OxoGTP can be generated not only by direct oxidation of GTP but also by phosphorylation of 8-oxoGDP by nucleotide diphosphate kinase, and the 8-oxoGTP thus formed can serve as a substrate for RNA polymerase II to induce transcription errors. (2) MTH1 protein carrying intrinsic 8-oxo-dGTPase activity has the potential to hydrolyze 8-oxoGTP to 8-oxoGMP, thus preventing misincorporation of 8-oxoguanine into RNA. 8-OxoGMP, the degradation produce, cannot be reutilized, since guanylate kinase, which has the potential to phosphorylate both GMP and dGMP, is inactive on 8-oxoGMP. (3) Ribonucleotide reductase, which catalyzes reduction of four naturally occurring ribonucleoside diphosphates, cannot convert 8-oxoguanine-containing ribonucleotide to the deoxyribonucleotide. This step appears to serve as a gatekeeper to prevent formation of mutagenic substrates for DNA synthesis from oxidized ribonucleotides.