Hayakawa H, Hofer A, Thelander L, Kitajima S, Cai Y, Oshiro S, Yakushiji H, Nakabeppu Y, Kuwano M, Sekiguchi M
Department of Biochemistry, Faculty of Medicine, Kyushu University, Fukuoka 812-8582, Japan.
Biochemistry. 1999 Mar 23;38(12):3610-4. doi: 10.1021/bi982361l.
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 product, 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.
在细胞核苷酸池中，含8-氧代-7,8-二氢鸟嘌呤（8-氧代鸟嘌呤）的核苷酸是由正常细胞代谢过程中产生的氧自由基作用生成的。我们研究了哺乳动物细胞中含8-氧代鸟嘌呤的核糖核苷酸的相互转化和代谢命运。（1）8-氧代鸟苷三磷酸（8-oxoGTP）不仅可以通过鸟苷三磷酸（GTP）的直接氧化产生，还可以通过核苷酸二磷酸激酶将8-氧代鸟苷二磷酸（8-oxoGDP）磷酸化生成，如此形成的8-氧代鸟苷三磷酸可作为RNA聚合酶II的底物，诱导转录错误。（2）具有内在8-氧代-dGTPase活性的MTH1蛋白有潜力将8-氧代鸟苷三磷酸水解为8-氧代鸟苷一磷酸（8-oxoGMP），从而防止8-氧代鸟嘌呤错误掺入RNA。降解产物8-氧代鸟苷一磷酸不能再利用，因为有磷酸化鸟苷一磷酸（GMP）和脱氧鸟苷一磷酸（dGMP）潜力的鸟苷酸激酶对8-氧代鸟苷一磷酸无活性。（3）催化四种天然存在的核糖核苷二磷酸还原的核糖核苷酸还原酶不能将含8-氧代鸟嘌呤的核糖核苷酸转化为脱氧核糖核苷酸。这一步似乎起到了守门人的作用，以防止由氧化的核糖核苷酸形成用于DNA合成的诱变底物。
