Human MTH3 (NUDT18) Protein Hydrolyzes Oxidized Forms of Guanosine and Deoxyguanosine Diphosphates COMPARISON WITH MTH1 AND MTH2
Human MTH3 (NUDT18) Protein Hydrolyzes Oxidized Forms of Guanosine and Deoxyguanosine Diphosphates COMPARISON WITH MTH1 AND MTH2
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DOI：
10.1074/jbc.m112.363010
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发表时间：
2012-06-15
影响因子：
4.8
通讯作者：
Sekiguchi, Mutsuo
中科院分区：
文献类型：
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作者：
Takagi, Yasumitsu;Setoyama, Daiki;Sekiguchi, Mutsuo
大多数携带23个残基的MutT相关序列的蛋白质能够水解具有连接到另一个部分X的核苷二磷酸的一般结构的化合物，并且被称为Nuvidine水解酶。在22种人类Nutritional蛋白（通过序列特征识别）中，一些仍然未被表征为没有确定底物的酶。在这里，我们揭示了NUDT 18蛋白，其底物是未知的，可以降解8-氧代-7，8-二氢鸟嘌呤（8-氧代-Gua）含有核苷二磷酸单磷酸。由于该酶与MTH 1（NUDT 1）和MTH 2（NUDT 15）密切相关，我们建议将其命名为MTH 3。虽然这三种人类蛋白质在序列上彼此相似，但它们的底物特异性差异很大。MTH 1切割8-氧代-dGTP，但不切割8-氧代-dGDP，而MTH 2可以降解8-氧代-dGTP和8-氧代-dGDP，尽管MTH 2的内在酶活性显著低于MTH 1。另一方面，MTH 3对8-oxo-dGDP具有特异性活性，并且几乎不切割8-oxodGTP。其他类型的氧化核苷二磷酸，2-羟基-dADP和8-羟基-dADP，也被MTH 3水解。MTH 3酶的另一个显著特征是其对核糖核苷酸对应物的作用。MTH 3可以像8-oxo-dGDP一样有效地降解8-oxo-GDP，这与MTH 1和MTH 2对核糖核苷酸对应物8-oxo-GTP显示出有限的活性的发现相反。这三种酶可能共同发挥作用，以帮助维持DNA复制和转录的高保真度在氧化应激下。
Most of the proteins carrying the 23-residue MutT-related sequence are capable of hydrolyzing compounds with a general structure of nucleoside diphosphate linked to another moiety X and are called the Nudix hydrolases. Among the 22 human Nudix proteins (identified by the sequence signature), some remain uncharacterized as enzymes without a defined substrate. Here, we reveal that the NUDT18 protein, whose substrate was unknown, can degrade 8-oxo-7,8-dihydroguanine (8-oxo-Gua)-containing nucleoside diphosphates to the monophosphates. Because this enzyme is closely related to MTH1 (NUDT1) and MTH2 (NUDT15), we propose that it should be named MTH3. Although these three human proteins resemble each other in their sequences, their substrate specificities differ considerably. MTH1 cleaves 8-oxo-dGTP but not 8-oxo-dGDP, whereas MTH2 can degrade both 8-oxo-dGTP and 8-oxo-dGDP, although the intrinsic enzyme activity of MTH2 is considerably lower than that of MTH1. On the other hand, MTH3 is specifically active against 8-oxo-dGDP and hardly cleaves 8-oxodGTP. Other types of oxidized nucleoside diphosphates, 2-hydroxy-dADP and 8-hydroxy-dADP, were also hydrolyzed by MTH3. Another notable feature of the MTH3 enzyme is its action toward the ribonucleotide counterpart. MTH3 can degrade 8-oxo-GDP as efficiently as 8-oxo-dGDP, which is in contrast to the finding that MTH1 and MTH2 show a limited activity against the ribonucleotide counterpart, 8-oxo-GTP. These three enzymes may function together to help maintain the high fidelity of DNA replication and transcription under oxidative stress.