8-oxo-GDP(3-)

• 分子结构分类: 有机化合物 - 核苷、核苷酸和类似物 - 嘌呤核苷酸
• 英文名称: 8-oxo-GDP(3-)
• 英文别名: [[(2R,3S,4R,5R)-5-(2-amino-6,8-dioxo-1,7-dihydropurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-oxidophosphoryl] phosphate
• 化学式: C10H12N5O12P2-3
• 分子量: 456.18
• InChiKey: PQVZQFDCRLHZRP-UMMCILCDSA-K

计算性质

• 辛醇/水分配系数(LogP)：
  -6.6
• 重原子数：
  29
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  271
• 氢给体数：
  5
• 氢受体数：
  12

反应信息

• 作为反应物：
  描述：

  8-oxo-GDP(3-) 、 水 生成 8-oxo-GMP(2-) 、 氢(+1)阳离子 、 H3PO4
  参考文献：
  名称：

  Mammalian enzymes for preventing transcriptional errors caused by oxidative damage

  摘要：

  8-氧代-7,8-二氢鸟嘌呤（8-oxoGua）是由细胞代谢过程中通常形成的活性氧在细胞中产生的。这种氧化碱可以与腺嘌呤和胞嘧啶配对，因此信使RNA中存在这种碱会导致翻译错误。大肠杆菌的MutT蛋白将含有8-oxoGua的核糖核苷二磷酸和三磷酸降解为单磷酸，从而防止8-oxoGua错误地掺入RNA。在这里，我们展示了人类MutT相关蛋白NUDT5和MTH1能够防止氧化损伤引起的翻译错误。在缺乏大肠杆菌mutT的细胞中，氧化损伤导致错误蛋白质的产生比野生型细胞增加了28倍。通过在细胞中表达NUDT5或MTH1，错误蛋白质的产生分别减少到1.4倍和1.2倍。NUDT5和MTH1将8-oxoGDP水解为8-oxoGMP，Vmax/Km值分别为1.3×10-3和1.7×10-3，这些值大大高于其正常对应物GDP（0.1-0.5×10-3）的值。MTH1（但不是NUDT5）具有将8-oxoGTP降解为单磷酸的额外活性。这些结果表明，从

  DOI：

  10.1093/nar/gki682
• 作为产物：
  描述：

  8-oxo-GTP 、 水 生成 8-oxo-GDP(3-) 、 氢(+1)阳离子 、 H3PO4
  参考文献：
  名称：

  Mycobacterium tuberculosis MutT1 (Rv2985) and ADPRase (Rv1700) Proteins Constitute a Two-stage Mechanism of 8-Oxo-dGTP and 8-Oxo-GTP Detoxification and Adenosine to Cytidine Mutation Avoidance

  摘要：

  Approximately one third of the world population is infected with Mycobacterium tuberculosis, the causative agent of tuberculosis. A better understanding of the pathogen biology is crucial to develop new tools/strategies to tackle its spread and treatment. In the host macrophages, the pathogen is exposed to reactive oxygen species, known to damage dGTP and GTP to 8-oxo-dGTP and 8-oxo-GTP, respectively. Incorporation of the damaged nucleotides in nucleic acids is detrimental to organisms. MutT proteins, belonging to a class of Nudix hydrolases, hydrolyze 8-oxo-G nucleoside triphosphates/diphosphates to the corresponding nucleoside monophosphates and sanitize the nucleotide pool. Mycobacteria possess several MutT proteins. However, a functional homolog of Escherichia coli MutT has not been identified. Here, we characterized MtuMutT1 and Rv1700 proteins of M. tuberculosis. Unlike other MutT proteins, MtuMutT1 converts 8-oxo-dGTP to 8-oxo-dGDP, and 8-oxo-GTP to 8-oxo-GDP. Rv1700 then converts them to the corresponding nucleoside monophosphates. This observation suggests the presence of a two-stage mechanism of 8-oxo-dGTP/8-oxo-GTP detoxification in mycobacteria. MtuMutT1 converts 8-oxo-dGTP to 8-oxo-dGDP with a K-m of similar to 50 mu M and V-max of similar to 0.9 pmol/min per ng of protein, and Rv1700 converts 8-oxo-dGDP to 8-oxo-dGMP with a K-m of similar to 9.5 mu M and V-max of similar to 0.04 pmol/min per ng of protein. Together, MtuMutT1 and Rv1700 offer maximal rescue to E. coli for its MutT deficiency by decreasing A to C mutations (a hallmark of MutT deficiency). We suggest that the concerted action of MtuMutT1 and Rv1700 plays a crucial role in survival of bacteria against oxidative stress.

  DOI：

  10.1074/jbc.m112.442566

文献信息

• Cleavage of oxidized guanine nucleotide and ADP sugar by human NUDT5 protein
  作者：R. Ito、M. Sekiguchi、D. Setoyama、Y. Nakatsu、Y. Yamagata、H. Hayakawa

  DOI：10.1093/jb/mvr028

  日期：2011.6.1

  MutT-related proteins, including Escherichia coli MutT and the human MTH1 (NUDT1), degrade 8-oxo-7, 8-dihydrodeoxyguanosine triphosphate (8-oxo-dGTP) to 8-oxo-dGMP and thereby prevent mutations caused by the misincorporation of 8-oxoguanine into DNA. The human NUDT5, which has an intrinsic activity to cleave ADP sugars to AMP and sugar phosphate, possesses the ability to degrade 8-oxo-dGDP to the monophosphate. Since 8-oxo-dGDP and 8-oxo-dGTP are interconvertible by cellular enzymes, NUDT5 has the potential to prevent errors during DNA replication. The two activities associated with NUDT5 exhibit different pH dependencies; the optimum for the cleavage of ADP ribose is pH 7–9, while that for 8-oxo-dGDPase is around pH 10. The kinetic parameters for the two types of reactions indicated that ADP ribose is a better substrate for NUDT5 compared with oxidized guanine nucleotides. The 8-oxo-dGDP cleavage was competitively inhibited by ADP ribose and its reaction product, AMP, and in reverse, the cleavage of ADP ribose was inhibited by 8-oxo-dGDP. These results imply that the two types of substrates may share the same binding site for catalysis.

  与 MutT 相关的蛋白，包括大肠杆菌 MutT 和人类 MTH1（NUDT1），可将 8-氧代-7，8-二氢脱氧鸟苷三磷酸（8-氧代-dGTP）降解为 8-氧代-dGMP，从而防止 8-氧代鸟嘌呤错并入 DNA 而导致突变。人类 NUDT5 本身具有将 ADP 糖裂解为 AMP 和磷酸糖的活性，它也具有将 8-氧代-dGDP 降解为单磷酸的能力。由于细胞酶可将 8-oxo-dGDP 和 8-oxo-dGTP 相互转换，因此 NUDT5 有可能防止 DNA 复制过程中出现错误。与 NUDT5 相关的两种活性表现出不同的 pH 依赖性；ADP 核糖的最佳裂解 pH 值为 7-9，而 8-氧代-dGDP 酶的最佳裂解 pH 值约为 10。两种反应的动力学参数表明，与氧化鸟嘌呤核苷酸相比，ADP 核糖是 NUDT5 更好的底物。8-oxo-dGDP 的裂解受到 ADP 核糖及其反应产物 AMP 的竞争性抑制，反之，ADP 核糖的裂解受到 8-oxo-dGDP 的抑制。这些结果表明，这两种底物可能具有相同的催化结合位点。
• A novel mechanism for preventing mutations caused by oxidation of guanine nucleotides
  作者：Toru Ishibashi、Hiroshi Hayakawa、Mutsuo Sekiguchi

  DOI：10.1038/sj.embor.embor838

  日期：2003.5

  MutT‐related proteins, including the Escherichia coli MutT and human MutT homologue 1 (MTH1) proteins, degrade 8‐oxo‐ 7,8‐dihydrodeoxyguanosine triphosphate (8‐oxo‐dGTP) to a monophosphate, thereby preventing mutations caused by the misincorporation of 8‐oxoguanine into DNA. Here, we report that human cells have another mechanism for cleaning up the nucleotide pool to ensure accurate DNA replication. The human Nudix type 5 (NUDT5) protein hydrolyses 8‐oxo‐dGDP to monophosphate with a Km of 0.77 µM, a value considerably lower than that for ADP sugars, which were originally identified as being substrates of NUDT5. NUDT5 hydrolyses 8‐oxo‐dGTP only at very low levels, but is able to substitute for MutT when it is defective. When NUDT5 is expressed in E. coli mutT− cells, the increased frequency of spontaneous mutations is decreased to normal levels. Considering the enzymatic parameters of MTH1 and NUDT5 for oxidized guanine nucleotides, NUDT5 might have a much greater role than MTH1 in preventing the occurrence of mutations that are caused by the misincorporation of 8‐oxoguanine in human cells.
• NUDT5 hydrolyzes oxidized deoxyribonucleoside diphosphates with broad substrate specificity
  作者：Hiroyuki Kamiya、Mika Hori、Takao Arimori、Mutsuo Sekiguchi、Yuriko Yamagata、Hideyoshi Harashima

  DOI：10.1016/j.dnarep.2009.07.011

  日期：2009.10

  The human NUDT5 protein catalyzes the hydrolysis of 8-hydroxy-dGDP. To examine its substrate specificity, four oxidized deoxyribonucleotides (2-hydroxy-dADP, 8-hydroxy-dADP, 5-formyl-dUDP, and 5-hydroxy-dCDP) were incubated with the NUDT5 protein. Interestingly, all of the nucleotides, except for 5-hydroxy-dCDP, were hydrolyzed with various efficiencies. The kinetic parameters indicated that 8-hydroxy-dADP was hydrolyzed as efficiently as 8-hydroxy-dGDP. The hydrolyzing activities for their triphosphate counterparts were quite weak. These results suggest that the NUDT5 protein eliminates various oxidized deoxyribonucleoside diphosphates from the nucleotide pool and prevents their toxic effects. (C) 2009 Elsevier B.V. All rights reserved.
• Crystal Structures of Human NUDT5 Reveal Insights into the Structural Basis of the Substrate Specificity
  作者：Manwu Zha、Chen Zhong、Yingjie Peng、Hongyu Hu、Jianping Ding

  DOI：10.1016/j.jmb.2006.09.078

  日期：2006.12

  Human NUDT5 (hNUDT5) is an ADP-ribose pyrophosphatase (ADPRase) belonging to the Nudix hydrolase superfamily. It presumably plays important roles in controlling the intracellular level of ADP-ribose (ADPR) to prevent non-enzymatic ADP-ribosylation by hydrolyzing ADPR to AMP and ribose 5'-phosphate. We report here the crystal structures of hNUDT5 in ago form, in complex with ADPR, and in complex with AMP with bound Mg2+. hNUDT5 forms a homodimer with substantial domain swapping and assumes a structure more similar to Escherichia coli ADPRase ORF209 than human ADPRase NUDT9. The adenine moiety of the substrates is specifically recognized by the enzyme via hydrogenbonding interactions between N1 and N6 of the base and Glu47 of one subunit, and between N7 of the base and Arg51 of the other subunit, providing the molecular basis for the high selectivity of hNUDT5 for ADP-sugars over other sugar nucleotides. Structural comparisons with E. coli ADPRase ORF209 and ADPXase ORF186 indicate that the existence of an aromatic residue on loop L8 in ORF186 seems to be positively correlated with its enzymatic activity on AP(n)A, whereas hNUDT5 and ORF209 contain no such residue and thus have low or no activities on APnA. (c) 2006 Elsevier Ltd. All rights reserved.
• Human MTH3 (NUDT18) Protein Hydrolyzes Oxidized Forms of Guanosine and Deoxyguanosine Diphosphates
  作者：Yasumitsu Takagi、Daiki Setoyama、Riyoko Ito、Hiroyuki Kamiya、Yuriko Yamagata、Mutsuo Sekiguchi

  DOI：10.1074/jbc.m112.363010

  日期：2012.6

  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.