dGTP

• 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: dGTP
• 英文别名: 2-amino-9-[2-deoxy-5-O-(hydroxy{[hydroxy(phosphonooxy)phosphoryl]oxy}phosphoryl)pentofuranosyl]-3,9-dihydro-6H-purin-6-one；[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl] phosphono hydrogen phosphate
• 化学式: C₁₀H₁₆N₅O₁₃P₃
• 分子量: 507.184
• InChiKey: HAAZLUGHYHWQIW-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -5.1
• 重原子数：
  31
• 可旋转键数：
  8
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  275
• 氢给体数：
  7
• 氢受体数：
  14

反应信息

• 作为反应物：
  描述：

  dGTP 以 水 为溶剂， 反应 0.5h， 生成 二磷酸酯 、 dGMP
  参考文献：
  名称：

  Crystal Structures and Inhibitor Interactions of Mouse and Dog MTH1 Reveal Species-Specific Differences in Affinity

  摘要：

  MTH1 可水解氧化的三磷酸核苷，从而使核苷酸池免受氧化损伤。这样就能防止受损核苷酸结合到 DNA 中，否则就会导致突变和细胞死亡。与非恶性细胞相比，癌细胞中的活性氧水平较高，导致癌细胞中的氧化核苷酸水平较高，从而使癌细胞更加依赖 MTH1 而存活。通过抑制 MTH1 来特异性靶向癌细胞的可能性凸显了 MTH1 是一个很有前景的癌症靶点。将 MTH1 抑制剂应用于临床需要进行动物实验，而了解抑制剂效力的物种差异至关重要。我们在此表明，人类 MTH1 抑制剂 TH588 对小鼠 MTH1 的抑制作用比人类、大鼠、猪和狗的 MTH1 蛋白低约 20 倍。我们展示了小鼠 MTH1 与 TH588 和狗 MTH1 复合物的晶体结构，并阐明了所观察到的与 TH588 亲和力差异的结构和序列基础。我们发现 MTH1 中的 116 氨基酸残基是决定 TH588 亲和力的重要因素。此外，我们还展示了小鼠 MTH1 与底物 8-oxo-dGTP 复合物的结构。晶体结构使我们深入了解了不同生物的 MTH1 蛋白之间的高度结构保守性，并提供了 MTH1 与抑制剂之间相互作用的详细视图，揭示了微小的结构差异会对亲和性和特异性产生巨大影响。

  DOI：

  10.1021/acs.biochem.7b01163

文献信息

• Enzymatic nucleic acid synthesis
  申请人：President and Fellows of Harvard College

  公开号：US10745814B2

  公开（公告）日：2020-08-18

  The present disclosure provides methods of activating an enzyme, such as error prone or template independent polymerase, using electricity to alter pH of a reaction zone and reaction site from an inactivating pH at which the enzyme is inactive to an activating pH at which the enzyme is active to add a nucleotide to an initiator or growing polymer chain. The activating pH can then be changed back to an inactivating pH and the process repeated as many times as desired to produce a target nucleic acid sequence.

  本公开提供了活化酶的方法，如易出错或与模板无关的聚合酶，利用电能改变反应区和反应位点的 pH 值，从酶无活性的失活 pH 值变为酶有活性的活化 pH 值，从而将核苷酸添加到引发剂或生长的聚合物链中。然后可将激活 pH 值变回失活 pH 值，并根据需要多次重复该过程，以产生目标核酸序列。
• NUCLEOTIDE ANALOGS
  申请人：Siddiqi Suhaib

  公开号：US20110081647A1

  公开（公告）日：2011-04-07

  The invention generally relates to nucleotide analogs and methods of their use in sequencing-by-synthesis reactions. In certain embodiments, the invention provides a nucleotide analog including a detectable label attached to a nitrogenous base portion of a nucleotide analog by a cleavable linker, in which contact of the analog with at least one activating agent results in cleavage of the label and elimination of the linker, thereby producing a natural nucleotide, a 9-deaza-G, 9-deaza-A, or ψ-uridine.
• Enzymatic Nucleic Acid Synthesis
  申请人：President and Fellows of Harvard College

  公开号：US20190145013A1

  公开（公告）日：2019-05-16

  The present disclosure provides methods of activating an enzyme, such as error prone or template independent polymerase, using electricity to alter pH of a reaction zone and reaction site from an inactivating pH at which the enzyme is inactive to an activating pH at which the enzyme is active to add a nucleotide to an initiator or growing polymer chain. The activating pH can then be changed back to an inactivating pH and the process repeated as many times as desired to produce a target nucleic acid sequence.
• US9163053B2
  申请人：——

  公开号：US9163053B2

  公开（公告）日：2015-10-20
• Crystal Structures and Inhibitor Interactions of Mouse and Dog MTH1 Reveal Species-Specific Differences in Affinity
  作者：Mohit Narwal、Ann-Sofie Jemth、Robert Gustafsson、Ingrid Almlöf、Ulrika Warpman Berglund、Thomas Helleday、Pål Stenmark

  DOI：10.1021/acs.biochem.7b01163

  日期：2018.2.6

  MTH1 hydrolyzes oxidized nucleoside triphosphates, thereby sanitizing the nucleotide pool from oxidative damage. This prevents incorporation of damaged nucleotides into DNA, which otherwise would lead to mutations and cell death. The high level of reactive oxygen species in cancer cells leads to a higher level of oxidized nucleotides in cancer cells compared to that in nonmalignant cells, making cancer cells more dependent on MTH1 for survival. The possibility of specifically targeting cancer cells by inhibiting MTH1 has highlighted MTH1 as a promising cancer target. The progression of MTH1 inhibitors into the clinic requires animal studies, and knowledge of species differences in the potency of inhibitors is vitally important. We here show that the human MTH1 inhibitor TH588 is approximately 20-fold less potent with respect to inhibition of mouse MTH1 than the human, rat, pig, and dog MTH1 proteins are. We present the crystal structures of mouse MTH1 in complex with TH588 and dog MTH1 and elucidate the structural and sequence basis for the observed difference in affinity for TH588. We identify amino acid residue 116 in MTH1 as an important determinant of TH588 affinity. Furthermore, we present the structure of mouse MTH1 in complex with the substrate 8-oxo-dGTP. The crystal structures provide insight into the high degree of structural conservation between MTH1 proteins from different organisms and provide a detailed view of interactions between MTH1 and the inhibitor, revealing that minute structural differences can have a large impact on affinity and specificity.

  MTH1 可水解氧化的三磷酸核苷，从而使核苷酸池免受氧化损伤。这样就能防止受损核苷酸结合到 DNA 中，否则就会导致突变和细胞死亡。与非恶性细胞相比，癌细胞中的活性氧水平较高，导致癌细胞中的氧化核苷酸水平较高，从而使癌细胞更加依赖 MTH1 而存活。通过抑制 MTH1 来特异性靶向癌细胞的可能性凸显了 MTH1 是一个很有前景的癌症靶点。将 MTH1 抑制剂应用于临床需要进行动物实验，而了解抑制剂效力的物种差异至关重要。我们在此表明，人类 MTH1 抑制剂 TH588 对小鼠 MTH1 的抑制作用比人类、大鼠、猪和狗的 MTH1 蛋白低约 20 倍。我们展示了小鼠 MTH1 与 TH588 和狗 MTH1 复合物的晶体结构，并阐明了所观察到的与 TH588 亲和力差异的结构和序列基础。我们发现 MTH1 中的 116 氨基酸残基是决定 TH588 亲和力的重要因素。此外，我们还展示了小鼠 MTH1 与底物 8-oxo-dGTP 复合物的结构。晶体结构使我们深入了解了不同生物的 MTH1 蛋白之间的高度结构保守性，并提供了 MTH1 与抑制剂之间相互作用的详细视图，揭示了微小的结构差异会对亲和性和特异性产生巨大影响。