((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl-5-t)methyl tetrahydrogen triphosphate | 865805-53-4

• 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: ((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl-5-t)methyl tetrahydrogen triphosphate
• 英文别名: [1'-³H]ATP
• CAS: 865805-53-4
• 化学式: C₁₀H₁₆N₅O₁₃P₃
• 分子量: 509.176
• InChiKey: ZKHQWZAMYRWXGA-RTYITZGISA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -1.63
• 重原子数：
  31.0
• 可旋转键数：
  8.0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  279.13
• 氢给体数：
  7.0
• 氢受体数：
  14.0

反应信息

• 作为反应物：
  描述：

  ((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl-5-t)methyl tetrahydrogen triphosphate 在 class II ribonucleotidetriphosphate reductase 、 adenosylcobalamine 、 2'-脱氧鸟苷 5'-(四氢三磷酸酯) 、 calcium chloride 、 1,4-二巯基-2,3-丁二醇 作用下， 反应 2.0h， 生成
  参考文献：
  名称：

  人胸苷磷酸化酶对胸苷水解的过渡态分析

  摘要：

  人胸苷磷酸化酶 (hTP) 负责胸苷 (dT) 稳态，其作用促进血管生成。在没有磷酸盐的情况下，hTP 催化 dT 的缓慢水解脱嘧啶，产生胸腺嘧啶和 2-脱氧核糖 (dRib)。其过渡态使用多重动力学同位素效应 (KIE) 测量进行表征。富含同位素的胸苷由葡萄糖或（脱氧）核糖酶促合成，内在 KIE 用于解释过渡态结构。来自 [1'-(14)C]-、[1-(15)N]-、[1'-(3)H]-、[2'R-(3)H]-、[2'S-( 3)H]-、[4'-(3)H]- 和 [5'-(3)H]dTs 提供的值为 1.033 ± 0.002、1.004 ± 0.002、1.325 ± 0.003、1.101 ± 0.004、± 1.085 、 1.040 ± 0.003 和 1.033 ± 0.003。过渡态分析揭示了一种逐步机制，即早期形成的 2-脱氧核糖化以及水分子对高能中间体的亲核攻击的更高能量

  DOI：

  10.1021/ja105041j
• 作为产物：
  描述：

  在 adenylate kinase 、 pyruvate kinase 、 磷烯醇丙酮酸 作用下， 生成 ((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl-5-t)methyl tetrahydrogen triphosphate
  参考文献：
  名称：

  Transition-State Variation in Human, Bovine, and Plasmodium falciparum Adenosine Deaminases

  摘要：

  Adenosine deaminases (ADAs) from human, bovine, and Plasmodium falciparum sources were analyzed by kinetic isotope effects (KIEs) and shown to have distinct but related transition states. Human adenosine deaminase (HsADA) is present in most mammalian cells and is involved in B- and T-cell development. The ADA from Plasmodium falciparum (PfADA) is essential in this purine auxotroph, and its inhibition is expected to have therapeutic effects for malaria. Therefore, ADA is of continuing interest for inhibitor design. Stable structural mimics of ADA transition states are powerful inhibitors. Here we report the transition-state structures of PfADA, HsADA, and bovine ADA (BtADA) solved using competitive kinetic isotope effects (KIE) and density functional calculations. Adenines labeled at [6-C-13], [6-N-15], [6-C-13, 6-N-15], and [1-N-15] were synthesized and enzymatically coupled with [1'-C-14] ribose to give isotopically labeled adenosines as ADA substrates for KIE analysis. [6-C-13], [6-N-15], and [1-N-15]adenosines reported intrinsic KIE values of (1.010, 1.011, 1.009), (1.005, 1.005, 1.002), and (1.004, 1.001, 0.995) for PfADA, HsADA, and BtADA, respectively. The differences in intrinsic KIEs reflect structural alterations in the transition states. The [1-N-15] KIEs and computational modeling results indicate that PfADA, HsADA, and BtADA adopt early SNAr transition states, where N1 protonation is partial and the bond order to the attacking hydroxyl nucleophile is nearly complete. The key structural variation among PfADA, HsADA, and BtADA transition states lies in the degree of N1 protonation with the decreased bond lengths of 1.92, 1.55, and 1.28 angstrom, respectively. Thus, PfADA has the earliest and BtADA has the most developed transition state. This conclusion is consistent with the 20-36-fold increase of k(cat) in comparing PfADA with HsADA and BtADA.

  DOI：

  10.1021/ja072122y

文献信息

• Transition State Structure of <i>E. coli t</i>RNA-Specific Adenosine Deaminase
  作者：Minkui Luo、Vern L. Schramm

  DOI：10.1021/ja078008x

  日期：2008.2.1

  rotation occur on the path to the transition state. The late SNAr transition-state established here for E. coli TadA is similar to the late transition state reported for cytidine deaminase. It differs from the early SNAr transition states described recently for the adenosine deaminases from human, bovine, and Plasmodium falciparum sources. The ecTadA transition state structure reveals the detailed architecture

  细菌 tRNA 特异性腺苷脱氨酶 (TadA) 在 tRNA 的摆动位置催化腺苷基本脱氨为肌苷，并且是允许单个 tRNA 物种识别多个密码子所必需的。大肠杆菌 TadA 的过渡态结构通过动力学同位素效应 (KIE) 和量子化学计算进行表征。大肠杆菌 tRNA(Arg2) 的茎环用作最小化的 TadA 底物，其腺苷酸编辑位点同位素标记为 [1'-(3)H]、[5'-(3)H2]、[1 '-(14)C], [6-(13)C], [6-(15)N], [6-(13)C, 6-(15)N] 和 [1-(15)N] . [6-(13)C]-, [6-(15)N]-, [1-(15)N]-, [1'- 的本征 KIE 分别为 1.014、1.022、0.994、1.014 和 0.963 (3)H]-、[5'-(3)H2]-分别标记的底物。KIE 套件与具有完整的亲 S 面羟基攻击和几乎完整的 N1 质子化的晚期
• The Transition-State Structure for Human MAT2A from Isotope Effects
  作者：Ross S. Firestone、Vern L. Schramm

  DOI：10.1021/jacs.7b05803

  日期：2017.10.4

  inhibitors. We used kinetic isotope effect (KIE), commitment factor (Cf), and binding isotope effect (BIE) measurements combined with quantum mechanical (QM) calculations to solve the transition state structure of human MAT2A. The reaction is characterized by an advanced SN2 transition state. The bond forming from the nucleophilic methionine sulfur to the 5′-C of ATP is 2.03 Å at the transition state (bond

  人甲硫氨酸S-腺苷基转移酶（MAT2A）催化由ATP和甲硫氨酸形成S-腺苷甲硫氨酸（SAM）。合成致死遗传分析已将MAT2A作为缺乏5'-甲基硫代腺苷磷酸化酶（MTAP）表达的肿瘤细胞的抗癌靶标。大约15％的人类癌症是MTAP – / –。其余的可以呈现MTAP -通过MTAP抑制剂。我们将动力学同位素效应（KIE），承诺因子（C f）和结合同位素效应（BIE）测量与量子力学（QM）计算结合使用，以解决人类MAT2A的过渡态结构。该反应的特征在于先进的S N2过渡状态。从亲核蛋氨酸硫到ATP的5'-C形成的键在过渡态（键序为0.67）为2.03Å。ATP的离去基团三磷酸的离解进展顺利，并在ATP的5'-C与三磷酸的氧之间形成2.32Å键（键序为0.23）。MAT2A及其MAT2B调节亚基的相互作用不会导致内在KIE发生变化，表明相同的过渡态结构。与来自大肠杆菌的蛋氨酸腺苷基转移酶的近对称过