[1'-(14)C]PRPP | 67024-61-7

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: [1'-(14)C]PRPP
• CAS: 67024-61-7
• 化学式: C₅H₁₃O₁₄P₃
• 分子量: 392.06
• InChiKey: PQGCEDQWHSBAJP-NGECMOOWSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -2.23
• 重原子数：
  22.0
• 可旋转键数：
  7.0
• 环数：
  1.0
• sp3杂化的碳原子比例：
  1.0
• 拓扑面积：
  229.74
• 氢给体数：
  7.0
• 氢受体数：
  9.0

反应信息

• 作为反应物：
  描述：

  [1'-(14)C]PRPP 、 腺嘌呤 在 adenine phosphoribosyltransferase 作用下， 生成 [1'-(14)C]AMP
  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
• 作为产物：
  描述：

  O⁵-phosphono-D-[1-¹⁴C]ribose 在 5’-三磷酸腺苷 作用下， 生成 [1'-(14)C]PRPP
  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 sturcture of 5'-methylthioadenosine/s-adenosylhomocysteine nucleosidases
  申请人：Schramm Vern L.

  公开号：US20110086812A1

  公开（公告）日：2011-04-14

  Provided are methods of designing a putative inhibitor of a 5′-methylthioadenosine/S-adenosylhomocysteine nucleosidase. The methods comprise designing a chemically stable compound that resembles the charge and geometry of the 5′-methylthioadenosine/S-adenosylhomocysteine nucleosidase transition state. Also provided are methods of inhibiting 5′-methylthioadenosine/S-adenosylhomocysteine nucleosidases using the inhibitors found by the above methods.

  提供了一种设计假想抑制剂5'-甲基硫腺苷/ S-腺苷基高同型半胱氨酸核苷酸酶的方法。该方法包括设计一种化学稳定的化合物，其类似于5'-甲基硫腺苷/ S-腺苷基高同型半胱氨酸核苷酸酶过渡态的电荷和几何形状。此外，还提供了使用上述方法发现的抑制剂抑制5'-甲基硫腺苷/ S-腺苷基高同型半胱氨酸核苷酸酶的方法。