(6R)-2-氨基-6-[(1R,2S)-1,2-二羟基丙基]-6,7-二氢-1H-蝶啶-4-酮 | 79647-29-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 蝶啶及其衍生物
• 中文名称: (6R)-2-氨基-6-[(1R,2S)-1,2-二羟基丙基]-6,7-二氢-1H-蝶啶-4-酮
• 英文名称: 6R(1'R,2'S)2'-dihydroxypropyl-7,8-dihydro(6H)-pterin
• 英文别名: 4a-Carbinolamine tetrahydrobiopterin；(6R)-2-amino-6-[(1R,2S)-1,2-dihydroxypropyl]-6,7-dihydro-3H-pteridin-4-one
• CAS: 79647-29-3
• 化学式: C₉H₁₃N₅O₃
• 分子量: 239.234
• InChiKey: ZHQJVZLJDXWFFX-RPDRRWSUSA-N

物化性质

• 物理描述：
  Solid
• 熔点：
  218-221°C

计算性质

• 辛醇/水分配系数(LogP)：
  -2.6
• 重原子数：
  17
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.56
• 拓扑面积：
  133
• 氢给体数：
  4
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (6R)-2-氨基-6-[(1R,2S)-1,2-二羟基丙基]-6,7-二氢-1H-蝶啶-4-酮 在 氧气 、 dihydropteridine reductase from Escherichia coli Bl-21 、 还原型辅酶Ⅰ 作用下， 以 aq. buffer 为溶剂， 反应 61.0h， 生成 7,8-二氢生物蝶呤
  参考文献：
  名称：

  还原酶催化的四氢生物蝶呤再生减轻了7,8-二氢生物蝶呤对酪氨酸羟基化的反竞争抑制作用

  摘要：

  酪氨酸羟化酶使L-酪氨酸羟化是制备许多保健食品和药物的重要反应。在细菌中构建这些途径的两个主要挑战是羟化酶催化效率的提高和辅因子四氢生物蝶呤（BH4）的产生。在这项研究中，我们通过PhyML和MAFFT分析了不同物种的酪氨酸羟化酶之间的进化关系和保守的蛋白质序列。最后，我们选择了7个酪氨酸羟化酶和6个sepaapterin还原酶。随后，通过组合的全细胞催化剂鉴定了不同基团的功能，并筛选了一系列新型的酪氨酸羟化酶/ septapterin还原酶（TH / SPR）合成系统，其中包括酪氨酸羟化酶（来自于Streptosporangium roseum）DSM 43021和Thermomonospora curvata DSM 43183）和sepiapterin还原酶（从发光菌damselae，Chlorobaculum thiosulfatiphilum和致病杆菌属poinarii），即作为SrTH

  DOI：

  10.1039/d0cy01958e
• 作为产物：
  描述：

  在 三羟甲基氨基甲烷盐酸盐 作用下， 生成 (6R)-2-氨基-6-[(1R,2S)-1,2-二羟基丙基]-6,7-二氢-1H-蝶啶-4-酮
  参考文献：
  名称：

  Synthesis of 4a-Hydroxytetrahydropterins and the Mechanism of Their Nonenzymic Dehydration to Quinoid Dihydropterins

  摘要：

  4a-Hydroxytetrahydropterins 2 (R = Me, Pr, and 1'(R),2'(S)-dihydroxypropyl) were synthesized by intramolecular Schiff base condensation of 2'-substituted 2-amino-6-[(aminoethyl)amino]-4,5-pyrimidinediones 6. The rate vs pH of cyclization of 6 (which is predominately monohydrated) follows a bell-shaped curve with maxima at pH 9.8 in H2O (consistent with pK values of 8.8 and 10.8) and pH 9.1 in MeOH. Although almost insignificant in organic solvents, substantial 7-substituted dihydropterin was generated in water, particularly with 6 (R = dihydroxypropyl). The minimum rate of dehydration of carbinolamine 2 (R = Me or Pr) in ''zero'' buffer (0.0035 s(-1) at 17 degrees C) occurs at pH 8.25, and is catalyzed by proton (1.3 x 10(5) M(-1) s(-1)) and general acids. Between pH 8.4 and pH 7.4 Delta H* decreases from 15 to 12 kcal/mol, while Delta S* decreases from -18 to -26 eu for 2 (R = Me or Pr), consistent with concerted proton transfer in the dehydration transition state. Surprisingly, the rate also increases in more alkaline conditions up to 12-fold (in zero buffer), coincident with formation of a pteridine anion (pK = 9.8). Below pH 11.5 catalysis by buffer base was also observed. A solvent kinetic isotope effect (k(H2O)/k(D2O)) of 2.6, 2.2, and 3.5 was found in dilute buffers at pH 7.4, 8.2, and 10.9, respectively. The overall rate of disappearance of 2 (R = dihydroxypropyl) is similar to that of the alkyl analogs, but a second pathway competes with dehydration to produce a compound tentatively identified as a side-chain 4a-cyclic adduct, which subsequently decays to quinoid 6(R)-dihydrobiopterin. These synthetic substrates have permitted the first kinetic characterization of 4a-hydroxytetrahydropterin dehydratase (Rebrin, I.; et al. Biochemistry 1995, 34, 5801-5810), the enzyme involved in cofactor regeneration during aromatic amino acid hydroxylation.

  DOI：

  10.1021/ja00146a005

文献信息

• Dihydropteridine Reductase from Bovine Liver
  作者：Hiroyuki HASEGAWA

  DOI：10.1093/oxfordjournals.jbchem.a131432

  日期：1977.1

  mole of the reductase. The occurrence of the reductase-NADH complex in bovine liver extract as a predominant form was in accord with the pyridine nucleotide specificity for NADH as a coenzyme. The results further support the view that NADH is the natural coenzyme of this reductase.

  从牛肝中纯化二氢蝶呤还原酶[EC 1.6.99.7]，产率为50％，并结晶。纯化的酶的理化性质与绵羊肝二氢蝶呤还原酶的理化性质非常相似。然而，在纯化过程中，通过在CM-Sephadex上进行柱色谱分析，发现该酶被分为2个主要峰和次要峰，其中一个主要峰被鉴定为该酶与NADH的二元复合物。还在体外制备了还原酶-NADH复合物并使其结晶。在将醌类-二氢蝶呤添加到复合物中后，NADH被氧化并从酶中释放。结合的NADH的量经计算为每摩尔还原酶2摩尔。还原酶-NADH的发生经计算为每摩尔还原酶2摩尔。牛肝提取物中以主要形式存在的还原酶-NADH复合物与作为辅酶的NADH的吡啶核苷酸特异性一致。结果进一步支持以下观点：NADH是该还原酶的天然辅酶。
• A New Enzyme, NADPH-Dihydropteridine Reductase in Bovine Liver
  作者：Nobuo NAKANISHI、Hiroyuki HASEGAWA、Shoji WATABE

  DOI：10.1093/oxfordjournals.jbchem.a131504

  日期：1977.3

  An enzyme designated as NADPH-dihydropteridine reductase was found in the extract of bovine liver and partially purified. In contrast to NADH-dependent dihydropteridine reductase [EC 1.6.99.7], the enzyme catalyzes the reduction of quinonoid-dihydropterin to tetrahydropterin the presence of NADPH. The two enzymes were separated by column chromatography on DEAE-Sephadex. Tyrosine formation in the phenylalanine hydroxylation system was also stimulated by NADPH-dihydropteridine reductase. The existence of these two dihydropteridine reductases suggests that the tetrahydro form of pteridine cofactor may be regenerated in two different ways in vivo.

  在牛肝提取物中发现了NADPH-二氢蝶啶还原酶，并对其进行了部分纯化。与NADH依赖性二氢蝶啶还原酶（EC 1.6.99.7）不同，该酶在NADPH存在的情况下催化醌二氢蝶啶还原为四氢蝶啶。通过DEAE-Sephadex柱层析法将这两种酶分离。苯丙氨酸羟化系统中的酪氨酸形成也受到NADPH-二氢蝶啶还原酶的刺激。这两种二氢蝶啶还原酶的存在表明，蝶啶辅因子的四氢形式可以在体内以两种不同的方式再生。
• Identification of the gene encoding alkylglycerol monooxygenase defines a third class of tetrahydrobiopterin-dependent enzymes
  作者：Katrin Watschinger、Markus A. Keller、Georg Golderer、Martin Hermann、Manuel Maglione、Bettina Sarg、Herbert H. Lindner、Albin Hermetter、Gabriele Werner-Felmayer、Robert Konrat、Nicolas Hulo、Ernst R. Werner

  DOI：10.1073/pnas.1002404107

  日期：2010.8.3

  Alkylglycerol monooxygenase (glyceryl-ether monooxygenase, EC 1.14.16.5) is the only enzyme known to cleave the O-alkyl bond of ether lipids which are essential components of brain membranes, protect the eye from cataract, interfere or mediate signalling processes, and are required for spermatogenesis. Along with phenylalanine hydroxylase, tyrosine hydroxylase, tryptophan hydroxylase, and nitric oxide

  烷基甘油单加氧酶（甘油醚单加氧酶，EC 1.14.16.5）是唯一一种已知能裂解醚脂质的 O-烷基键的酶，醚脂质是脑膜的重要组成部分，保护眼睛免受白内障，干扰或介导信号传递过程，并且精子发生所必需的。与苯丙氨酸羟化酶、酪氨酸羟化酶、色氨酸羟化酶和一氧化氮合酶一起，烷基甘油单加氧酶是依赖于四氢生物蝶呤的五种已知酶促反应之一。尽管首次描述于 1964 年，但由于它在蛋白质纯化尝试中失去活性，因此到目前为止还没有为该酶指定序列。使用转染到 CHO 细胞的大鼠肝脏表达文库的质粒库进行功能文库筛选也不成功。因此，我们通过生物信息学方法和部分纯化酶的蛋白质组学分析选择了人类候选基因，并测试了用表达质粒转染的 CHO 细胞中的烷基甘油单加氧酶活性。跨膜蛋白 195 是一种预测的膜蛋白，具有未指定的功能，发生在双侧动物中，被发现编码依赖于四氢生物蝶呤的烷基甘油单加氧酶。这种序列分配通过将跨膜蛋白 195 cRNA
• Glyceryl-ether monooxygenase [EC 1.14.16.5]. A microsomal enzyme of ether lipid metabolism
  作者：Hiroyasu Taguchi、Wilfred L. F. Armarego

  DOI：10.1002/(sici)1098-1128(199801)18:1<43::aid-med3>3.0.co;2-s

  日期：1998.1

  glyceryl ethers, as well as their chemical syntheses, biosynthesis, and their chemical and physical properties are briefly reviewed as background information for appreciating the importance of the enzyme glyceryl-ether monooxygenase, and for embarking on new studies of this enzyme. The occurrence, isolation and general properties of the microsomal, membrane-bound, glyceryl-ether monooxygenase from rat

  简要回顾了甘油醚的历史，生物学和医学方面，以及它们的化学合成，生物合成及其化学和物理性质，以此作为背景信息，以了解甘油醚单加氧酶的重要性，并着手进行新的研究。这种酶的研究。描述了来自大鼠肝脏的微粒体，膜结合的甘油醚单加氧酶的发生，分离和一般性质。详细介绍了该酶的放射，非放射，耦合和直接分光光度法。描述了去污剂对该酶动力学的影响以及化学计量和抑制剂的作用。蝶呤辅因子和醚脂质底物的构效关系，包括其立体特异性，从酶动力学数据中总结了这些数据，也将这些数据制成表格。由这些表观动力学数据提出了甘油醚的酶促羟基化的机理和甘油醚单加氧酶活性位点的模型。已经对这种单加氧酶的有用的未来研究作了记录。
• Autoxidation Kinetics of Tetrahydrobiopterin—Giving Quinonoid Dihydrobiopterin the Consideration It Deserves
  作者：Ayoub Boulghobra、Myriam Bonose、Eskandar Alhajji、Antoine Pallandre、Emmanuel Flamand-Roze、Bruno Baudin、Marie-Claude Menet、Fathi Moussa

  DOI：10.3390/molecules28031267

  日期：——

  an efficient HPLC-MS/MS method to achieve the separation of qH2Bip from H4Bip and other oxidation products in less than 3.5 min. The application of this method to the investigation of H4Bip autoxidation kinetics clearly shows that qH2Bip's half-life is much longer than previously reported, and mostly longer than that of H4Bip, irrespective of the considered experimental conditions. These findings definitely

  在人类中，四氢生物蝶呤 (H4Bip) 是几种重要羟基化反应的辅助因子，其功能障碍会在任何年龄段导致非常严重的疾病。因此，生物介质中蝶呤的测定对于 H4Bip 缺陷的诊断和监测至关重要。在发现 H4Bip 的生理作用以及最近出现与 H4Bip 缺乏相关的多巴胺和血清素紊乱的基因治疗半个多世纪后，醌类二氢生物蝶呤 (qH2Bip)（H4Bip 的瞬时中间体）的定量尚未被考虑然而。这主要是由于其半衰期较短，根据之前的研究，半衰期为 0.9 至 5 分钟。基于我们最近披露的 qH2Bip 的特定 MS/MS 转变，我们开发了一种高效的 HPLC-MS/MS 方法，可在 3.5 分钟内实现 qH2Bip 与 H4Bip 和其他氧化产物的分离。该方法在 H4Bip 自氧化动力学研究中的应用清楚地表明，无论考虑的实验条件如何，qH2Bip 的半衰期比以前报道的要长得多，并且大多比 H4Bip 长。这些发现明确证实