4a-Hydroxytetrahydrobiopterin | 1379003-93-6

• 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
• 英文名称: 4a-Hydroxytetrahydrobiopterin
• 英文别名: (4aS,6R)-2-amino-6-[(1R,2S)-1,2-dihydroxypropyl]-4a-hydroxy-3,5,6,7-tetrahydropteridin-4-one
• CAS: 1379003-93-6
• 化学式: C₉H₁₅N₅O₄
• 分子量: 257.25
• InChiKey: KJKIEFUPAPPGBC-XXKOCQOQSA-N

物化性质

• 物理描述：
  Solid

计算性质

• 辛醇/水分配系数(LogP)：
  -3.7
• 重原子数：
  18
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.67
• 拓扑面积：
  153
• 氢给体数：
  6
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  4a-Hydroxytetrahydrobiopterin 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 、 水
  参考文献：
  名称：

  Hauer C.R.; Rebrin I.; Thoeny B., J Biol Chem, 1993, 0021-9258, 4828-31

  摘要：

  DOI：
• 作为产物：
  描述：

  (6R)-L-erythro-5,6,7,8-tetrahydrobiopterin 、 L-苯丙氨酸 、 氧气 生成 4a-Hydroxytetrahydrobiopterin 、 L-M-酪氨酸
  参考文献：
  名称：

  Identification of Phenylalanine 3-Hydroxylase for meta-Tyrosine Biosynthesis

  摘要：

  Phenylalanine hydroxylase (PheH) is an iron (II)-dependent enzyme that catalyzes the hydroxylation of aromatic amino acid L-phenylalanine (L-Phe) to L-tyrosine (L-Tyr). The enzymatic modification has been demonstrated to be highly regiospecific, forming proteinogenic para-Tyr (p-Tyr) exclusively. Here we biochemically characterized the first example of a phenylalanine 3-hydroxylase (Phe3H) that catalyzes the synthesis of meta-Tyr (m-Tyr) from Phe. Subsequent mutagenesis studies revealed that two residues in the active site of Phe3H (Cys187 and Thr202) contribute to C-3 rather than C-4 hydroxylation of the phenyl ring. This work sets the stage for the mechanistic and structural study of regiospecific control of the substrate hydroxylation by PheH.

  DOI：

  10.1021/bi200733c

文献信息

• Divergence in enzyme regulation between <i>Caenorhabditis elegans</i> and human tyrosine hydroxylase, the key enzyme in the synthesis of dopamine
  作者：Ana C. Calvo、Angel L. Pey、Antonio Miranda-Vizuete、Anne P. Døskeland、Aurora Martinez

  DOI：10.1042/bj20101561

  日期：2011.2.15

  TH (tyrosine hydroxylase) is the rate-limiting enzyme in the synthesis of catecholamines. The cat-2 gene of the nematode Caenorhabditis elegans is expressed in mechanosensory dopaminergic neurons and has been proposed to encode a putative TH. In the present paper, we report the cloning of C. elegans full-length cat-2 cDNA and a detailed biochemical characterization of the encoded CAT-2 protein. Similar to other THs, C. elegans CAT-2 is composed of an N-terminal regulatory domain followed by a catalytic domain and a C-terminal oligomerization domain and shows high substrate specificity for L-tyrosine. Like hTH (human TH), CAT-2 is tetrameric and is phosphorylated at Ser35 (equivalent to Ser40 in hTH) by PKA (cAMP-dependent protein kinase). However, CAT-2 is devoid of characteristic regulatory mechanisms present in hTH, such as negative co-operativity for the cofactor, substrate inhibition or feedback inhibition exerted by catecholamines, end-products of the pathway. Thus TH activity in C. elegans displays a weaker regulation in comparison with the human orthologue, resembling a constitutively active enzyme. Overall, our data suggest that the intricate regulation characteristic of mammalian TH might have evolved from more simple models to adjust to the increasing complexity of the higher eukaryotes neuroendocrine systems.

  TH（酪氨酸羟化酶）是儿茶酚胺合成过程中的限速酶。线虫秀丽隐杆线虫的 cat-2 基因在机械感觉多巴胺能神经元中表达，被认为编码一种推定的 TH。在本文中，我们报告了优雅线虫全长 cat-2 cDNA 的克隆以及所编码 CAT-2 蛋白的详细生化特征。与其他 TH 类似，秀丽隐杆线虫 CAT-2 蛋白由 N 端调控结构域、催化结构域和 C 端寡聚结构域组成，对 L-酪氨酸具有高度底物特异性。与 hTH（人类 TH）一样，CAT-2 也是四聚体，并在 Ser35（相当于 hTH 中的 Ser40）处被 PKA（cAMP 依赖性蛋白激酶）磷酸化。然而，CAT-2 不具备 hTH 中特有的调节机制，如辅助因子的负协同作用、底物抑制或儿茶酚胺（该途径的最终产物）的反馈抑制。因此，与人类直向同源物相比，草履虫的 TH 活性显示出较弱的调节性，类似于一种组成型活性酶。总之，我们的数据表明，哺乳动物 TH 的复杂调控特征可能是从更简单的模型进化而来，以适应高等真核生物神经内分泌系统日益增长的复杂性。
• Crystal structure of tyrosine hydroxylase at 2.3 Å and its implications for inherited neurodegenerative diseases
  作者：Kenneth E. Goodwill、Christelle Sabatier、Cara Marks、Reetta Raag、Paul F. Fitzpatrick、Raymond C. Stevens

  DOI：10.1038/nsb0797-578

  日期：1997.7

  Tyrosine hydroxylase (TyrOH) catalyzes the conversion of tyrosine to L-DOPA, the rate-limiting step in the biosynthesis of the catecholamines dopamine, adrenaline, and noradrenaline. TyrOH is highly homologous in terms of both protein sequence and catalytic mechanism to phenylalanine hydroxylase (PheOH) and tryptophan hydroxylase (TrpOH). The crystal structure of the catalytic and tetramerization domains of TyrOH reveals a novel α-helical basket holding the catalytic iron and a 40 Å long anti-parallel coiled coil which forms the core of the tetramer. The catalytic iron is located 10 Å below the enzyme surface in a 17 Å deep active site pocket and is coordinated by the conserved residues His 331, His 336 and Glu 376. The structure provides a rationale for the effect of point mutations in TyrOH that cause L-DOPA responsive parkinsonism and Segawa's syndrome. The location of 112 different point mutations in PheOH that lead to phenylketonuria (PKU) are predicted based on the TyrOH structure.

  酪氨酸羟化酶（TyrOH）催化酪氨酸转化为L-多巴，这是儿茶酚胺多巴胺、肾上腺素和去甲肾上腺素生物合成中的限速步骤。在蛋白质序列和催化机理方面，酪氨酸羟化酶与苯丙氨酸羟化酶（PheOH）和色氨酸羟化酶（TrpOH）高度同源。酪氨酸羟化酶的催化区和四聚区晶体结构揭示了一个新的β螺旋篮，其中包含催化铁和40Å长的反平行螺旋线圈，后者构成了四聚体的核心。催化铁位于酶表面下方10Å处，在一个17Å深的活性位点口袋中，由保守残基His 331、His 336和Glu 376协调。该结构为酪氨酸羟化酶中导致L-多巴反应性帕金森症和Segawa综合征的点突变效应提供了理论依据。根据酪氨酸羟化酶的结构，预测了苯丙氨酸羟化酶中导致苯丙酮尿症（PKU）的112个不同点突变的位置。
• Influence of Steric Bulk and Electrostatics on the Hydroxylation Regiospecificity of Tryptophan Hydroxylase:  Characterization of Methyltryptophans and Azatryptophans as Substrates
  作者：Graham R. Moran、Robert S. Phillips、Paul F. Fitzpatrick

  DOI：10.1021/bi991983j

  日期：1999.12.1

  Tryptophan hydroxylase is a pterin-dependent amino acid hydroxylase that catalyzes the incorporation of one atom of molecular oxygen into tryptophan to form 5-hydroxytryptophan. The substrate specificity and hydroxylation regiospecificity of tryptophan hydroxylase have been investigated using tryptophan analogues that have methyl substituents or nitrogens incorporated into the indole ring. The products

  色氨酸羟化酶是一种依赖于蝶呤的氨基酸羟化酶，可催化一个分子氧原子并入色氨酸形成5-羟色氨酸。色氨酸羟化酶的底物特异性和羟基化区域特异性已使用具有甲基取代基或氮并入吲哚环的色氨酸类似物进行了研究。反应产物表明色氨酸羟化酶的区域特异性很严格。响应于底物拓扑结构或原子电荷的变化，羟基不会在4或6个碳原子处发生。5-羟甲基色氨酸和5-羟基-4-甲基色氨酸是5-甲基色氨酸的产物。这些产物证明羟基化中间体足以将苄基碳羟基化，并且色氨酸羟化酶中NIH的移动方向是从碳5到碳4。对氨基酸V / K值的影响表明该酶是对吲哚环位置5的变化最敏感。氨基酸羟化的V（max）值与色氨酸相比最多相差3倍，而羟四氢蝶呤消耗的羟化效率变化了6倍，这与氧部分转移至氨基酸或完全限制生产催化的速率。对氨基酸的V / K值的影响表明该酶对吲哚环第5位的变化最敏感。氨基酸羟化的V（max）值与色氨酸相比最多相差3倍，而羟四氢蝶呤消耗
• Insights into the Catalytic Mechanisms of Phenylalanine and Tryptophan Hydroxylase from Kinetic Isotope Effects on Aromatic Hydroxylation
  作者：Jorge Alex Pavon、Paul F. Fitzpatrick

  DOI：10.1021/bi0607554

  日期：2006.9.1

  shows a similar inverse isotope effect with [4-(2)H]-phenylalanine. Intramolecular isotope effects, determined from the deuterium contents of the tyrosine formed from [4-(2)H]-and [3,5(2)H(2)]-phenylalanine, are identical for Delta117PheH and Delta117PheH V379D, suggesting that steps subsequent to oxygen addition are unaffected in the mutant protein. The inverse effects are consistent with the reaction

  苯丙氨酸羟化酶（PheH）和色氨酸羟化酶（TrpH）催化苯丙氨酸和色氨酸的芳香族羟基化反应，分别形成酪氨酸和5-羟色氨酸。已经用[4-（2）H]-，[3,5-（2）H（2）]-和（2）H（5）-苯丙氨酸作为底物研究了PheH和TrpH的反应。所有（D）k（cat）值在Delta117PheH（大鼠苯丙氨酸羟化酶的催化核心）中都正常，范围为1.12-1.41。相反，对于Delta117PheH V379D，一种突变蛋白，其中改变了四氢蝶呤氧化和氨基酸羟基化之间的化学计量关系，[4-（2）H]-苯丙氨酸的（D）k（cat）值为0.92，但与[3，5-（2）H（2）]-苯丙氨酸。Delta117PheH V379D的四氢蝶呤氧化与氨基酸羟化的比率显示出与[4-（2）H]-苯丙氨酸类似的逆同位素效应。由[4-（2）H]-和[3,5（2）H（2）]-苯丙氨酸形成的酪氨酸的氘含量确定的分子内同位素效应
• High resolution crystal structures of the catalytic domain of human phenylalanine hydroxylase in its catalytically active Fe(II) form and binary complex with tetrahydrobiopterin
  作者：Ole Andreas Andersen、Torgeir Flatmark、Edward Hough

  DOI：10.1006/jmbi.2001.5061

  日期：2001.11

  catalytic iron with a C4a-iron distance of 5.9 A. BH4 binds at the same site as L-erythro-7,8-dihydrobiopterin (BH2) in the binary hPheOH-Fe(III)-BH2 complex forming an aromatic pi-stacking interaction with Phe254 and a network of hydrogen bonds. However, compared to that structure the pterin ring is displaced about 0.5 A and rotated about 10 degrees, and the torsion angle between the hydroxyl groups of the

  人苯丙氨酸羟化酶（hPheOH）的催化结构铁（II）和具有还原的蝶呤辅因子6（R）-L-erythro-5的二元配合物的催化结构域（DeltaN1-102 / DeltaC428-452）的晶体结构已确定1,6,7,8-四氢生物蝶呤（BH4）分别为1.7和1.5A。当与报道的各种催化惰性Fe（III）形式的结构进行比较时，已观察到一些重要的差异，特别是在活性位点。因此，非配体的hPheOH-Fe（II）结构仅显示出三个水分子之一的良好定义的电子密度，据报道，这三个水分子以高自旋Fe（III）形式与铁配位，并且电子密度较差用于Glu330的配位侧链部分。减少的辅因子（ ），它采用了预期的半半椅子构型，以5.9 A的C4a-铁距离结合在催化铁的第二个配位域中。 与二元hPheOH-Fe（III）-中的L-赤型-7,8-二氢生物蝶呤（BH2）结合在同一位点 络合物与Phe254和氢键