N-(3-Hydroxy-L-tyrosyl)-L-tyrosine dihydrate | 37181-70-7

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: N-(3-Hydroxy-L-tyrosyl)-L-tyrosine dihydrate
• 英文别名: (2S)-2-[[(2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoyl]amino]-3-(4-hydroxyphenyl)propanoic acid
• CAS: 37181-70-7
• 化学式: C₁₈H₂₀N₂O₆
• 分子量: 360.367
• InChiKey: QPLWMBAYFYUFLE-KBPBESRZSA-N

物化性质

• 沸点：
  751.4±60.0 °C(Predicted)
• 密度：
  1.445±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  -2.2
• 重原子数：
  26
• 可旋转键数：
  7
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.22
• 拓扑面积：
  153
• 氢给体数：
  6
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  N-(3-Hydroxy-L-tyrosyl)-L-tyrosine dihydrate 以 甲苯 、 正丁醇 为溶剂， 反应 2.0h， 生成 (3S,6S)-3-(3,4-dihydroxybenzyl)-6-(4-hydroxybenzyl)piperazine-2,5-dione
  参考文献：
  名称：

  Substrate and Reaction Specificity of Mycobacterium tuberculosis Cytochrome P450 CYP121

  摘要：

  Cytochrome P450 CYP121 is essential for the viability of Mycobacterium tuberculosis. Studies in vitro show that it can use the cyclodipeptide cyclo(L-Tyr-L-Tyr) (cYY) as a substrate. We report an investigation of the substrate and reaction specificities of CYP121 involving analysis of the interaction between CYP121 and 14cYY analogues with various modifications of the side chains or the diketopiperazine (DKP) ring. Spectral titration experiments show that CYP121 significantly bound only cyclodipeptides with a conserved DKP ring carrying two aryl side chains in L-configuration. CYP121 did not efficiently or selectively transform any of the cYY analogues tested, indicating a high specificity for cYY. The molecular determinants of this specificity were inferred from both crystal structures of CYP121-analog complexes solved at high resolution and solution NMR spectroscopy of the analogues. Bound cYY or its analogues all displayed a similar set of contacts with CYP121 residues Asn(85), Phe(168), and Trp(182). The propensity of the cYY tyrosyl to point toward Arg(386) was dependent on the presence of the DKP ring that limits the conformational freedom of the ligand. The correct positioning of the hydroxyl of this tyrosyl was essential for conversion of cYY. Thus, the specificity of CYP121 results from both a restricted binding specificity and a fine-tuned P450 substrate relationship. These results document the catalytic mechanism of CYP121 and improve our understanding of its function in vivo. This work contributes to progress toward the design of inhibitors of this essential protein of M. tuberculosis that could be used for antituberculosis therapy.

  DOI：

  10.1074/jbc.m112.443853
• 作为产物：
  描述：

  在 N,N-二甲基甲酰胺 作用下， 以 二氯甲烷 为溶剂， 反应 2.0h， 生成 N-(3-Hydroxy-L-tyrosyl)-L-tyrosine dihydrate
  参考文献：
  名称：

  Substrate and Reaction Specificity of Mycobacterium tuberculosis Cytochrome P450 CYP121

  摘要：

  Cytochrome P450 CYP121 is essential for the viability of Mycobacterium tuberculosis. Studies in vitro show that it can use the cyclodipeptide cyclo(L-Tyr-L-Tyr) (cYY) as a substrate. We report an investigation of the substrate and reaction specificities of CYP121 involving analysis of the interaction between CYP121 and 14cYY analogues with various modifications of the side chains or the diketopiperazine (DKP) ring. Spectral titration experiments show that CYP121 significantly bound only cyclodipeptides with a conserved DKP ring carrying two aryl side chains in L-configuration. CYP121 did not efficiently or selectively transform any of the cYY analogues tested, indicating a high specificity for cYY. The molecular determinants of this specificity were inferred from both crystal structures of CYP121-analog complexes solved at high resolution and solution NMR spectroscopy of the analogues. Bound cYY or its analogues all displayed a similar set of contacts with CYP121 residues Asn(85), Phe(168), and Trp(182). The propensity of the cYY tyrosyl to point toward Arg(386) was dependent on the presence of the DKP ring that limits the conformational freedom of the ligand. The correct positioning of the hydroxyl of this tyrosyl was essential for conversion of cYY. Thus, the specificity of CYP121 results from both a restricted binding specificity and a fine-tuned P450 substrate relationship. These results document the catalytic mechanism of CYP121 and improve our understanding of its function in vivo. This work contributes to progress toward the design of inhibitors of this essential protein of M. tuberculosis that could be used for antituberculosis therapy.

  DOI：

  10.1074/jbc.m112.443853

文献信息

• [EN] LIQUID COMPOSITIONS COMPRISING A LEVODOPA AMINO ACID CONJUGATE AND USES THEREOF<br/>[FR] COMPOSITIONS LIQUIDES COMPRENANT UN CONJUGUÉ D'ACIDES AMINÉS DE LÉVODOPA ET LEURS UTILISATIONS
  申请人：NEURODERM LTD

  公开号：WO2021044420A1

  公开（公告）日：2021-03-11

  Disclosed herein are liquid pharmaceutical formulations comprising levodopa amino acid conjugates that may further comprise a decarboxylase inhibitor, such as carbidopa, an antioxidant, a solvent, or any other pharmaceutically acceptable excipient. Further disclosed are methods of treating generative conditions and/or conditions characterized by reduced levels of dopamine in the brain, such as Parkinson's disease, comprising administering the disclosed liquid pharmaceutical formulations. Disclosed also are LDAA conjugate compounds.

  本文披露了包含左多巴氨基酸共轭物的液体药物配方，该共轭物可能进一步包含一个脱羧酶抑制剂，如卡比多巴，一种抗氧化剂，一种溶剂或任何其他药学上可接受的辅料。进一步披露了治疗神经退行性疾病和/或大脑中多巴胺水平降低的疾病的方法，例如帕金森病，包括给予披露的液体药物配方。还披露了LDAA共轭物化合物。
• [EN] LEVODOPA-PRODRUGS AND CARBIDOPA-PRODRUGS FOR USE IN THE TREATMENT OF PARKINSON'S DISEASE<br/>[FR] PROMÉDICAMENTS LEVODOPA ET PROMÉDICAMENTS CARBIDOPA POUR LE TRAITEMENT DE LA MALADIE DE PARKINSON
  申请人：MITSUBISHI TANABE PHARMA CORP

  公开号：WO2022191338A1

  公开（公告）日：2022-09-15

  An object of the present invention is to provide a combination medicament useful for treatment of Parkinson's disease. The present invention provides a prophylactic or therapeutic agent for Parkinson's disease, the agent containing a combination medicament containing a levodopa prodrug and a carbidopa prodrug.

  本发明的目的是提供一种组合药物，用于治疗帕金森病。本发明提供了一种预防或治疗帕金森病的药物，该药物含有一种组合药物，其中包含一种左旋多巴前药和一种卡比多巴前药。
• Substrate and Reaction Specificity of Mycobacterium tuberculosis Cytochrome P450 CYP121
  作者：Matthieu Fonvielle、Marie-Hélène Le Du、Olivier Lequin、Alain Lecoq、Mickaël Jacquet、Robert Thai、Steven Dubois、Guillaume Grach、Muriel Gondry、Pascal Belin

  DOI：10.1074/jbc.m112.443853

  日期：2013.6

  Cytochrome P450 CYP121 is essential for the viability of Mycobacterium tuberculosis. Studies in vitro show that it can use the cyclodipeptide cyclo(L-Tyr-L-Tyr) (cYY) as a substrate. We report an investigation of the substrate and reaction specificities of CYP121 involving analysis of the interaction between CYP121 and 14cYY analogues with various modifications of the side chains or the diketopiperazine (DKP) ring. Spectral titration experiments show that CYP121 significantly bound only cyclodipeptides with a conserved DKP ring carrying two aryl side chains in L-configuration. CYP121 did not efficiently or selectively transform any of the cYY analogues tested, indicating a high specificity for cYY. The molecular determinants of this specificity were inferred from both crystal structures of CYP121-analog complexes solved at high resolution and solution NMR spectroscopy of the analogues. Bound cYY or its analogues all displayed a similar set of contacts with CYP121 residues Asn(85), Phe(168), and Trp(182). The propensity of the cYY tyrosyl to point toward Arg(386) was dependent on the presence of the DKP ring that limits the conformational freedom of the ligand. The correct positioning of the hydroxyl of this tyrosyl was essential for conversion of cYY. Thus, the specificity of CYP121 results from both a restricted binding specificity and a fine-tuned P450 substrate relationship. These results document the catalytic mechanism of CYP121 and improve our understanding of its function in vivo. This work contributes to progress toward the design of inhibitors of this essential protein of M. tuberculosis that could be used for antituberculosis therapy.