prostaglandin E2(1-) | 960003-10-5

• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 脂肪酰基
• 英文名称: prostaglandin E2(1-)
• 英文别名: (Z)-7-[(1R,2R,3R)-3-hydroxy-2-[(E,3S)-3-hydroxyoct-1-enyl]-5-oxocyclopentyl]hept-5-enoate
• CAS: 960003-10-5
• 化学式: C20H31O5-
• 分子量: 351.5
• InChiKey: XEYBRNLFEZDVAW-ARSRFYASSA-M

计算性质

• 辛醇/水分配系数(LogP)：
  3.5
• 重原子数：
  25
• 可旋转键数：
  11
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.7
• 拓扑面积：
  97.7
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  prostaglandin E2(1-) 生成 水 、 (5Z,13E,15S)-15-hydroxy-9-oxoprosta-5,10,13-trien-1-oate
  参考文献：
  名称：

  Polet H.; Levine L., J Biol Chem, 1975, 0021-9258, 351-7

  摘要：

  DOI：
• 作为产物：
  描述：

  prostaglandin H2(1-) 生成 prostaglandin E2(1-)
  参考文献：
  名称：

  Identification of human prostaglandin E synthase: A microsomal, glutathione-dependent, inducible enzyme, constituting a potential novel drug target

  摘要：

  人类前列腺素（PG）E合成酶（EC 5.3.99.3）是一种膜相关蛋白超家族的成员，该超家族包括参与环氧化物和谷胱甘肽代谢的膜相关蛋白（MAPEG家族）。该蛋白的先前名称为PIG12和MGST1-L1。PGE合成酶在大肠杆菌中表达，并制备了细胞质和膜分离物。Western blot分析特异性地检测到膜分离物中的15-至16-kDa蛋白质。在还原型谷胱甘肽的存在下，两个分离物均与前列腺素H2一起孵育或不孵育。发现膜分离物而不是细胞质分离物具有高谷胱甘肽依赖性PGE合成酶活性（0.25μmol/min/mg）。通过Northern blot分析分析了人类组织分布。在A549和HeLa癌细胞系中检测到高水平的PGE合成酶mRNA表达。在胎盘、前列腺、睾丸、乳腺和膀胱中表现出中等水平的表达，而在其他几种组织中观察到低水平的mRNA表达。 A549细胞已被用作研究IL-1β诱导环氧合酶-2的模型系统。如果A549细胞在IL-1β的存在下生长，则通过Western blot分析观察到PGE合成酶的显着诱导。此外，Western blot分析特异性地检测到羊精囊中的16-kDa蛋白质。总之，我们已经确定了一种人类膜结合的PGE合成酶。酶活性依赖于谷胱甘肽，并且蛋白质表达受到促炎细胞因子IL-1β的诱导。 PGE合成酶是药物开发的潜在新靶点。

  DOI：

  10.1073/pnas.96.13.7220

文献信息

• Identification of Dual Cyclooxygenase–Eicosanoid Oxidoreductase Inhibitors: NSAIDs That Inhibit PG-LX Reductase/LTB4 Dehydrogenase
  作者：Clary B. Clish、Yee-Ping Sun、Charles N. Serhan

  DOI：10.1006/bbrc.2001.5841

  日期：2001.11

  (2) by 70 and 95%, respectively. Also, a COX-2 inhibitor, niflumic acid, inhibited the PG-LXR/LTB(4)DH eicosanoid oxidoreductase (EOR) by 80% while other COX-2 inhibitors such as nimesulide and NS-398 did not inhibit this enzyme. These results indicate that certain clinically useful NSAIDs such as diclofenac and indomethacin, in addition to inhibiting cyclooxygenases (1 and 2), also interfere with

  类花生酸在许多生理和疾病过程中起着关键作用，非甾体类抗炎药（NSAIDs）对它们的调节对于许多治疗方法至关重要。这些autacoids被特定的酶快速灭活，例如15-hydroxyprostaglandin脱氢酶（15-PGDH）和15-oxoprostaglandin 13-还原酶/白三烯B（4）12-羟基脱氢酶（PGR / LTB（4）DH）。类二十烷酸（即白三烯，前列腺素），最近发现可在脂蛋白失活中起作用。在这里，评估了一组NSAID，以确定每种化合物抑制重组15-PGDH或PG-LXR / LTB（4）DH的类花生酸定向活性的能力。对前列腺素E（2）（PGE（2））和脂蛋白A（4）（LXA（4））都起作用的重组15-PGDH不受NSAIDs的明显抑制。相反，一些广泛使用的NSAID是有效的PG-LXR / LTB（4）DH抑制剂，可代谢15-oxo-PGE（2）和LTB（4）以及15-oxo-LXA（4）
• Bacterial expression and site-directed mutagenesis of two critical residues (tyrosine-151 and lysine-155) of human placental NAD+ -dependent 15-hydroxyprostaglandin dehydrogenase
  作者：Charles Mark Ensor、Hsin-Hsiung Tai

  DOI：10.1016/0167-4838(94)90172-4

  日期：1994.9

  prostaglandins and NAD+ indicate that the recombinant enzyme does not appear to be kinetically different from the human placental enzyme. Site-directed mutagenesis was used to examine the importance of two residues which are highly conserved in the short-chain dehydrogenases which are known to be related to 15-PGDH. Tyrosine-151 was changed to phenylalanine and serine while lysine-155 was changed to glutamine

  NAD（+）依赖的15-羟基前列腺素脱氢酶（15-PGDH）催化前列腺素分解代谢途径的第一步。该酶氧化前列腺素的15-羟基基团，产生通常在生物学上无活性的15-酮代谢产物。在这项研究中，人胎盘15-PGDH的cDNA在大肠杆菌中表达，并将重组酶纯化至均一并进行了表征。对重组蛋白的N末端进行测序，发现与已知的15-PGDH氨基酸序列相同。对许多前列腺素和NAD +的Km和Vmax值的测定表明重组酶似乎与人胎盘酶在动力学上没有差异。使用定点诱变来检查两个残基的重要性，这两个残基在已知与15-PGDH相关的短链脱氢酶中高度保守。酪氨酸151变为苯丙氨酸和丝氨酸，而赖氨酸155变为谷氨酰胺和亮氨酸。Western印迹分析表明突变体和野生型蛋白以相似的水平表达。但是，发现所有的突变蛋白都没有活性。这些结果表明15-PGDH活性需要酪氨酸151和赖氨酸155。发现所有突变蛋白均无活性。这些结果表明15
• NAD+-Linked 15-Hydroxyprostaglandin Dehydrogenase: Structure and Biological Functions
  作者：H- Tai、H. Cho、M. Tong、Y. Ding

  DOI：10.2174/138161206776055958

  日期：2006.3.1

  NAD+-linked 15-hydroxyprostaglandin dehydrogenase (15-PGDH) catalyzes the oxidation of 15(S)-hydroxyl group of prostaglandins and lipoxins resulting in the formation of 15-keto metabolites which exhibit greatly reduced biological activities. Therefore, this enzyme has been considered the key enzyme responsible for the inactivation of prostaglandins and lipoxins. Both the cDNA and the genomic DNA of the 15-PGDH gene have been cloned. Structural characterization, transcriptional regulation and biological functions of this enzyme have been investigated. Molecular modeling corroborated with site-directed mutagenesis has identified key residues and domains involved in coenzyme and substrate binding. Catalytic mechanism has been proposed. Studies on the regulation of enzyme expression and activity by physiological and pharmacological agents have begun to uncover its significant roles in cancer, inflammation and reproduction. Apparently, 15-PGDH works with cyclooxygenase-2 to control the cellular levels of prostaglandins. Their reciprocal regulation within the same cells appears to determine the fate of the cells. Because of its ability to inactivate both prostaglandins and lipoxins of two opposite biological activities, the roles of 15-PGDH in cancer and inflammation are particularly intriguing and challenging. Future investigations in these areas are warranted.

  NAD+ 链接的 15-羟基前列腺素脱氢酶（15-PGDH）催化前列腺素和脂质毒素的 15（S）-羟基氧化，形成 15-酮代谢物，其生物活性大大降低。因此，这种酶被认为是导致前列腺素和脂质毒素失活的关键酶。15-PGDH 基因的 cDNA 和基因组 DNA 均已克隆。对这种酶的结构特征、转录调控和生物功能进行了研究。通过分子建模和定点突变，确定了参与辅酶和底物结合的关键残基和结构域。提出了催化机理。对生理和药理作用对酶表达和活性的调控研究已开始揭示其在癌症、炎症和生殖方面的重要作用。显然，15-PGDH 与环氧化酶-2 共同作用，控制着细胞中前列腺素的水平。它们在同一细胞内的相互调节似乎决定着细胞的命运。由于 15-PGDH 能够灭活具有两种相反生物活性的前列腺素和脂质毒素，因此它在癌症和炎症中的作用尤其引人关注，也极具挑战性。未来有必要在这些领域开展研究。
• Purification of prostaglandin E₂ -9-oxoreductase from human decidua vera
  作者：W. Schlegel、S. Krüger、K. Korte

  DOI：10.1016/0014-5793(84)80475-5

  日期：1984.6.4

  Prostaglandin E2‐9‐oxoreductase (PGE2‐9‐OR), the enzyme which converts prostaglandin E2 (PGE2) to prostaglandin F2α (PGF2α), has been detected in human decidua vera. A 105‐fold purification was achieved when the centrifuged homogenate was fractionated sequentially by DEAE—Trisacryl, hydroxyapatite—agarose gel, ultrogel AcA 44 and Matrex gel blue A gel chromatographies. The following kinetic constants

  前列腺素 E2-9-氧化还原酶 (PGE2-9-OR) 是一种将前列腺素 E2 (PGE2) 转化为前列腺素 F2α (PGF2α) 的酶，已在人类蜕膜中检测到。当离心的匀浆通过 DEAE-Trisacryl、羟基磷灰石-琼脂糖凝胶、ultrogel AcA 44 和 Matrex gel blue A 凝胶色谱法依次分级时，实现了 105 倍的纯化。已获得 PGE2-9-OR 的以下动力学常数。PGE2 的平衡常数为 83 μM，PGE2 的米氏常数 K m 为 80 μM，NADPH 为 1.6 μM。正向反应的最大速度为 V 1 = .203 pmol/min。该酶被孕酮、雌二醇-17β、皮质醇和药物抑制。可以用 Ca2+ 和催产素证明激活作用。蜕膜中 PGE2-9-OR 的出现表明该酶可能是这些组织中 PGE2 转化为 PGF2α 的原因。这可能是启动和维持子宫收缩的重要机制。
• Identification of human prostaglandin E synthase: A microsomal, glutathione-dependent, inducible enzyme, constituting a potential novel drug target
  作者：Per-Johan Jakobsson、Staffan Thorén、Ralf Morgenstern、Bengt Samuelsson

  DOI：10.1073/pnas.96.13.7220

  日期：1999.6.22

  Human prostaglandin (PG) E synthase (EC 5.3.99.3 ) is a member of a recently recognized protein superfamily consisting of membrane associated proteins involved in eicosanoid and glutathione metabolism (the MAPEG family). Previous designations of the protein are PIG12 and MGST1-L1. PGE synthase was expressed in Escherichia coli , and both cytosolic and membrane fractions were prepared. Western blot analysis specifically detected a 15- to 16-kDa protein in the membrane fraction. Both fractions were incubated with prostaglandin H ₂ in the presence or absence of reduced glutathione. The membrane but not the cytosolic fraction was found to possess high glutathione-dependent PGE synthase activity (0.25 μmol/min/mg). The human tissue distribution was analyzed by Northern blot analysis. High expression of PGE synthase mRNA was detected in A549 and HeLa cancer cell lines. Intermediate level of expression was demonstrated in placenta, prostate, testis, mammary gland, and bladder whereas low mRNA expression was observed in several other tissues. A549 cells have been used as a model system to study cyclooxygenase-2 induction by IL-1β. If A549 cells were grown in the presence of IL-1β, a significant induction of the PGE synthase was observed by Western blot analysis. Also, Western blot analysis specifically detected a 16-kDa protein in sheep seminal vesicles. In summary, we have identified a human membrane bound PGE synthase. The enzyme activity is glutathione-dependent, and the protein expression is induced by the proinflammatory cytokine IL-1β. PGE synthase is a potential novel target for drug development.

  人类前列腺素（PG）E合成酶（EC 5.3.99.3）是一种膜相关蛋白超家族的成员，该超家族包括参与环氧化物和谷胱甘肽代谢的膜相关蛋白（MAPEG家族）。该蛋白的先前名称为PIG12和MGST1-L1。PGE合成酶在大肠杆菌中表达，并制备了细胞质和膜分离物。Western blot分析特异性地检测到膜分离物中的15-至16-kDa蛋白质。在还原型谷胱甘肽的存在下，两个分离物均与前列腺素H2一起孵育或不孵育。发现膜分离物而不是细胞质分离物具有高谷胱甘肽依赖性PGE合成酶活性（0.25μmol/min/mg）。通过Northern blot分析分析了人类组织分布。在A549和HeLa癌细胞系中检测到高水平的PGE合成酶mRNA表达。在胎盘、前列腺、睾丸、乳腺和膀胱中表现出中等水平的表达，而在其他几种组织中观察到低水平的mRNA表达。 A549细胞已被用作研究IL-1β诱导环氧合酶-2的模型系统。如果A549细胞在IL-1β的存在下生长，则通过Western blot分析观察到PGE合成酶的显着诱导。此外，Western blot分析特异性地检测到羊精囊中的16-kDa蛋白质。总之，我们已经确定了一种人类膜结合的PGE合成酶。酶活性依赖于谷胱甘肽，并且蛋白质表达受到促炎细胞因子IL-1β的诱导。 PGE合成酶是药物开发的潜在新靶点。