prostaglandin I2(1-)

• 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 I2(1-)
• 英文别名: (5Z)-5-[(3aR,4R,5R,6aS)-5-hydroxy-4-[(E,3S)-3-hydroxyoct-1-enyl]-3,3a,4,5,6,6a-hexahydrocyclopenta[b]furan-2-ylidene]pentanoate
• 化学式: C20H31O5-
• 分子量: 351.5
• InChiKey: KAQKFAOMNZTLHT-OZUDYXHBSA-M

计算性质

• 辛醇/水分配系数(LogP)：
  3.6
• 重原子数：
  25
• 可旋转键数：
  9
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.75
• 拓扑面积：
  89.8
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  NADP⁺ 、 prostaglandin I2(1-) 生成 15-dehydro-prostaglandin I2(1-) 、 氢(+1)阳离子 、 NADPH(4-)
  参考文献：
  名称：

  兔肾脏中NADP +依赖性PGI2特异性15-羟基前列腺素脱氢酶的分离及性质。

  摘要：

  DOI：

  10.1016/0076-6879(82)86185-5
• 作为产物：
  描述：

  prostaglandin H2(1-) 生成 prostaglandin I2(1-)
  参考文献：
  名称：

  Purification and Characterization of Recombinant Human Prostacyclin Synthase

  摘要：

  催化前列腺素（PG）H2 转化为前列环素（PGI2）的前列环素合成酶（PGIS）是细胞色素 P-450 （P450）超家族 CYP8A1 的成员。为了研究人类 PGIS 的酶和蛋白质特性，我们利用杆状病毒表达系统在弗氏蹼翅虫 21（Sf21）细胞中过表达了该酶。用磷酸钙凝胶吸收法从溶解的微粒体部分分离出全酶，再用DEAE-Sepharose和羟基磷灰石柱层析法纯化至均一。24°C 时，纯化的人 PGIS 对 PGH2 的 Km 值和 Vmax 值分别为 30 µM 和 15 µmol/min/mg 蛋白。该酶的光学吸收和 EPR 光谱显示了 P450 氧化态低自旋形式的特征。不过，一氧化碳还原差异光谱在 418 nm 而不是 450 nm 处显示了一个峰值。向酶中加入 PGH2 类似物 U46619 会产生氧配体类型的差异光谱，最大吸收波长为 407 纳米，最小吸收波长为 430 纳米。用另一种 PGH2 类似物 U44069 处理会在光谱中产生波长为 387 纳米的峰值和波长为 432 纳米的谷值（I 型），而用 PGIS 抑制剂氨酰丙咪嗪处理会产生波长为 434 纳米的峰值和波长为 412 纳米的谷值（II 型）。该酶的 Cys441His 突变体不具有血红素结合能力或酶活性。因此，我们成功地从受感染的昆虫细胞中获得了足量的纯化重组人 PGIS 用于光谱分析，它具有很高的特异性活性和 P450 的特征，表明了底物的特异性。

  DOI：

  10.1093/jb/mvh059

文献信息

• Structures of Prostacyclin Synthase and Its Complexes with Substrate Analog and Inhibitor Reveal a Ligand-specific Heme Conformation Change
  作者：Yi-Ching Li、Chia-Wang Chiang、Hui-Chun Yeh、Pei-Yung Hsu、Frank G. Whitby、Lee-Ho Wang、Nei-Li Chan

  DOI：10.1074/jbc.m707470200

  日期：2008.2

  Prostacyclin synthase (PGIS) is a cytochrome P450 ( P450) enzyme that catalyzes production of prostacyclin from prostaglandin H-2. PGIS is unusual in that it catalyzes an isomerization rather than a monooxygenation, which is typical of P450 enzymes. To understand the structural basis for prostacyclin biosynthesis in greater detail, we have determined the crystal structures of ligand-free, inhibitor ( minoxidil)-bound and substrate analog U51605-bound PGIS. These structures demonstrate a stereo-specific substrate binding and suggest features of the enzyme that facilitate isomerization. Unlike most microsomal P450s, where large substrate-induced conformational changes take place at the distal side of the heme, conformational changes in PGIS are observed at the proximal side and in the heme itself. The conserved and extensive heme propionate-protein interactions seen in all other P450s, which are largely absent in the ligand-free PGIS, are recovered upon U51605 binding accompanied by water exclusion from the active site. In contrast, when minoxidil binds, the propionate-protein interactions are not recovered and water molecules are largely retained. These findings suggest that PGIS represents a divergent evolution of the P450 family, in which a heme barrier has evolved to ensure strict binding specificity for prostaglandin H-2, leading to a radical-mediated isomerization with high product fidelity. The U51605-bound structure also provides a view of the substrate entrance and product exit channels.
• Prostacyclin and thromboxane synthases
  作者：Tadashi Tanabe、Volker Ullrich

  DOI：10.1016/0929-7855(95)00031-k

  日期：1995.10
• Analysis of genetic polymorphism and biochemical characterization of a functionally decreased variant in prostacyclin synthase gene (CYP8A1) in humans
  作者：Sun-Ah Cho、Katie Jo Rohn-Glowacki、Yazun B. Jarrar、Myeongjin Yi、Woo-Young Kim、Jae-Gook Shin、Su-Jun Lee

  DOI：10.1016/j.abb.2015.01.012

  日期：2015.3

  Prostacyclin synthase (CYP8A1) is an enzyme responsible for the biosynthesis of prostacyclin (PGI(2)) which inhibits platelet activation and exhibits anti-inflammatory effect. The objectives of this study were to identify CYP8A1 genetic variants and characterize functional consequences of CYP8A1 variants. In total, 27 variants including four previously unidentified single-nucleotide polymorphisms (SNPs) were identified by direct DNA sequencing in Koreans (n = 48). Among them, CYP8A1 A447T and E314Stop were newly assigned as CYP8A1*5 and CYP8A1*6 by the Human Cytochrome P450 Allele Nomenclature Committee, respectively. CYP8A1*5 was found in the heme binding area in three individuals as a heterozygous mutation. To investigate the functional change of CYP8A1*5, CYP8A1*5 and wild-type CYP8A1 protein were overexpressed in an Escherichia coil expression system and purified. Metabolism of PGH(2) by the CYP8A1*5 protein exhibited significantly decreased activity, resulting in a 45% decrease in V-max and a 1.8-fold decrease in intrinsic clearance compared to the wild-type. Based on the predicted crystal structure of CYP8A1*5 using the Molecular Operating Environment platform, the distance from CYP8A1 Cys441 to the heme was altered with a significantly changed binding free energy for the mutant protein. Further studies would be needed to determine the effect of CYP8A1*5 on PGI(2) levels in humans. (C) 2015 Elsevier Inc. All rights reserved.
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