Arachidonate

• 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: Arachidonate
• 英文别名: (5Z,8Z,11Z,14Z)-icosa-5,8,11,14-tetraenoate
• 化学式: C20H31O2-
• 分子量: 303.5
• InChiKey: YZXBAPSDXZZRGB-DOFZRALJSA-M

计算性质

• 辛醇/水分配系数(LogP)：
  6.9
• 重原子数：
  22
• 可旋转键数：
  13
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.55
• 拓扑面积：
  40.1
• 氢给体数：
  0
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  Arachidonate 、 5-Hydroxyicosa-6,8,11,14-tetraeneperoxoic acid 生成 花生四烯酸
  参考文献：
  名称：

  Oxaindene derivatives and process for the preparation thereof

  摘要：

  本发明涉及新的氧杂萘衍生物，其制备方法和包括其在内的药物组成物。根据本发明，所述化合物的一般式为（1）##STR1##其中R1代表低C1-4烷基，低C1-4烷氧基或低C3-6环烷基，R2代表氢，低C1-4烷基或低C3-6环烷基，R3代表氢，低C1-4烷基，低C1-4烷氧基或苄氧基，X代表氢，脂肪族C1-4-酰基或苯甲酰基或萘甲酰基，可选地被1个或多个硝基或C1-4-烷氧基取代，或者是公式R5R6N-R7-的基团，其中R7代表低C1-4烷基，并且R5和R6各自代表低C1-4烷基，或者R5和R6与它们连接的氮原子一起形成哌啶基或吗啉基，A和B一起形成乙烯基或乙烯基基团，n为1、2或3，并具有强烈的5-脂氧合酶（5-LO）酶抑制活性。

  公开号：

  US05716986A1
• 作为产物：
  描述：

  水 、 (5Z,8Z,11Z,14Z)-Icosa-5,8,11,14-tetraenoic acid ((E)-(1S,2R)-2-hydroxy-1-hydroxymethyl-heptadec-3-enyl)-amide 生成 Arachidonate 、 Sphingosine(1+)
  参考文献：
  名称：

  Alkaline Ceramidase 3 (ACER3) Hydrolyzes Unsaturated Long-chain Ceramides, and Its Down-regulation Inhibits Both Cell Proliferation and Apoptosis

  摘要：

  Ceramides with different fatty acyl chains may vary in their physiological or pathological roles; however, it remains unclear how cellular levels of individual ceramide species are regulated. Here, we demonstrate that our previously cloned human alkaline ceramidase 3 (ACER3) specifically controls the hydrolysis of ceramides carrying unsaturated long acyl chains, unsaturated long-chain (ULC) ceramides. In vitro, ACER3 only hydrolyzed C-18:1-, C-20:1-, C-20:4-ceramides, dihydroceramides, and phytoceramides. In cells, ACER3 overexpression decreased C-18:1- and C-20:1-ceramides and dihydroceramides, whereas ACER3 knockdown by RNA interference had the opposite effect, suggesting that ACER3 controls the catabolism of ULC ceramides and dihydroceramides. ACER3 knockdown inhibited cell proliferation and up-regulated the cyclin-dependent kinase inhibitor p21(CIP1/WAF1). Blocking p21(CIP1/WAF1) up-regulation attenuated the inhibitory effect of ACER3 knockdown on cell proliferation, suggesting that ACER3 knockdown inhibits cell proliferation because of p21(CIP1/WAF1) up-regulation. ACER3 knockdown inhibited cell apoptosis in response to serum deprivation. ACER3 knockdown up-regulated the expression of the alkaline ceramidase 2 (ACER2), and the ACER2 up-regulation decreased non-ULC ceramide species while increasing both sphingosine and its phosphate. Collectively, these data suggest that ACER3 catalyzes the hydrolysis of ULC ceramides and dihydroceramides and that ACER3 coordinates with ACER2 to regulate cell proliferation and survival.

  DOI：

  10.1074/jbc.m109.063586

文献信息

• Mutations of Triad Determinants Changes the Substrate Alignment at the Catalytic Center of Human ALOX5
  作者：Igor Ivanov、Alexey B. Golovanov、Cristián Ferretti、Miquel Canyelles-Niño、Dagmar Heydeck、Sabine Stehling、José M. Lluch、Àngels González-Lafont、Hartmut Kühn

  DOI：10.1021/acschembio.9b00674

  日期：2019.12.20

  arachidonic acid mainly to 5(S)-hydroperoxyeicosatetraenoic acid (HpETE). In contrast, 15(S)- and 8(S)-H(p)ETE were formed by the mutant enzyme. In addition to arachidonic acid, wild-type ALOX5 accepted eicosapentaenoic acid (EPA) as substrate, but C18 fatty acids were not oxygenated. The quadruple mutant also accepted linoleic acid and α- and γ-linolenic acid as substrate. Structural analysis of the

  对于不同哺乳动物的ALOX15直系同源物的特异性，氨基酸Phe353，Ile418，Met419和Ile593（“三联决定簇”）的几何形状很重要，这些残基的诱变改变了这些酶的反应特异性。在这里，我们在Sf9昆虫细胞中表达了野生型人ALOX5及其F359W / A424I / N425M / A603I突变体，并表征了这两种酶变体的催化差异。我们发现野生型ALOX5主要将花生四烯酸转化为5（S）-氢过氧二十碳四烯酸（HpETE）。相反，由突变酶形成15（S）-和8（S）-H（p）ETE。除花生四烯酸外，野生型ALOX5还接受二十碳五烯酸（EPA）作为底物，但C18脂肪酸未被氧化。该四重突变体还接受亚油酸以及α-和γ-亚麻酸作为底物。氧化产物的结构分析和立体定向标记的11（S）-和11（R）-氘代亚油酸的动力学研究表明了活性位点上底物取向的替代方法。在计算机对接研究中，分子动力学模拟和量子力学/分子力学（QM
• Analysis of epoxyeicosatrienoic acids by chiral liquid chromatography/electron capture atmospheric pressure chemical ionization mass spectrometry using [¹³C]-analog internal standards
  作者：Clementina Mesaros、Seon Hwa Lee、Ian A. Blair

  DOI：10.1002/rcm.4760

  日期：2010.11.30

  they are present in only trace amounts and they are extremely difficult to separate from each other. In addition, the deuterium-labeled internal standards that are commonly used for stable isotope dilution liquid chromatography/mass spectrometry (LC/MS) analyses have different LC retention times when compared with the corresponding protium forms. Therefore, quantification by LC/MS-based methodology can

  花生四烯酸 (AA) 代谢为环氧二十碳三烯酸 (EET) 被认为主要由来自 2 家族（2C9、2C19、2D6 和 2J2）的细胞色素 P450 (P450s) 介导。相比之下，4 家族的 P450 主要参与 AA（4A11 和 4A22）的 omega 氧化。确定区域异构 EET 的对映选择性形成的能力对于建立它们的潜在生物活性和评估哪些 P450 同工型参与了它们的形成很重要。分析生物体液中的单个 EET 对映异构体极其困难，因为它们仅以痕量存在，而且极难相互分离。此外，常用于稳定同位素稀释液相色谱/质谱 (LC/MS) 分析的氘标记内标与相应的镨形式相比具有不同的 LC 保留时间。因此，通过基于 LC/MS 的方法进行的定量可能会受到接近洗脱异构体电离的差异抑制的影响。我们报告了 [(13)C(20)]-EET 模拟内标的制备以及使用经过验证的高灵敏度手性 LC/电子捕获大气压化学电离
• Single protein from human leukocytes possesses 5-lipoxygenase and leukotriene A4 synthase activities.
  作者：C A Rouzer、T Matsumoto、B Samuelsson

  DOI：10.1073/pnas.83.4.857

  日期：1986.2

  The activity of leukotriene A4 (LTA4) synthase in crude human leukocyte homogenates was found to have a similar requirement for Ca2+ and ATP as had been noted previously for 5-lipoxygenase activity. Purification of the 5-lipoxygenase using ammonium sulfate fractionation, AcA 44 gel-filtration chromatography, and HPLC on anion-exchange and hydroxyapatite columns demonstrated that LTA4 synthase activity copurified with the 5-lipoxygenase with similar recoveries and increases in specific activity. Furthermore, the two enzymatic activities coeluted exactly on three different HPLC systems. Maximal activity of purified LTA4 synthase required the addition of three nondialyzable stimulatory factors, two of which were cytosolic and one of which was membrane-bound. These findings were identical for 5-lipoxygenase activity. When incubated with arachidonic acid, the purified 5-lipoxygenase converted approximately equal to 15% of its endogenously generated 5-hydroperoxyicosatetraenoic acid (5-HPETE) to LTA4. LTA4 production was more efficient when the enzyme utilized 5-HPETE generated from arachidonic acid than when 5-HPETE was exogenously supplied as substrate. These findings suggest that a single protein from human leukocytes possesses 5-lipoxygenase and LTA4 synthase activities and that the synthesis of LTA4 from 5-HPETE is controlled by the same complex multicomponent system that regulates the 5-lipoxygenase reaction.

  在人类白细胞匀浆中，白三烯A4（LTA4）合酶的活性发现具有与5-脂氧合酶活性先前观察到的相似的对Ca2+和ATP的需求。使用硫酸铵分级、AcA 44凝胶过滤色谱和阴离子交换和羟基磷灰石柱高效液相色谱纯化5-脂氧合酶，表明LTA4合酶活性与5-脂氧合酶一起共纯化，具有相似的回收率和特异性增加。此外，两种酶活性在三个不同的高效液相色谱系统上完全共洗。纯化的LTA4合酶的最大活性需要添加三种非透析刺激因子，其中两种是细胞质的，一种是膜结合的。这些发现对于5-脂氧合酶活性是相同的。当与花生四烯酸一起孵育时，纯化的5-脂氧合酶将其内源性产生的5-羟基过氧化物四烯酸（5-HPETE）的约15％转化为LTA4。当酶利用从花生四烯酸产生的5-HPETE时，LTA4的产生更为高效，而当5-HPETE作为底物外源性供应时，则不是这样。这些发现表明，人类白细胞中的单个蛋白质具有5-脂氧合酶和LTA4合酶活性，并且来自5-HPETE的LTA4的合成受到同一复杂多组分系统的调节，该系统调节5-脂氧合酶反应。
• ATP Allosterically Activates the Human 5-Lipoxygenase Molecular Mechanism of Arachidonic Acid and 5(<i>S</i>)-Hydroperoxy-6(<i>E</i>),8(<i>Z</i>),11(<i>Z</i>),14(<i>Z</i>)-eicosatetraenoic Acid
  作者：Christopher J. Smyrniotis、Shannon R. Barbour、Zexin Xia、Mark S. Hixon、Theodore R. Holman

  DOI：10.1021/bi401621d

  日期：2014.7.15

  with arachidonic acid (AA) to first generate 5(S)-hydroperoxy-6(E),8(Z),11(Z),14(Z)-eicosatetraenoic acid [5(S)-HpETE] and then an epoxide from 5(S)-HpETE to form leukotriene A4, from a single polyunsaturated fatty acid. This work investigates the kinetic mechanism of these two processes and the role of ATP in their activation. Specifically, it was determined that epoxidation of 5(S)-HpETE (dehydration

  5-脂氧化酶 (5-LOX) 与花生四烯酸 (AA) 反应，首先生成 5( S )-氢过氧-6( E ),8( Z ),11( Z ),14( Z )-二十碳四烯酸 [5( S )-HpETE]，然后是来自 5( S )-HpETE的环氧化物，以从单一多不饱和脂肪酸形成白三烯 A 4。这项工作研究了这两个过程的动力学机制以及 ATP 在其活化中的作用。具体而言，已确定 5( S )-HpETE（氢过氧化物的脱水）的环氧化具有底物捕获速率 ( V max / K m) 明显低于 AA 氢过氧化（AA 氧化形成氢过氧化物）；然而，ATP 激活的双曲线动力学参数表明 AA 和 5( S )-HpETE 的激活类似。氢过氧化和环氧化的溶剂同位素效应结果表明，其分子机制中的特定步骤发生了变化，可能是因为限速步骤对氢原子提取的依赖性降低，而对氢键重排的依赖性增加。因此，细胞内 ATP 浓度的变化会影响
• The suppression of 5-lipoxygenation of arachidonic acid in human polymorphonuclear leucocytes by the 15-lipoxygenase product (15<i>S</i>)-hydroxy-(5<i>Z</i>,8<i>Z</i>,11<i>Z</i>,13<i>E</i>)-eicosatetraenoic acid: structure-activity relationship and mechanism of action
  作者：Karen PETRICH、Peter LUDWIG、Hartmut KÜHN、Tankred SCHEWE

  DOI：10.1042/bj3140911

  日期：1996.3.15

  (15S)-Hydroxy-(5Z,8Z,11Z,13E)-eicosatetraenoic acid (15-HETE) suppresses in ionophore-A23187-stimulated human polymorphonuclear leucocytes (PMN) the conversion of exogenous arachidonic acid into leukotriene B4 (LTB4) and (5S)-hydroxy-(6E,8Z,11Z,14Z)-eicosatetraenoic acid (5-HETE). However, contrary to earlier suggestions, 15-HETE is not a genuine 5-lipoxygenase inhibitor under these conditions, but rather suppresses the 5-lipoxygenation of arachidonic acid by switching-over of substrate utilization, as judged from a sizeable formation of labelled (5S,15S)-dihydroxy-(6E,8Z,11Z,13E)-eicosatetraenoic acid (5,15-diHETE) from 15-[1-14C]HETE. Identical results were obtained with human recombinant 5-lipoxygenase. In PMN the formation of 5,15-diHETE is strongly stimulated by either hydroperoxypolyenoic fatty acids or arachidonic acid, suggesting a crucial role of the hydroperoxide tone of the cell. A comparison of a selection of hydroxypolyenoic fatty acids with respect to their capability of suppressing 5-lipoxygenation of arachidonic acid revealed that 15-monohydroxyeicosanoids throughout exhibit the highest inhibitory potencies, whereas the other HETEs, 5,15-diHETE as well as octadecanoids, are modest or poor inhibitors. The R and S enantiomers of 15-HETE do not differ from each other, excluding a receptor-like binding of the 15-hydroxy group.

  （15S）-羟基-（5Z，8Z，11Z，13E）-二十碳四烯酸（15-HETE）抑制离子载体-A23187刺激的人类多形核白细胞（PMN）外源花生四烯酸转化为白三烯B4（LTB4）和（5S）-羟基-（6E，8Z，11Z，14Z）-二十碳四烯酸（5-HETE）。然而，与早期的建议相反，在这些条件下，15-HETE不是真正的5-脂氧合酶抑制剂，而是通过转换底物利用来抑制花生四烯酸的5-脂氧化，从标记的（5S，15S）-二羟基-（6E，8Z，11Z，13E）-二十碳四烯酸（5,15-diHETE）的大量形成可以判断。人重组5-脂氧合酶也得到了相同的结果。在PMN中，5,15-diHETE的形成受到羟基过氧化多烯酸或花生四烯酸的强烈刺激，表明细胞的过氧化物质浓度起着关键作用。在选择一些羟基多烯酸的能力方面，抑制花生四烯酸的5-脂氧化，15-单羟基二十碳烯酸类在整个过程中表现出最高的抑制效力，而其他HETE，5,15-diHETE以及十八碳烷酸类则是适度或较差的抑制剂。15-HETE的R和S对映异构体彼此没有区别，排除了15-羟基基团的受体样结合。