CDP-1,2-dioleoyl-sn-glycerol(2-)

• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 甘油磷脂
• 英文名称: CDP-1,2-dioleoyl-sn-glycerol(2-)
• 英文别名: [[(2R,3S,4R,5R)-5-(4-amino-2-oxopyrimidin-1-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-oxidophosphoryl] [(2R)-2,3-bis[[(Z)-octadec-9-enoyl]oxy]propyl] phosphate
• 化学式: C48H83N3O15P2-2
• 分子量: 1004.1
• InChiKey: WVVFFOKRFKIBHD-RFROFZNGSA-L

计算性质

• 辛醇/水分配系数(LogP)：
  9.8
• 重原子数：
  68
• 可旋转键数：
  44
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.79
• 拓扑面积：
  269
• 氢给体数：
  3
• 氢受体数：
  15

反应信息

• 作为反应物：
  描述：

  CDP-1,2-dioleoyl-sn-glycerol(2-) 、 1D-myo-inositol-3-phosphate 生成 1,2-dioleoyl-sn-glycero-3-phospho-(1D-myo-inositol-3'-phosphate)(3-) 、 cytidine 5'-monophosphate 、 氢(+1)阳离子
  参考文献：
  名称：

  A revised biosynthetic pathway for phosphatidylinositol in Mycobacteria

  摘要：

  在过去的十年中，人们一直认为分枝杆菌中的磷脂酰肌醇（PI）是由PI合成酶在ATP的作用下，从游离肌醇和CDP-二酰基甘油合成而来的。然而，人们并不了解ATP在这一过程中的作用。此外，与酵母的PI合成酶活性相比，分枝杆菌的PI合成酶活性极低。当CDP-二酰基甘油和[14C]1L-肌醇-1-磷酸与分枝杆菌的细胞壁成分一起培养时，通过快速原子轰击质谱法和薄层色谱法鉴定，形成了磷脂酰肌醇磷酸（PIP）和PI。PI是通过与细胞壁成分一起培养从PIP形成的。因此，分枝杆菌的PI是通过CDP-二酰基甘油和肌醇-1-磷酸通过PIP合成的，而PIP被去磷酸化为PI。四种分枝杆菌的编码PIP合成酶的基因被克隆并在大肠杆菌中表达，并证实了PIP合成酶的活性。在分枝杆菌细胞壁制剂中，游离[3H]肌醇以非常低但显著的水平掺入PI中，但在重组大肠杆菌细胞匀浆中则没有。这种活性可以通过两种次要的PI代谢途径来解释：PI/肌醇交换反应和肌醇在进入PIP合成酶途径之前由ATP磷酸化。

  DOI：

  10.1093/jb/mvq093
• 作为产物：
  描述：

  Dioleoyl phosphatidate 、 cytidine 5'-triphosphate 、 氢(+1)阳离子 生成 CDP-1,2-dioleoyl-sn-glycerol(2-) 、 pyrophosphoric acid
  参考文献：
  名称：

  Distinct Properties of the Two Isoforms of CDP-Diacylglycerol Synthase

  摘要：

  CDP-diacylglycerol synthases (CDS) are critical enzymes that catalyze the formation of CDP-diacylglycerol (CDP-DAG) from phosphatidic acid (PA). Here we show in vitro that the two isoforms of human CDS, CDS1 and CDS2, show different acyl chain specificities for its lipid substrate. CDS2 is selective for the acyl chains at the sn-1 and sn-2 positions, the most preferred species being 1-stearoyl-2-arachidonoyl-sn-phosphatidic acid. CDS1, conversely, shows no particular substrate specificity, displaying similar activities for almost all substrates tested. Additionally, we show that inhibition of CDS2 by phosphatidylinositol is also acyl chain-dependent, with the strongest inhibition seen with the 1-stearoyl-2-arachidonoyl species. CDS1 shows no acyl chain-dependent inhibition. Both CDS1 and CDS2 are inhibited by their anionic phospholipid end products, with phosphatidylinositol-(4,5)-bisphosphate showing the strongest inhibition. Our results indicate that CDS1 and CDS2 could create different CDP-DAG pools that may serve to enrich different phospholipid species with specific acyl chains.

  DOI：

  10.1021/bi501250m

文献信息

• Studies of inositol 1-phosphate analogues as inhibitors of the phosphatidylinositol phosphate synthase in mycobacteria
  作者：Hiroyuki Morii、Tatsuo Okauchi、Hiroki Nomiya、Midori Ogawa、Kazumasa Fukuda、Hatsumi Taniguchi

  DOI：10.1093/jb/mvs141

  日期：2013.3

  homologues of inositol 1-phosphate, a PIP synthase substrate, would act as PIP synthase inhibitors, and the results confirmed that all synthesized compounds inhibited PIP synthase activity. The phosphonate analogue of inositol 1-phosphate (Ino-C-P) had the greatest inhibitory effect among the synthesized compounds examined. Kinetic analysis indicated that Ino-C-P acted as a competitive inhibitor of inositol

  我们以前报道了通过磷脂酰肌醇磷酸酯（PIP）在分枝杆菌中生物合成磷脂酰肌醇的新途径[Morii H.，Ogawa，M.，Fukuda，K.，Taniguchi，H.，and Koga，Y（2010）J.Biochem。148，593-602]。该途径中的PIP合酶是开发新的抗分枝杆菌药物的有希望的靶标。在本研究中，我们评估了结核分枝杆菌的PIP合酶的特征。基于以下假设，化学合成了四种类型的化合物：肌醇1-磷酸（PIP合酶底物）的结构同源物将充当PIP合酶抑制剂，结果证实所有合成的化合物均抑制PIP合酶活性。在所研究的合成化合物中，肌醇1-磷酸酯的膦酸酯类似物（Ino-CP）具有最大的抑制作用。动力学分析表明，Ino-CP是肌醇1-磷酸的竞争性抑制剂。Ino-CP抑制PIP合酶活性的IC（50）值估计为2.0 mM。有趣的是，以与正常PIP合酶底物相同的方式利用Ino-CP，从而合成了PIP
• Structure of Mycobacterium tuberculosis phosphatidylinositol phosphate synthase reveals mechanism of substrate binding and metal catalysis
  作者：Kristīne Grāve、Matthew D. Bennett、Martin Högbom

  DOI：10.1038/s42003-019-0427-1

  日期：——

  million yearly deaths, and drug resistance is rapidly developing. Mycobacterium tuberculosis phosphatidylinositol phosphate synthase (PgsA1) is an integral membrane enzyme involved in biosynthesis of inositol-derived phospholipids required for formation of the mycobacterial cell wall, and a potential drug target. Here we present three crystal structures of M. tuberculosis PgsA1: in absence of substrates

  结核病每年导致超过一百万人死亡，并且耐药性正在迅速发展。结核分枝杆菌磷脂酰肌醇磷酸合酶 (PgsA1) 是一种整合膜酶，参与分枝杆菌细胞壁形成所需的肌醇衍生磷脂的生物合成，也是潜在的药物靶点。在这里，我们展示了结核分枝杆菌 PgsA1 的三种晶体结构：没有底物 (2.9 Å)、与 Mn2+ 和柠檬酸盐复合 (1.9 Å) 以及与 CDP-DAG 底物 (1.8 Å) 复合。这些结构揭示了底物结合的原子细节以及催化金属位点的配位和动力学。此外，诱变支持的分子对接表明了第二种底物 D-肌醇-3-磷酸的结合模式。这些数据共同描述了 M 的结构基础。
• Structural basis for phosphatidylinositol-phosphate biosynthesis
  作者：Oliver B. Clarke、David Tomasek、Carla D. Jorge、Meagan Belcher Dufrisne、Minah Kim、Surajit Banerjee、Kanagalaghatta R. Rajashankar、Lawrence Shapiro、Wayne A. Hendrickson、Helena Santos、Filippo Mancia

  DOI：10.1038/ncomms9505

  日期：——

  Phosphatidylinositol is critical for intracellular signalling and anchoring of carbohydrates and proteins to outer cellular membranes. The defining step in phosphatidylinositol biosynthesis is catalysed by CDP-alcohol phosphotransferases, transmembrane enzymes that use CDP-diacylglycerol as donor substrate for this reaction, and either inositol in eukaryotes or inositol phosphate in prokaryotes as the acceptor alcohol. Here we report the structures of a related enzyme, the phosphatidylinositol-phosphate synthase from Renibacterium salmoninarum, with and without bound CDP-diacylglycerol to 3.6 and 2.5 Å resolution, respectively. These structures reveal the location of the acceptor site, and the molecular determinants of substrate specificity and catalysis. Functional characterization of the 40%-identical ortholog from Mycobacterium tuberculosis, a potential target for the development of novel anti-tuberculosis drugs, supports the proposed mechanism of substrate binding and catalysis. This work therefore provides a structural and functional framework to understand the mechanism of phosphatidylinositol-phosphate biosynthesis.

  磷脂酰肌醇在细胞内信号传导和蛋白质与碳水化合物锚定于细胞外膜中起着重要作用。磷脂酰肌醇生物合成的关键步骤是由CDP醇磷酸转移酶催化的，这些跨膜酶使用CDP二酰基甘油作为供体底物进行反应，而真核生物中使用肌醇，原核生物中使用肌醇磷酸作为受体醇。在这里，我们报道了来自Renibacterium salmoninarum的磷脂酰肌醇磷酸合成酶的结构，包括与CDP二酰基甘油结合和未结合的两种状态，分别分辨率为3.6和2.5 Å。这些结构揭示了受体位点的位置以及底物特异性和催化的分子决定因素。来自Mycobacterium tuberculosis的40%同源基因的功能性特征，是研发新型抗结核药物的潜在靶点，支持了所提出的底物结合和催化机制。因此，这项工作为理解磷脂酰肌醇磷酸生物合成机制提供了结构和功能框架。

• Distinct Properties of the Two Isoforms of CDP-Diacylglycerol Synthase
  作者：Kenneth D’Souza、Yeun Ju Kim、Tamas Balla、Richard M. Epand

  DOI：10.1021/bi501250m

  日期：2014.12.2

  CDP-diacylglycerol synthases (CDS) are critical enzymes that catalyze the formation of CDP-diacylglycerol (CDP-DAG) from phosphatidic acid (PA). Here we show in vitro that the two isoforms of human CDS, CDS1 and CDS2, show different acyl chain specificities for its lipid substrate. CDS2 is selective for the acyl chains at the sn-1 and sn-2 positions, the most preferred species being 1-stearoyl-2-arachidonoyl-sn-phosphatidic acid. CDS1, conversely, shows no particular substrate specificity, displaying similar activities for almost all substrates tested. Additionally, we show that inhibition of CDS2 by phosphatidylinositol is also acyl chain-dependent, with the strongest inhibition seen with the 1-stearoyl-2-arachidonoyl species. CDS1 shows no acyl chain-dependent inhibition. Both CDS1 and CDS2 are inhibited by their anionic phospholipid end products, with phosphatidylinositol-(4,5)-bisphosphate showing the strongest inhibition. Our results indicate that CDS1 and CDS2 could create different CDP-DAG pools that may serve to enrich different phospholipid species with specific acyl chains.
• A revised biosynthetic pathway for phosphatidylinositol in Mycobacteria
  作者：Hiroyuki Morii、Midori Ogawa、Kazumasa Fukuda、Hatsumi Taniguchi、Yosuke Koga

  DOI：10.1093/jb/mvq093

  日期：2010.11

  For the last decade, it has been believed that phosphatidylinositol (PI) in mycobacteria is synthesized from free inositol and CDP-diacylglycerol by PI synthase in the presence of ATP. The role of ATP in this process, however, is not understood. Additionally, the PI synthase activity is extremely low compared with the PI synthase activity of yeast. When CDP-diacylglycerol and [14C]1L-myo-inositol 1-phosphate were incubated with the cell wall components of Mycobacterium smegmatis, both phosphatidylinositol phosphate (PIP) and PI were formed, as identified by fast atom bombardment-mass spectrometry and thin-layer chromatography. PI was formed from PIP by incubation with the cell wall components. Thus, mycobacterial PI was synthesized from CDP-diacylglycerol and myo-inositol 1-phosphate via PIP, which was dephosphorylated to PI. The gene-encoding PIP synthase from four species of mycobacteria was cloned and expressed in Escherichia coli, and PIP synthase activity was confirmed. A very low, but significant level of free [3H]inositol was incorporated into PI in mycobacterial cell wall preparations, but not in recombinant E. coli cell homogenates. This activity could be explained by the presence of two minor PI metabolic pathways: PI/inositol exchange reaction and phosphorylation of inositol by ATP prior to entering the PIP synthase pathway.

  在过去的十年中，人们一直认为分枝杆菌中的磷脂酰肌醇（PI）是由PI合成酶在ATP的作用下，从游离肌醇和CDP-二酰基甘油合成而来的。然而，人们并不了解ATP在这一过程中的作用。此外，与酵母的PI合成酶活性相比，分枝杆菌的PI合成酶活性极低。当CDP-二酰基甘油和[14C]1L-肌醇-1-磷酸与分枝杆菌的细胞壁成分一起培养时，通过快速原子轰击质谱法和薄层色谱法鉴定，形成了磷脂酰肌醇磷酸（PIP）和PI。PI是通过与细胞壁成分一起培养从PIP形成的。因此，分枝杆菌的PI是通过CDP-二酰基甘油和肌醇-1-磷酸通过PIP合成的，而PIP被去磷酸化为PI。四种分枝杆菌的编码PIP合成酶的基因被克隆并在大肠杆菌中表达，并证实了PIP合成酶的活性。在分枝杆菌细胞壁制剂中，游离[3H]肌醇以非常低但显著的水平掺入PI中，但在重组大肠杆菌细胞匀浆中则没有。这种活性可以通过两种次要的PI代谢途径来解释：PI/肌醇交换反应和肌醇在进入PIP合成酶途径之前由ATP磷酸化。