dipalmitoylphosphatidylinositol 5-phosphate

• 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: dipalmitoylphosphatidylinositol 5-phosphate
• 英文别名: 1,2-dipalmitoyl-sn-glycero-3-phospho-(1D-myo-inositol-5-phosphate)(3-)；[(1S,2R,3R,4R,5R,6R)-3-[[(2R)-2,3-di(hexadecanoyloxy)propoxy]-oxidophosphoryl]oxy-2,4,5,6-tetrahydroxycyclohexyl] phosphate
• 化学式: C₄₁H₇₇O₁₆P₂
• 分子量: 888.0
• InChiKey: SZPQTEWIRPXBTC-LNNNXZRXSA-K

计算性质

• 辛醇/水分配系数(LogP)：
  8.9
• 重原子数：
  59
• 可旋转键数：
  39
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.95
• 拓扑面积：
  265
• 氢给体数：
  4
• 氢受体数：
  16

反应信息

• 作为反应物：
  描述：

  dipalmitoylphosphatidylinositol 5-phosphate 在 乙二胺四乙酸 、 sodium acetate 1,2-己酰磷脂酰胆碱 、 phosphoinositide-specific phospholipase C-δ1 、 calcium chloride 作用下， 以 重水 为溶剂， 生成 D-myo-Inositol-1,5-bisphosphate 、
  参考文献：
  名称：

  New aspects of formation of 1,2-cyclic phosphates by phospholipase C-δ1

  摘要：

  Phosphoinositide-specific phospholipase C-delta1 (PI-PLC-delta1) cleaves phosphatidylinositol 4,5-bisphosphate (PI-4,5-P-2, 1), 5-phosphate (PI-5-P, 2) and 4-phosphate (PI-4-P, 3) to form the mixture of the corresponding 4,5-, 5- and 4-phosphorylated inositol 1,2-cyclic phosphate (IcP) and 1-phosphate (IP) (4-6 and 7-9, respectively). In this work, we have studied the rates of the cleavage and the ratios of the cyclic-to-acyclic phosphate products under various pH and Ca2+ concentration conditions using P-31 NMR to monitor the reactions. In agreement with the previous report (Kim et al. Biochim. Biophys. Acta 1989, 163, 177), our results indicate that the IcP/IP ratios strongly depend on the reaction conditions, with the cyclic phosphate products formed predominantly at low pH (pH 5.0) and high calcium concentration (5 mM). Surprisingly, however, we have found that at pH 8.0 and 5 mM Ca2+, PI-5-P rather than PI-4,5-P2 is the most preferred substrate with the highest V-max. The cleavage of PI-5-P generated also more cyclic phosphate product than the other two substrates. In addition, we have studied the analogous reaction of phosphorothioate analogues of 1 with the sulfur placed in the nonbridging (10) or bridging (13) positions. We have found that the phosphorothioate analogue 10 produced exclusively the cyclic product 11, whereas the analogue 13 afforded exlusively the acyclic product 7. These results are discussed in terms of the mechanism of PI-PLC, where the cyclic product is formed by 'leaking' from the active site before its subsequent hydrolysis. The potential significance of the cyclic products in the signaling pathways is also discussed. (C) 2003 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0968-0896(03)00150-0
• 作为产物：
  描述：

  1,2-dihexadecanoyl-sn-glycero-3-phospho-(1D-myo-inositol-3,5-phosphate) 、 水 生成 dipalmitoylphosphatidylinositol 5-phosphate 、 H3PO4
  参考文献：
  名称：

  Analysis of phosphoinositide binding domain properties within the myotubularin-related protein MTMR3

  摘要：

  肌管管素是一类大型的磷脂酰肌醇特异性磷酸酶，其底物特异性为PtdIns3P和PtdIns（3,5）P2。除了一个N端的PH-GRAM（PH-G）结构域和一个与其他家族成员共享的标志性催化结构域外，MTMR3还包含一个C端的FYVE结构域。我们展示了MTMR3的FYVE结构域是非典型的，既不赋予内体定位，也不结合脂质PtdIns3P。此外，FYVE结构域对于MTMR3的体外酶活性也不是必需的。相反，PH-GRAM结构域能够结合磷脂酰肌醇脂质，其中变构调节剂PtdIns5P是首选的配对体。因此，通过异源表达细菌磷酸酶IpgD来在质膜上生成PtdIns5P会导致MTMR3的转位，这需要PH-G结构域的参与。删除PH-G结构域会导致MTMR3在体外失去活性，并且令人惊讶的是，当与活性位点突变相结合时，会在高尔基复合体上积累蛋白质。

  DOI：

  10.1242/jcs.02325

文献信息

• Characterization of MTMR3
  作者：Donna M. Walker、Sylvie Urbé、Stephen K. Dove、Danielle Tenza、Graça Raposo、Michael J. Clague

  DOI：10.1016/s0960-9822(01)00501-2

  日期：2001.10

  Inositol lipids play key roles in many fundamental cellular processes that include growth, cell survival, motility, and membrane trafficking. Recent studies on the PTEN and Myotubularin proteins have underscored the importance of inositol lipid 3-phosphatases in cell function. Inactivating mutations in the genes encoding PTEN and Myotubularin are key steps in the progression of some cancers and in the onset of X-linked myotubular myopathy, respectively. Myotubularin-related protein 3 (MTMR3) shows extensive homology to Myotubularin, including the catalytic domain, but additionally possesses a C-terminal extension that includes a FYVE domain. We show that MTMR3 is an inositol lipid 3-phosphatase, with a so-far-unique substrate specificity. It is able to hydrolyze PtdIns3P and PtdIns(3,5)P-2, both in vitro and when heterologously expressed in S. cerevisiae, and to thereby provide the first clearly defined route for the cellular production of PtdIns5P. Overexpression of a catalytically dead MTMR3 (C413S) in mammalian cells induces a striking formation of vacuolar compartments that enclose membranous structures that are highly concentrated in mutant proteins.
• Phosphatidylinositol-5-Phosphate Activation and Conserved Substrate Specificity of the Myotubularin Phosphatidylinositol 3-Phosphatases
  作者：Julia Schaletzky、Stephen K. Dove、Benjamin Short、Oscar Lorenzo、Michael J. Clague、Francis A. Barr

  DOI：10.1016/s0960-9822(03)00132-5

  日期：2003.3

  Phosphoinositides control many different processes required for normal cellular function [1,2]. Myotubularins are a family of Phosphatidylinositol 3-phosphate (PtdIns3P) phosphatases identified by the positional cloning of the MTM1 gene in patients suffering from X-linked myotubular myopathy and the MTMR2 gene in patients suffering from the demyelinating neuropathy Charcot-Marie-Tooth disease type 4B [3-9]. MTM1 is a phosphatidylinositol phosphatase with reported specificity toward PtdIns3P [6, 7], while the related proteins MTMR2 and MTMR3 hydrolyze both PtdIns3P and PtdIns(3,5)P2 [10, 11]. We have investigated MTM1 and MTMR6 and find that they use PtdIns(3,5)P2 in addition to PtdIns3P as a substrate in vitro. The product of PtdIns(3,5)P2 hydrolysis, PtdIns5P, causes MTM1 to form a heptameric ring that is 12.5 nm in diameter, and it is a specific allosteric activator of MTM1, MTMR3, and MTMR6. A disease-causing mutation at arginine 69 of MTM1 failing within a putative pleckstrin homology domain reduces the ability of the enzyme to respond to PtdIns5P. We propose that the myotubularin family of enzymes utilize both PtdIns3P and PtdIns(3,5)P2 as substrates, and that PtdIns5P functions in a positive feedback loop controlling their activity. These findings highlight the importance of regulated phosphatase activity for the control of phosphoinositide metabolism.
• The Lipid Kinase PI5P4Kβ Is an Intracellular GTP Sensor for Metabolism and Tumorigenesis
  作者：Kazutaka Sumita、Yu-Hua Lo、Koh Takeuchi、Miki Senda、Satoshi Kofuji、Yoshiki Ikeda、Jumpei Terakawa、Mika Sasaki、Hirofumi Yoshino、Nazanin Majd、Yuxiang Zheng、Emily Rose Kahoud、Takehiro Yokota、Brooke M. Emerling、John M. Asara、Tetsuo Ishida、Jason W. Locasale、Takiko Daikoku、Dimitrios Anastasiou、Toshiya Senda、Atsuo T. Sasaki

  DOI：10.1016/j.molcel.2015.12.011

  日期：2016.1

  While cellular GTP concentration dramatically changes in response to an organism's cellular status, whether it serves as a metabolic cue for biological signaling remains elusive due to the lack of molecular identification of GTP sensors. Here we report that PI5P4K beta, a phosphoinositide kinase that regulates PI(5)P levels, detects GTP concentration and converts them into lipid second messenger signaling. Biochemical analyses show that PI5P4K beta preferentially utilizes GTP, rather than ATP, for PI(5) P phosphorylation, and its activity reflects changes in direct proportion to the physiological GTP concentration. Structural and biological analyses reveal that the GTP-sensing activity of PI5P4K beta is critical for metabolic adaptation and tumorigenesis. These results demonstrate that PI5P4K beta is the missing GTP sensor and that GTP concentration functions as a metabolic cue via PI5P4K beta. The critical role of the GTP-sensing activity of PI5P4K beta in cancer signifies this lipid kinase as a cancer therapeutic target.
• High-Throughput, Cell-Free, Liposome-Based Approach for Assessing In Vitro Activity of Lipid Kinases
  作者：Douglas J. Demian、Susan L. Clugston、Meta M. Foster、Lucia Rameh、Deborah Sarkes、Sharon A. Townson、Lily Yang、Melvin Zhang、Maura E. Charlton

  DOI：10.1177/1087057109339205

  日期：2009.8

  Lipid kinases are central players in lipid signaling pathways involved in inflammation, tumorigenesis, and metabolic syndrome. A number of these kinase targets have proven difficult to investigate in higher throughput cell-free assay systems. This challenge is partially due to specific substrate interaction requirements for several of the lipid kinase family members and the resulting incompatibility of these substrates with most established, homogeneous assay formats. Traditional, cell-free in vitro investigational methods for members of the lipid kinase family typically involve substrate incorporation of [gamma-P-32] and resolution of signal by thin-layer chromatography (TLC) and autoradiograph densitometry. This approach, although highly sensitive, does not lend itself to high-throughput testing of large numbers of small molecules (100 s to 1 MM+). The authors present the development and implementation of a fully synthetic, liposome-based assay for assessing in vitro activity of phosphatidylinositol-5-phosphate-4-kinase isoforms (PIP4KII beta and alpha) in 2 commonly used homogeneous technologies. They have validated these assays through compound testing in both traditional TLC and radioactive filterplate approaches as well as binding validation using isothermic calorimetry. A directed library representing known kinase pharmacophores was screened against type II beta phosphatidylinositol-phosphate kinase (PIPK) to identify small-molecule inhibitors. This assay system can be applied to other types and isoforms of PIPKs as well as a variety of other lipid kinase targets. (Journal of Biomolecular Screening 2009:838-844)
• Analysis of phosphoinositide binding domain properties within the myotubularin-related protein MTMR3
  作者：Óscar Lorenzo、Sylvie Urbé、Michael J. Clague

  DOI：10.1242/jcs.02325

  日期：2005.5.1

  The myotubularins are a large family of phosphoinositide-specific phosphatases with substrate specificity for PtdIns3P and PtdIns(3,5)P2. In addition to an N-terminal PH-GRAM (PH-G) domain and a signature catalytic domain shared with other family members, MTMR3 contains a C-terminal FYVE domain. We show that the FYVE domain of MTMR3 is atypical in that it neither confers endosomal localisation nor binds to the lipid PtdIns3P. Furthermore the FYVE domain is not required for in vitro enzyme activity of MTMR3. In contrast, the PH-GRAM domain is able to bind to phosphoinositide lipids, of which the allosteric regulator PtdIns5P is the preferred partner. Consequently, generation of PtdIns5P at the plasma membrane by ectopic expression of the bacterial phosphatase IpgD leads to a translocation of MTMR3 that requires the PH-G domain. Deletion of the PH-G domain leads to loss of activity of MTMR3 in vitro, and surprisingly, when combined with an active site mutation, accumulates the protein on the Golgi complex.

  肌管管素是一类大型的磷脂酰肌醇特异性磷酸酶，其底物特异性为PtdIns3P和PtdIns（3,5）P2。除了一个N端的PH-GRAM（PH-G）结构域和一个与其他家族成员共享的标志性催化结构域外，MTMR3还包含一个C端的FYVE结构域。我们展示了MTMR3的FYVE结构域是非典型的，既不赋予内体定位，也不结合脂质PtdIns3P。此外，FYVE结构域对于MTMR3的体外酶活性也不是必需的。相反，PH-GRAM结构域能够结合磷脂酰肌醇脂质，其中变构调节剂PtdIns5P是首选的配对体。因此，通过异源表达细菌磷酸酶IpgD来在质膜上生成PtdIns5P会导致MTMR3的转位，这需要PH-G结构域的参与。删除PH-G结构域会导致MTMR3在体外失去活性，并且令人惊讶的是，当与活性位点突变相结合时，会在高尔基复合体上积累蛋白质。