N-palmitoyl-1-oleoyl-sn-glycero-3-phosphoethanolamine(1-)

• 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: N-palmitoyl-1-oleoyl-sn-glycero-3-phosphoethanolamine(1-)
• 英文别名: 2-(hexadecanoylamino)ethyl [(2R)-2-hydroxy-3-[(Z)-octadec-9-enoyl]oxypropyl] phosphate
• 化学式: C39H75NO8P-
• 分子量: 717.0
• InChiKey: VSRSTHVWSWNJCC-OTMQOFQLSA-M

计算性质

• 辛醇/水分配系数(LogP)：
  12.3
• 重原子数：
  49
• 可旋转键数：
  39
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.9
• 拓扑面积：
  134
• 氢给体数：
  2
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  水 、 N-palmitoyl-1-oleoyl-sn-glycero-3-phosphoethanolamine(1-) 生成 oleate 、 氢(+1)阳离子 、 N-hexadecanoyl-sn-glycero-3-phosphoethanolamine(1-)
  参考文献：
  名称：

  Endocannabinoid Biosynthesis Proceeding through Glycerophospho-N-acyl Ethanolamine and a Role for α/β-Hydrolase 4 in This Pathway

  摘要：

  N-Acyl ethanolamines (NAEs) are a large class of signaling lipids implicated in diverse physiological processes, including nociception, cognition, anxiety, appetite, and inflammation. It has been proposed that NAEs are biosynthesized from their corresponding N-acyl phosphatidylethanolamines (NAPEs) in a single enzymatic step catalyzed by a phospholipase D (NAPE-PLD). The recent generation of NAPE-PLD(-/-) mice has revealed that these animals possess lower brain levels of saturated NAEs but essentially unchanged concentrations of polyunsaturated NAEs, including the endogenous cannabinoid anandamide. These findings suggest the existence of additional enzymatic routes for the production of NAEs in vivo. Here, we report evidence for an alternative pathway for NAE biosynthesis that proceeds through the serine hydrolase-catalyzed double-deacylation of NAPE to generate glycerophospho-NAE, followed by the phosphodiesterase-mediated cleavage of this intermediate to liberate NAE. Furthermore, we describe the functional proteomic isolation and identification of a heretofore uncharacterized enzyme alpha/beta-hydrolase 4 (Abh4) as a lysophospholipase/phospholipase B that selectively hydrolyzes NAPEs and lysoNAPEs. Abh4 accepts lysoNAPEs bearing both saturated and polyunsaturated N-acyl chains as substrates and displays a distribution that closely mirrors lysoNAPE-lipase activity in mouse tissues. These results support the existence of an NAPE-PLD-independent route for NAE biosynthesis and suggest that Abh4 plays a role in this metabolic pathway by acting as a (lyso) NAPE-selective lipase.

  DOI：

  10.1074/jbc.m604660200
• 作为产物：
  描述：

  水 、 N-palmitoyl-1,2-dioleoyl-sn-glycero-3-phosphoethanolamine(1-) 生成 oleate 、 氢(+1)阳离子 、 N-palmitoyl-1-oleoyl-sn-glycero-3-phosphoethanolamine(1-)
  参考文献：
  名称：

  Biosynthesis of anandamide and N-palmitoylethanolamine by sequential actions of phospholipase A2 and lysophospholipase D

  摘要：

  安乃近（一种内源性大麻素）和其他具有生物活性的长链 NAE（N-酰乙醇胺）是由 PLD（磷脂酶 D）从 N-酰-PE（N-酰基磷脂酰乙醇胺）中直接释放出来的。不过，以前也有人提出过 N-酰基-PE可能存在两步途径，其中包括：(1) N-酰基-PE通过 PLA1/PLA2 酶水解为 N-酰基-lysoPE；(2) N-酰基-lysoPE通过溶血磷脂酶 D（lysoPLD）酶释放出 NAE。在本研究中，我们首次报告了负责这一途径的酶的特征。在大鼠的多种组织中发现了 N-棕榈酰-PE 的 PLA1/PLA2 活性，其中胃中的活性最高。这种胃酶被鉴定为 IB 组 sPLA2（分泌型 PLA2），其产物被确定为 N-酰基-1-酰基-lysoPE。重组的 IB、IIA 和 V 组 sPLA2 对 N-棕榈酰-PE 也有活性，而 X 组 sPLA2 和细胞质 PLA2α 则没有活性。此外，我们还发现从 N-棕榈酰-lysoPE生成 N-棕榈酰乙醇胺的溶菌 PLD 活性在大鼠组织中分布广泛，其中大脑和睾丸中的活性较高。sPLA2-IB 的剂量依赖性增强了显示溶菌酶活性的脑匀浆中 N-棕榈酰-PE 生成 N-棕榈酰乙醇胺的能力。N- arachidonoyl-PE 和 N- arachidonoyl-lysoPE 作为安乃近前体也分别是 sPLA2-IB 和 lysoPLD 的良好底物。这些结果表明，PLA2 和 lysoPLD 的相继作用可能构成包括安乃近酰胺在内的 NAEs 的另一种生物合成途径。

  DOI：

  10.1042/bj20040031

文献信息

• Glycerophosphodiesterase GDE4 as a novel lysophospholipase D: a possible involvement in bioactive N-acylethanolamine biosynthesis
  作者：Kazuhito Tsuboi、Yoko Okamoto、Iffat Ara Sonia Rahman、Toru Uyama、Tomohito Inoue、Akira Tokumura、Natsuo Ueda

  DOI：10.1016/j.bbalip.2015.01.002

  日期：2015.5

  Bioactive N-acylethanolamines include anti-inflammatory palmitoylethanolamide, anorexic oleoylethanolamide, and an endocannabinoid arachidonoylethanolamide (anandamide). In animal tissues, these molecules are biosynthesized from N-acylethanolamine phospholipids directly by phospholipase D-type enzyme or through multi-step routes via N-acylethanolamine lysophospholipids. We previously found that mouse

  具有生物活性的N-酰基乙醇胺包括抗炎棕榈酰乙醇酰胺，厌食性油酰基乙醇酰胺和内源性大麻素花生四烯酰基乙醇酰胺（anandamide）。在动物组织中，这些分子是通过磷脂酶D型酶直接从N-酰基乙醇胺磷脂或通过N-酰基乙醇胺溶血磷脂通过多步路线生物合成的。我们以前发现，小鼠大脑中有溶血磷脂酶d（lysoPLD）活性水解ñ -acylethanolamine溶血磷脂到ñ-酰基乙醇胺，这种活性可能部分归因于甘油磷酸二酯酶（GDE）1。在本研究中，我们研究了GDE家族另一个成员GDE4的催化性能。当在HEK293细胞中过表达时，鼠GDE4主要存在于膜级分中。纯化的GDE4对多种溶血磷脂显示了lysoPLD活性，包括N-酰基乙醇胺溶血磷脂以及溶血磷脂酰乙醇胺和溶血磷脂酰胆碱。当HEK293细胞被N- [ 14 C]棕榈酰乙醇胺溶血磷脂代谢标记时，GDE4的瞬时表达增加了[ 14C]棕榈酰乙醇酰胺水平，而内
• Calcium-dependent generation of N-acylethanolamines and lysophosphatidic acids by glycerophosphodiesterase GDE7
  作者：Iffat Ara Sonia Rahman、Kazuhito Tsuboi、Zahir Hussain、Ryouhei Yamashita、Yoko Okamoto、Toru Uyama、Naoshi Yamazaki、Tamotsu Tanaka、Akira Tokumura、Natsuo Ueda

  DOI：10.1016/j.bbalip.2016.09.008

  日期：2016.12

  N-Acylethanolamines form a class of lipid mediators and include an endocannabinoid arachidonoylethanolamide (anandamide), analgesic and anti-inflammatory palmitoylethanolamide, and appetite-suppressing oleoylethanolamide. In animal tissues, N-acylethanolamines are synthesized from N-acylated ethanolamine phospholipids directly by N-acylphosphatidylethanolamine-hydrolyzing phospholipase D or through multi-step pathways via N-acylethanolamine lysophospholipids. We previously reported that glycerophosphodiesterase (GDE) 4, a member of the GDE family, has lysophospholipase D (lysoPLD) activity hydrolyzing N-acylethanolamine lysophospholipids to N-acylethanolamines. Recently, GDE7 was shown to have lysoPLD activity toward lysophosphatidylcholine to produce lysophosphatidic acid (LPA). Here, we examined the reactivity of GDE7 with N-acylethanolamine lysophospholipids as well as the requirement of divalent cations for its catalytic activity. When overexpressed in HEK293 cells, recombinant GDE7 proteins of human and mouse showed lysoPLD activity toward N-palmitoyl, N-oleoyl, and N-arachidonoyl-lysophosphatidylethanolamines and N-palmitoyl-lysoplasmenylethanolamine to generate their corresponding N-acylethanolamines and LPAs. However, GDE7 hardly hydrolyzed glycerophospho-N-palmitoylethanolamine. Overexpression of GDE7 in HEK293 cells increased endogenous levels of N-acylethanolamines and LPAs. Interestingly, GDE7 was stimulated by micromolar concentrations ofCa(2+) but not by millimolar concentrations of Mg2+, while GDE4 was stimulated by Mg2+ but was insensitive to Ca2+. GDE7 was widely distributed in various tissues of humans and mice with the highest levels in their kidney tissues. These results suggested that GDE7 is a novel Ca2+-dependent lysoPLD, which is involved in the generation of both N-acylethanolamines and LPAs. (C) 2016 Elsevier B.V. All rights reserved.
• Endocannabinoid Biosynthesis Proceeding through Glycerophospho-N-acyl Ethanolamine and a Role for α/β-Hydrolase 4 in This Pathway
  作者：Gabriel M. Simon、Benjamin F. Cravatt

  DOI：10.1074/jbc.m604660200

  日期：2006.9

  N-Acyl ethanolamines (NAEs) are a large class of signaling lipids implicated in diverse physiological processes, including nociception, cognition, anxiety, appetite, and inflammation. It has been proposed that NAEs are biosynthesized from their corresponding N-acyl phosphatidylethanolamines (NAPEs) in a single enzymatic step catalyzed by a phospholipase D (NAPE-PLD). The recent generation of NAPE-PLD(-/-) mice has revealed that these animals possess lower brain levels of saturated NAEs but essentially unchanged concentrations of polyunsaturated NAEs, including the endogenous cannabinoid anandamide. These findings suggest the existence of additional enzymatic routes for the production of NAEs in vivo. Here, we report evidence for an alternative pathway for NAE biosynthesis that proceeds through the serine hydrolase-catalyzed double-deacylation of NAPE to generate glycerophospho-NAE, followed by the phosphodiesterase-mediated cleavage of this intermediate to liberate NAE. Furthermore, we describe the functional proteomic isolation and identification of a heretofore uncharacterized enzyme alpha/beta-hydrolase 4 (Abh4) as a lysophospholipase/phospholipase B that selectively hydrolyzes NAPEs and lysoNAPEs. Abh4 accepts lysoNAPEs bearing both saturated and polyunsaturated N-acyl chains as substrates and displays a distribution that closely mirrors lysoNAPE-lipase activity in mouse tissues. These results support the existence of an NAPE-PLD-independent route for NAE biosynthesis and suggest that Abh4 plays a role in this metabolic pathway by acting as a (lyso) NAPE-selective lipase.
• Biosynthesis of anandamide and N-palmitoylethanolamine by sequential actions of phospholipase A2 and lysophospholipase D
  作者：Yong-Xin SUN、Kazuhito TSUBOI、Yasuo OKAMOTO、Takeharu TONAI、Makoto MURAKAMI、Ichiro KUDO、Natsuo UEDA

  DOI：10.1042/bj20040031

  日期：2004.6.15

  Anandamide (an endocannabinoid) and other bioactive long-chain NAEs (N-acylethanolamines) are formed by direct release from N-acyl-PE (N-acyl-phosphatidylethanolamine) by a PLD (phospholipase D). However, the possible presence of a two-step pathway from N-acyl-PE has also been suggested previously, which comprises (1) the hydrolysis of N-acyl-PE to N-acyl-lysoPE by PLA1/PLA2 enzyme(s) and (2) the release of NAEs from N-acyllysoPE by lysoPLD (lysophospholipase D) enzyme(s). In the present study we report for the first time the characterization of enzymes responsible for this pathway. The PLA1/PLA2 activity for N-palmitoyl-PE was found in various rat tissues, with the highest activity in the stomach. This stomach enzyme was identified as group IB sPLA2 (secretory PLA2), and its product was determined as N-acyl-1-acyl-lysoPE. Recombinant group IB, IIA and V of sPLA2s were also active with N-palmitoyl-PE, whereas group X sPLA2 and cytosolic PLA2α were inactive. In addition, we found wide distribution of lysoPLD activity generating N-palmitoylethanolamine from N-palmitoyl-lysoPE in rat tissues, with higher activities in the brain and testis. Based on several lines of enzymological evidence, the lysoPLD enzyme could be distinct from the known N-acyl-PE-hydrolysing PLD. sPLA2-IB dose dependently enhanced the production of N-palmitoylethanolamine from N-palmitoyl-PE in the brain homogenate showing the lysoPLD activity. N-Arachidonoyl-PE and N-arachidonoyl-lysoPE as anandamide precursors were also good substrates of sPLA2-IB and the lysoPLD respectively. These results suggest that the sequential actions of PLA2 and lysoPLD may constitute another biosynthetic pathway for NAEs, including anandamide.

  安乃近（一种内源性大麻素）和其他具有生物活性的长链 NAE（N-酰乙醇胺）是由 PLD（磷脂酶 D）从 N-酰-PE（N-酰基磷脂酰乙醇胺）中直接释放出来的。不过，以前也有人提出过 N-酰基-PE可能存在两步途径，其中包括：(1) N-酰基-PE通过 PLA1/PLA2 酶水解为 N-酰基-lysoPE；(2) N-酰基-lysoPE通过溶血磷脂酶 D（lysoPLD）酶释放出 NAE。在本研究中，我们首次报告了负责这一途径的酶的特征。在大鼠的多种组织中发现了 N-棕榈酰-PE 的 PLA1/PLA2 活性，其中胃中的活性最高。这种胃酶被鉴定为 IB 组 sPLA2（分泌型 PLA2），其产物被确定为 N-酰基-1-酰基-lysoPE。重组的 IB、IIA 和 V 组 sPLA2 对 N-棕榈酰-PE 也有活性，而 X 组 sPLA2 和细胞质 PLA2α 则没有活性。此外，我们还发现从 N-棕榈酰-lysoPE生成 N-棕榈酰乙醇胺的溶菌 PLD 活性在大鼠组织中分布广泛，其中大脑和睾丸中的活性较高。sPLA2-IB 的剂量依赖性增强了显示溶菌酶活性的脑匀浆中 N-棕榈酰-PE 生成 N-棕榈酰乙醇胺的能力。N- arachidonoyl-PE 和 N- arachidonoyl-lysoPE 作为安乃近前体也分别是 sPLA2-IB 和 lysoPLD 的良好底物。这些结果表明，PLA2 和 lysoPLD 的相继作用可能构成包括安乃近酰胺在内的 NAEs 的另一种生物合成途径。