N-Acylethanolamine

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Natsuo Ueda - One of the best experts on this subject based on the ideXlab platform.

  • Endocannabinoids and related N-Acylethanolamines: biological activities and metabolism.
    Inflammation and regeneration, 2018
    Co-Authors: Kazuhito Tsuboi, Toru Uyama, Yasuo Okamoto, Natsuo Ueda
    Abstract:

    The plant Cannabis sativa contains cannabinoids represented by Δ9-tetrahydrocannabinol, which exert psychoactivity and immunomodulation through cannabinoid CB1 and CB2 receptors, respectively, in animal tissues. Arachidonoylethanolamide (also referred to as anandamide) and 2-arachidonoylglycerol (2-AG) are well known as two major endogenous agonists of these receptors (termed “endocannabinoids”) and show various cannabimimetic bioactivities. However, only 2-AG is a full agonist for CB1 and CB2 and mediates retrograde signals at the synapse, strongly suggesting that 2-AG is physiologically more important than anandamide. The metabolic pathways of these two endocannabinoids are completely different. 2-AG is mostly produced from inositol phospholipids via diacylglycerol by phospholipase C and diacylglycerol lipase and then degraded by monoacylglycerol lipase. On the other hand, anandamide is concomitantly produced with larger amounts of other N-Acylethanolamines via N-acyl-phosphatidylethanolamines (NAPEs). Although this pathway consists of calcium-dependent N-acyltransferase and NAPE-hydrolyzing phospholipase D, recent studies revealed the involvement of several new enzymes. Quantitatively major N-Acylethanolamines include palmitoylethanolamide and oleoylethanolamide, which do not bind to cannabinoid receptors but exert anti-inflammatory, analgesic, and anorexic effects through receptors such as peroxisome proliferator-activated receptor α. The biosynthesis of these non-endocannabinoid N-Acylethanolamines rather than anandamide may be the primary significance of this pathway. Here, we provide an overview of the biological activities and metabolisms of endocannabinoids (2-AG and anandamide) and non-endocannabinoid N-Acylethanolamines.

  • Mammalian enzymes responsible for the biosynthesis of N-Acylethanolamines.
    Biochimica et biophysica acta. Molecular and cell biology of lipids, 2017
    Co-Authors: Zahir Hussain, Toru Uyama, Kazuhito Tsuboi, Natsuo Ueda
    Abstract:

    Abstract Bioactive N-Acylethanolamines (NAEs) are ethanolamides of long-chain fatty acids, including palmitoylethanolamide, oleoylethanolamide and anandamide. In animal tissues, NAEs are biosynthesized from membrane phospholipids. The classical “transacylation-phosphodiesterase” pathway proceeds via N-acyl-phosphatidylethanolamine (NAPE), which involves the actions of two enzymes, NAPE-generating Ca2+-dependent N-acyltransferase (Ca-NAT) and NAPE-hydrolyzing phospholipase D (NAPE-PLD). Recent identification of Ca-NAT as Ɛ isoform of cytosolic phospholipase A2 enabled the further molecular biological approaches toward this enzyme. In addition, Ca2+-independent NAPE formation was shown to occur by N-acyltransferase activity of a group of proteins named phospholipase A/acyltransferases (PLAAT)-1–5. The analysis of NAPE-PLD-deficient mice confirmed that NAEs can be produced through multi-step pathways bypassing NAPE-PLD. The NAPE-PLD-independent pathways involved three members of the glycerophosphodiesterase (GDE) family (GDE1, GDE4 and GDE7) as well as α/β-hydrolase domain-containing protein (ABHD)4. In this review article, we will focus on recent progress made and latest insights in the enzymes involved in NAE synthesis and their further characterization.

  • Calcium-dependent generation of N-Acylethanolamines and lysophosphatidic acids by glycerophosphodiesterase GDE7
    Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids, 2016
    Co-Authors: Iffat Ara Sonia Rahman, Toru Uyama, Kazuhito Tsuboi, Zahir Hussain, Ryouhei Yamashita, Yoko Okamoto, Naoshi Yamazaki, Tamotsu Tanaka, Akira Tokumura, Natsuo Ueda
    Abstract:

    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 of Ca2+ 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.

  • Glycerophosphodiesterase GDE4 as a novel lysophospholipase D: a possible involvement in bioactive N-Acylethanolamine biosynthesis.
    Biochimica et biophysica acta, 2015
    Co-Authors: Kazuhito Tsuboi, Toru Uyama, Iffat Ara Sonia Rahman, Yoko Okamoto, Akira Tokumura, Tomohito Inoue, Natsuo Ueda
    Abstract:

    Abstract 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 brain has a lysophospholipase D (lysoPLD) activity hydrolyzing N-Acylethanolamine lysophospholipids to N-Acylethanolamines and that this activity could be partially attributed to glycerophosphodiesterase (GDE) 1. In the present study, we examined catalytic properties of GDE4, another member of the GDE family. When overexpressed in HEK293 cells, murine GDE4 mostly resided in the membrane fraction. Purified GDE4 showed lysoPLD activity toward various lysophospholipids, including N-Acylethanolamine lysophospholipids as well as lysophosphatidylethanolamine and lysophosphatidylcholine. When HEK293 cells were metabolically labeled with N-[14C]palmitoylethanolamine lysophospholipid, the transient expression of GDE4 increased the [14C]palmitoylethanolamide level, while the knockdown of endogenous GDE4 decreased this level. These results suggested that GDE4 functions as an N-Acylethanolamine-generating lysoPLD in living cells. Moreover, the expression of GDE4 increased most species of lysophosphatidic acid (LPA), which can be produced from various lysophospholipids by the lysoPLD activity of GDE4. GDE4 mRNA was widely distributed among mouse tissues including brain, stomach, ileum, colon, and testis. In conclusion, GDE4 may act as a lysoPLD, which is involved in the generation of N-Acylethanolamines and LPA.

  • metabolism of endocannabinoids and related n acylethanolamines canonical and alternative pathways
    FEBS Journal, 2013
    Co-Authors: Natsuo Ueda, Kazuhito Tsuboi, Toru Uyama
    Abstract:

    : Endocannabinoids are endogenous ligands of the cannabinoid receptors CB1 and CB2. Two arachidonic acid derivatives, arachidonoylethanolamide (anandamide) and 2-arachidonoylglycerol, are considered to be physiologically important endocannabinoids. In the known metabolic pathway in mammals, anandamide and other bioactive N-Acylethanolamines, such as palmitoylethanolamide and oleoylethanolamide, are biosynthesized from glycerophospholipids by a combination of Ca(2+)-dependent N-acyltransferase and N-acyl-phosphatidylethanolamine-hydrolyzing phospholipase D, and are degraded by fatty acid amide hydrolase. However, recent studies have shown the involvement of other enzymes and pathways, which include the members of the tumor suppressor HRASLS family (the phospholipase A/acyltransferase family) functioning as Ca(2+)-independent N-acyltransferases, N-acyl-phosphatidylethanolamine-hydrolyzing phospholipaseD-independent multistep pathways via N-acylated lysophospholipid, and N-Acylethanolamine-hydrolyzing acid amidase, a lysosomal enzyme that preferentially hydrolyzes palmitoylethanolamide. Although their physiological significance is poorly understood, these new enzymes/pathways may serve as novel targets for the development of therapeutic drugs. For example, selective N-Acylethanolamine-hydrolyzing acid amidase inhibitors are expected to be new anti-inflammatory and analgesic drugs. In this minireview, we focus on advances in the understanding of these enzymes/pathways. In addition, recent findings on 2-arachidonoylglycerol metabolism are described.

Kazuhito Tsuboi - One of the best experts on this subject based on the ideXlab platform.

  • Endocannabinoids and related N-Acylethanolamines: biological activities and metabolism.
    Inflammation and regeneration, 2018
    Co-Authors: Kazuhito Tsuboi, Toru Uyama, Yasuo Okamoto, Natsuo Ueda
    Abstract:

    The plant Cannabis sativa contains cannabinoids represented by Δ9-tetrahydrocannabinol, which exert psychoactivity and immunomodulation through cannabinoid CB1 and CB2 receptors, respectively, in animal tissues. Arachidonoylethanolamide (also referred to as anandamide) and 2-arachidonoylglycerol (2-AG) are well known as two major endogenous agonists of these receptors (termed “endocannabinoids”) and show various cannabimimetic bioactivities. However, only 2-AG is a full agonist for CB1 and CB2 and mediates retrograde signals at the synapse, strongly suggesting that 2-AG is physiologically more important than anandamide. The metabolic pathways of these two endocannabinoids are completely different. 2-AG is mostly produced from inositol phospholipids via diacylglycerol by phospholipase C and diacylglycerol lipase and then degraded by monoacylglycerol lipase. On the other hand, anandamide is concomitantly produced with larger amounts of other N-Acylethanolamines via N-acyl-phosphatidylethanolamines (NAPEs). Although this pathway consists of calcium-dependent N-acyltransferase and NAPE-hydrolyzing phospholipase D, recent studies revealed the involvement of several new enzymes. Quantitatively major N-Acylethanolamines include palmitoylethanolamide and oleoylethanolamide, which do not bind to cannabinoid receptors but exert anti-inflammatory, analgesic, and anorexic effects through receptors such as peroxisome proliferator-activated receptor α. The biosynthesis of these non-endocannabinoid N-Acylethanolamines rather than anandamide may be the primary significance of this pathway. Here, we provide an overview of the biological activities and metabolisms of endocannabinoids (2-AG and anandamide) and non-endocannabinoid N-Acylethanolamines.

  • Mammalian enzymes responsible for the biosynthesis of N-Acylethanolamines.
    Biochimica et biophysica acta. Molecular and cell biology of lipids, 2017
    Co-Authors: Zahir Hussain, Toru Uyama, Kazuhito Tsuboi, Natsuo Ueda
    Abstract:

    Abstract Bioactive N-Acylethanolamines (NAEs) are ethanolamides of long-chain fatty acids, including palmitoylethanolamide, oleoylethanolamide and anandamide. In animal tissues, NAEs are biosynthesized from membrane phospholipids. The classical “transacylation-phosphodiesterase” pathway proceeds via N-acyl-phosphatidylethanolamine (NAPE), which involves the actions of two enzymes, NAPE-generating Ca2+-dependent N-acyltransferase (Ca-NAT) and NAPE-hydrolyzing phospholipase D (NAPE-PLD). Recent identification of Ca-NAT as Ɛ isoform of cytosolic phospholipase A2 enabled the further molecular biological approaches toward this enzyme. In addition, Ca2+-independent NAPE formation was shown to occur by N-acyltransferase activity of a group of proteins named phospholipase A/acyltransferases (PLAAT)-1–5. The analysis of NAPE-PLD-deficient mice confirmed that NAEs can be produced through multi-step pathways bypassing NAPE-PLD. The NAPE-PLD-independent pathways involved three members of the glycerophosphodiesterase (GDE) family (GDE1, GDE4 and GDE7) as well as α/β-hydrolase domain-containing protein (ABHD)4. In this review article, we will focus on recent progress made and latest insights in the enzymes involved in NAE synthesis and their further characterization.

  • Calcium-dependent generation of N-Acylethanolamines and lysophosphatidic acids by glycerophosphodiesterase GDE7
    Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids, 2016
    Co-Authors: Iffat Ara Sonia Rahman, Toru Uyama, Kazuhito Tsuboi, Zahir Hussain, Ryouhei Yamashita, Yoko Okamoto, Naoshi Yamazaki, Tamotsu Tanaka, Akira Tokumura, Natsuo Ueda
    Abstract:

    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 of Ca2+ 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.

  • Glycerophosphodiesterase GDE4 as a novel lysophospholipase D: a possible involvement in bioactive N-Acylethanolamine biosynthesis.
    Biochimica et biophysica acta, 2015
    Co-Authors: Kazuhito Tsuboi, Toru Uyama, Iffat Ara Sonia Rahman, Yoko Okamoto, Akira Tokumura, Tomohito Inoue, Natsuo Ueda
    Abstract:

    Abstract 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 brain has a lysophospholipase D (lysoPLD) activity hydrolyzing N-Acylethanolamine lysophospholipids to N-Acylethanolamines and that this activity could be partially attributed to glycerophosphodiesterase (GDE) 1. In the present study, we examined catalytic properties of GDE4, another member of the GDE family. When overexpressed in HEK293 cells, murine GDE4 mostly resided in the membrane fraction. Purified GDE4 showed lysoPLD activity toward various lysophospholipids, including N-Acylethanolamine lysophospholipids as well as lysophosphatidylethanolamine and lysophosphatidylcholine. When HEK293 cells were metabolically labeled with N-[14C]palmitoylethanolamine lysophospholipid, the transient expression of GDE4 increased the [14C]palmitoylethanolamide level, while the knockdown of endogenous GDE4 decreased this level. These results suggested that GDE4 functions as an N-Acylethanolamine-generating lysoPLD in living cells. Moreover, the expression of GDE4 increased most species of lysophosphatidic acid (LPA), which can be produced from various lysophospholipids by the lysoPLD activity of GDE4. GDE4 mRNA was widely distributed among mouse tissues including brain, stomach, ileum, colon, and testis. In conclusion, GDE4 may act as a lysoPLD, which is involved in the generation of N-Acylethanolamines and LPA.

  • metabolism of endocannabinoids and related n acylethanolamines canonical and alternative pathways
    FEBS Journal, 2013
    Co-Authors: Natsuo Ueda, Kazuhito Tsuboi, Toru Uyama
    Abstract:

    : Endocannabinoids are endogenous ligands of the cannabinoid receptors CB1 and CB2. Two arachidonic acid derivatives, arachidonoylethanolamide (anandamide) and 2-arachidonoylglycerol, are considered to be physiologically important endocannabinoids. In the known metabolic pathway in mammals, anandamide and other bioactive N-Acylethanolamines, such as palmitoylethanolamide and oleoylethanolamide, are biosynthesized from glycerophospholipids by a combination of Ca(2+)-dependent N-acyltransferase and N-acyl-phosphatidylethanolamine-hydrolyzing phospholipase D, and are degraded by fatty acid amide hydrolase. However, recent studies have shown the involvement of other enzymes and pathways, which include the members of the tumor suppressor HRASLS family (the phospholipase A/acyltransferase family) functioning as Ca(2+)-independent N-acyltransferases, N-acyl-phosphatidylethanolamine-hydrolyzing phospholipaseD-independent multistep pathways via N-acylated lysophospholipid, and N-Acylethanolamine-hydrolyzing acid amidase, a lysosomal enzyme that preferentially hydrolyzes palmitoylethanolamide. Although their physiological significance is poorly understood, these new enzymes/pathways may serve as novel targets for the development of therapeutic drugs. For example, selective N-Acylethanolamine-hydrolyzing acid amidase inhibitors are expected to be new anti-inflammatory and analgesic drugs. In this minireview, we focus on advances in the understanding of these enzymes/pathways. In addition, recent findings on 2-arachidonoylglycerol metabolism are described.

Harald S. Hansen - One of the best experts on this subject based on the ideXlab platform.

  • non endocannabinoid n acylethanolamines and 2 monoacylglycerols in the intestine
    British Journal of Pharmacology, 2019
    Co-Authors: Harald S. Hansen, Vasiliki Vana
    Abstract:

    This review focuses on recent findings of the physiological and pharmacological role of non-endocannabinoid N-Acylethanolamines (NAEs) and 2-monoacylglycerols (2-MAGs) in the intestine and their involvement in the gut-brain signalling. Dietary fat suppresses food intake, and much research concerns the known gut peptides, for example, glucagon-like peptide-1 (GLP-1) and cholecystokinin (CCK). NAEs and 2-MAGs represent another class of local gut signals most probably involved in the regulation of food intake. We discuss the putative biosynthetic pathways and targets of NAEs in the intestine as well as their anorectic role and changes in intestinal levels depending on the dietary status. NAEs can activate the transcription factor PPARα, but studies to evaluate the role of endogenous NAEs are generally lacking. Finally, we review the role of diet-derived 2-MAGs in the secretion of anorectic gut peptides via activation of GPR119. Both PPARα and GPR119 have potential as pharmacological targets for the treatment of obesity and the former for treatment of intestinal inflammation. LINKED ARTICLES: This article is part of a themed section on 8th European Workshop on Cannabinoid Research. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.10/issuetoc.

  • non endocannabinoid n acylethanolamines and monoacylglycerols old molecules new targets
    The Endocannabinoidome#R##N#The World of Endocannabinoids and Related Mediators, 2015
    Co-Authors: Harald S. Hansen, Karen Kleberg, Helle A Hassing
    Abstract:

    Abstract N -Acylethanolamine (NAE) and 2-monoacylglycerol (2-MAG) containing arachidonic acid are being called endocannabinoids since they can activate cannabinoid receptors. The same molecules containing stearic acid, palmitic acid, oleic acid, or linoleic acid cannot activate cannabinoid receptors, and are thus called non-endocannabinoid NAEs and 2-MAGs. However, these molecules do also have biological activities, e.g., via activation of the transcription factor PPARα, which mediate anti-inflammatory, antinociceptive, and anorectic effects. Furthermore, activation of the G-protein coupled receptor GPR119 in the small intestine could mediate release of the incretin hormone GLP-1. The present chapter describes the formation and degradation of these lipid molecules, as well as their pharmacology and their related drug targets.

  • Pitfalls in the sample preparation and analysis of N-Acylethanolamines
    Journal of lipid research, 2010
    Co-Authors: Christian Skonberg, Andreas Artmann, Steen Honoré Hansen, Claus Cornett, Harald S. Hansen
    Abstract:

    N-Acylethanolamines (NAEs) are a group of lipid mediators synthesized in response to a number of physiological and pathological stimuli. Because of the low tissue concentrations of NAEs, analyses often include liquid extraction followed by solid-phase extraction and subsequent quantitation by LC/MS or GC/MS. Reported levels of NAEs vary considerably, however, and often no explanation is given for these discrepancies. Brought on by difficulties encountered during method development, the effects of using four different brands of silica-containing solid phase extraction (SPE) columns and five different brands of chloroform for sample preparation were investigated. Considerable variation in the retention and recoveries of seven NAEs and 2-arachidonoylglycerol existed between the SPE columns. Furthermore, it was found that some chloroforms contained quantifiable amounts of N-palmitoylethanolamine and N-stearoylethanolamine. Finally, it was found that use of one of the chloroforms resulted in a loss of N-oleoylethanolamine from solution due to addition of chlorine to the ω-9 bond. The identity of this reaction product was confirmed by LC-MS/MS and NMR. It is recommended that these aspects of sample preparation and analysis should be thoroughly validated during method development and the relevant information on specific brands used be reported in future communications in order to better estimate the validity of reported quantitative data.

  • N-Acylethanolamines, anandamide and food intake
    Biochemical pharmacology, 2009
    Co-Authors: Harald S. Hansen, Thi Ai Diep
    Abstract:

    Anandamide and the other N-Acylethanolamines, e.g. oleoylethanolamide (OEA), palmitoylethanolamide (PEA), and linoleoylethanolamide (LEA), may be formed by several enzymatic pathways from their precursors, which are the N-acylated ethanolamine phospholipids. The exact enzymatic pathways involved in their biosynthesis in specific tissues are not clarified. It has been suggested that endogenous anandamide could stimulate food intake by activation of cannabinoid receptors in the brain and/or in the intestinal tissue. On the other hand, endogenous OEA and PEA have been suggested to inhibit food intake by acting on receptors in the intestine. At present, there is no clear role for endogenous anandamide in controlling food intake via cannabinoid receptors, neither centrally nor in the gastrointestinal tract. However, OEA, PEA and perhaps also LEA may be involved in regulation of food intake by selective prolongation of feeding latency and post-meal interval. These N-Acylethanolamines seem to be formed locally in the intestine, where they can activate PPARalpha located in close proximity to their site of synthesis. The rapid onset of OEA response and its reliance on an intact vagus nerve suggests that activation of PPARalpha does not result in formation of a transcription-dependent signal but must rely on an unidentified non-genomic signal that translates to activation of vagal afferents. Whether GPR119, TRPV1 and/or intestinal ceramide levels also contribute to the anorectic and weight-reducing effect of exogenous OEA is less clear. Prolonged intake of dietary fat (45 energy%) may promote over-consumption of food by decreasing the endogenous levels of OEA, PEA and LEA in the intestine.

  • Ketogenic diet is antiepileptogenic in pentylenetetrazole kindled mice and decrease levels of N-Acylethanolamines in hippocampus.
    Neurochemistry international, 2008
    Co-Authors: Suzanne L. Hansen, Gitte Petersen, Andreas Artmann, Ane H Nielsen, Katrine E Knudsen, Uffe Kristiansen, Steen H Hansen, Harald S. Hansen
    Abstract:

    The ketogenic diet (KD) is used for the treatment of refractory epilepsy in children, however, the mechanism(s) remains largely unknown. Also, the antiepileptogenic potential in animal models of epilepsy has been poorly addressed. Activation of cannabinoid type-1 receptor (CB(1)-R) upon seizure activity may mediate neuroprotection as may several N-Acylethanolamines. It is unknown how the KD interfere with the endocannabinoid system. We investigated the antiepileptogenic potential of the KD in the pentylenetetrazole kindling model in young mice and measured the hippocampal levels of CB(1)-R by Western blot and of endocannabinoids and N-Acylethanolamines by mass spectrometry. The KD significantly decreased incidence and severity of seizures, and significantly increased the latency to clonic convulsions. There were no changes in levels of endocannabinoids or CB(1)-R expression by either seizure activity or type of diet. The level of oleoylethanolamide as well as the sum of N-Acylethanolamines were significantly decreased by the KD, but were unaffected by seizure activity. The study shows that the KD had clear antiepileptogenic properties in the pentylenetetrazole kindling model and does not support a role of endocannabinoids in this model. The significance of the decreased hippocampal level of oleoylethanolamide awaits further studies.

Toru Uyama - One of the best experts on this subject based on the ideXlab platform.

  • Endocannabinoids and related N-Acylethanolamines: biological activities and metabolism.
    Inflammation and regeneration, 2018
    Co-Authors: Kazuhito Tsuboi, Toru Uyama, Yasuo Okamoto, Natsuo Ueda
    Abstract:

    The plant Cannabis sativa contains cannabinoids represented by Δ9-tetrahydrocannabinol, which exert psychoactivity and immunomodulation through cannabinoid CB1 and CB2 receptors, respectively, in animal tissues. Arachidonoylethanolamide (also referred to as anandamide) and 2-arachidonoylglycerol (2-AG) are well known as two major endogenous agonists of these receptors (termed “endocannabinoids”) and show various cannabimimetic bioactivities. However, only 2-AG is a full agonist for CB1 and CB2 and mediates retrograde signals at the synapse, strongly suggesting that 2-AG is physiologically more important than anandamide. The metabolic pathways of these two endocannabinoids are completely different. 2-AG is mostly produced from inositol phospholipids via diacylglycerol by phospholipase C and diacylglycerol lipase and then degraded by monoacylglycerol lipase. On the other hand, anandamide is concomitantly produced with larger amounts of other N-Acylethanolamines via N-acyl-phosphatidylethanolamines (NAPEs). Although this pathway consists of calcium-dependent N-acyltransferase and NAPE-hydrolyzing phospholipase D, recent studies revealed the involvement of several new enzymes. Quantitatively major N-Acylethanolamines include palmitoylethanolamide and oleoylethanolamide, which do not bind to cannabinoid receptors but exert anti-inflammatory, analgesic, and anorexic effects through receptors such as peroxisome proliferator-activated receptor α. The biosynthesis of these non-endocannabinoid N-Acylethanolamines rather than anandamide may be the primary significance of this pathway. Here, we provide an overview of the biological activities and metabolisms of endocannabinoids (2-AG and anandamide) and non-endocannabinoid N-Acylethanolamines.

  • Mammalian enzymes responsible for the biosynthesis of N-Acylethanolamines.
    Biochimica et biophysica acta. Molecular and cell biology of lipids, 2017
    Co-Authors: Zahir Hussain, Toru Uyama, Kazuhito Tsuboi, Natsuo Ueda
    Abstract:

    Abstract Bioactive N-Acylethanolamines (NAEs) are ethanolamides of long-chain fatty acids, including palmitoylethanolamide, oleoylethanolamide and anandamide. In animal tissues, NAEs are biosynthesized from membrane phospholipids. The classical “transacylation-phosphodiesterase” pathway proceeds via N-acyl-phosphatidylethanolamine (NAPE), which involves the actions of two enzymes, NAPE-generating Ca2+-dependent N-acyltransferase (Ca-NAT) and NAPE-hydrolyzing phospholipase D (NAPE-PLD). Recent identification of Ca-NAT as Ɛ isoform of cytosolic phospholipase A2 enabled the further molecular biological approaches toward this enzyme. In addition, Ca2+-independent NAPE formation was shown to occur by N-acyltransferase activity of a group of proteins named phospholipase A/acyltransferases (PLAAT)-1–5. The analysis of NAPE-PLD-deficient mice confirmed that NAEs can be produced through multi-step pathways bypassing NAPE-PLD. The NAPE-PLD-independent pathways involved three members of the glycerophosphodiesterase (GDE) family (GDE1, GDE4 and GDE7) as well as α/β-hydrolase domain-containing protein (ABHD)4. In this review article, we will focus on recent progress made and latest insights in the enzymes involved in NAE synthesis and their further characterization.

  • Calcium-dependent generation of N-Acylethanolamines and lysophosphatidic acids by glycerophosphodiesterase GDE7
    Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids, 2016
    Co-Authors: Iffat Ara Sonia Rahman, Toru Uyama, Kazuhito Tsuboi, Zahir Hussain, Ryouhei Yamashita, Yoko Okamoto, Naoshi Yamazaki, Tamotsu Tanaka, Akira Tokumura, Natsuo Ueda
    Abstract:

    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 of Ca2+ 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.

  • Glycerophosphodiesterase GDE4 as a novel lysophospholipase D: a possible involvement in bioactive N-Acylethanolamine biosynthesis.
    Biochimica et biophysica acta, 2015
    Co-Authors: Kazuhito Tsuboi, Toru Uyama, Iffat Ara Sonia Rahman, Yoko Okamoto, Akira Tokumura, Tomohito Inoue, Natsuo Ueda
    Abstract:

    Abstract 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 brain has a lysophospholipase D (lysoPLD) activity hydrolyzing N-Acylethanolamine lysophospholipids to N-Acylethanolamines and that this activity could be partially attributed to glycerophosphodiesterase (GDE) 1. In the present study, we examined catalytic properties of GDE4, another member of the GDE family. When overexpressed in HEK293 cells, murine GDE4 mostly resided in the membrane fraction. Purified GDE4 showed lysoPLD activity toward various lysophospholipids, including N-Acylethanolamine lysophospholipids as well as lysophosphatidylethanolamine and lysophosphatidylcholine. When HEK293 cells were metabolically labeled with N-[14C]palmitoylethanolamine lysophospholipid, the transient expression of GDE4 increased the [14C]palmitoylethanolamide level, while the knockdown of endogenous GDE4 decreased this level. These results suggested that GDE4 functions as an N-Acylethanolamine-generating lysoPLD in living cells. Moreover, the expression of GDE4 increased most species of lysophosphatidic acid (LPA), which can be produced from various lysophospholipids by the lysoPLD activity of GDE4. GDE4 mRNA was widely distributed among mouse tissues including brain, stomach, ileum, colon, and testis. In conclusion, GDE4 may act as a lysoPLD, which is involved in the generation of N-Acylethanolamines and LPA.

  • metabolism of endocannabinoids and related n acylethanolamines canonical and alternative pathways
    FEBS Journal, 2013
    Co-Authors: Natsuo Ueda, Kazuhito Tsuboi, Toru Uyama
    Abstract:

    : Endocannabinoids are endogenous ligands of the cannabinoid receptors CB1 and CB2. Two arachidonic acid derivatives, arachidonoylethanolamide (anandamide) and 2-arachidonoylglycerol, are considered to be physiologically important endocannabinoids. In the known metabolic pathway in mammals, anandamide and other bioactive N-Acylethanolamines, such as palmitoylethanolamide and oleoylethanolamide, are biosynthesized from glycerophospholipids by a combination of Ca(2+)-dependent N-acyltransferase and N-acyl-phosphatidylethanolamine-hydrolyzing phospholipase D, and are degraded by fatty acid amide hydrolase. However, recent studies have shown the involvement of other enzymes and pathways, which include the members of the tumor suppressor HRASLS family (the phospholipase A/acyltransferase family) functioning as Ca(2+)-independent N-acyltransferases, N-acyl-phosphatidylethanolamine-hydrolyzing phospholipaseD-independent multistep pathways via N-acylated lysophospholipid, and N-Acylethanolamine-hydrolyzing acid amidase, a lysosomal enzyme that preferentially hydrolyzes palmitoylethanolamide. Although their physiological significance is poorly understood, these new enzymes/pathways may serve as novel targets for the development of therapeutic drugs. For example, selective N-Acylethanolamine-hydrolyzing acid amidase inhibitors are expected to be new anti-inflammatory and analgesic drugs. In this minireview, we focus on advances in the understanding of these enzymes/pathways. In addition, recent findings on 2-arachidonoylglycerol metabolism are described.

Daniele Piomelli - One of the best experts on this subject based on the ideXlab platform.

  • N-Acylethanolamine Acid Amidase (NAAA): Mechanism of Palmitoylethanolamide Hydrolysis Revealed by Mechanistic Simulations
    ACS Catalysis, 2020
    Co-Authors: Laura Scalvini, Andrea Ghidini, Alessio Lodola, Donatella Callegari, Silvia Rivara, Daniele Piomelli, Marco Mor
    Abstract:

    The N-terminal cysteine hydrolase N-Acylethanolamine acid amidase (NAAA) catalyzes the hydrolytic deactivation of the lipid messenger, palmitoylethanolamide (PEA), with optimal activity at acidic p...

  • N-Acylethanolamine Acid Amidase (NAAA): Structure, Function, and Inhibition.
    Journal of medicinal chemistry, 2020
    Co-Authors: Daniele Piomelli, Laura Scalvini, Alessio Lodola, Yannick Fotio, Gilberto Spadoni, Giorgio Tarzia, Marco Mor
    Abstract:

    N-Acylethanolamine acid amidase (NAAA) is an N-terminal cysteine hydrolase primarily found in the endosomal–lysosomal compartment of innate and adaptive immune cells. NAAA catalyzes the hydrolytic ...

  • n acylethanolamine acid amidase naaa structure function and inhibition
    Journal of Medicinal Chemistry, 2020
    Co-Authors: Daniele Piomelli, Laura Scalvini, Alessio Lodola, Yannick Fotio, Gilberto Spadoni, Giorgio Tarzia, Marco Mor
    Abstract:

    N-Acylethanolamine acid amidase (NAAA) is an N-terminal cysteine hydrolase primarily found in the endosomal-lysosomal compartment of innate and adaptive immune cells. NAAA catalyzes the hydrolytic deactivation of palmitoylethanolamide (PEA), a lipid-derived peroxisome proliferator-activated receptor-α (PPAR-α) agonist that exerts profound anti-inflammatory effects in animal models. Emerging evidence points to NAAA-regulated PEA signaling at PPAR-α as a critical control point for the induction and the resolution of inflammation and to NAAA itself as a target for anti-inflammatory medicines. The present Perspective discusses three key aspects of this hypothesis: the role of NAAA in controlling the signaling activity of PEA; the structural bases for NAAA function and inhibition by covalent and noncovalent agents; and finally, the potential value of NAAA-targeting drugs in the treatment of human inflammatory disorders.

  • Novel activity-based probes for N-Acylethanolamine acid amidase
    Chemical communications (Cambridge England), 2017
    Co-Authors: Rita Petracca, Elisa Romeo, Marc P. Baggelaar, Marta Artola, Silvia Pontis, Stefano Ponzano, Herman S. Overkleeft, Mario Van Der Stelt, Daniele Piomelli
    Abstract:

    The cysteine hydrolase, N-Acylethanolamine acid amidase (NAAA) is a promising target for analgesic and anti-inflammatory drugs. Here, we describe the development of two unprecedented NAAA-reactive activity-based probes as research tools for application in the discovery of new inhibitors and for the in-depth characterization of NAAA in its cellular environment.

  • activity based probe for n acylethanolamine acid amidase
    ACS Chemical Biology, 2015
    Co-Authors: Elisa Romeo, Stefano Ponzano, Andrea Armirotti, Maria Summa, Fabio Bertozzi, Gianpiero Garau, Tiziano Bandiera, Daniele Piomelli
    Abstract:

    N-Acylethanolamine acid amidase (NAAA) is a lysosomal cysteine hydrolase involved in the degradation of saturated and monounsaturated fatty acid ethanolamides (FAEs), a family of endogenous lipid signaling molecules that includes oleoylethanolamide (OEA) and palmitoylethanolamide (PEA). Among the reported NAAA inhibitors, α-amino-β-lactone (3-aminooxetan-2-one) derivatives have been shown to prevent FAE hydrolysis in innate-immune and neural cells and to reduce reactions to inflammatory stimuli. Recently, we disclosed two potent and selective NAAA inhibitors, the compounds ARN077 (5-phenylpentyl-N-[(2S,3R)-2-methyl-4-oxo-oxetan-3-yl]carbamate) and ARN726 (4-cyclohexylbutyl-N-[(S)-2-oxoazetidin-3-yl]carbamate). The former is active in vivo by topical administration in rodent models of hyperalgesia and allodynia, while the latter exerts systemic anti-inflammatory effects in mouse models of lung inflammation. In the present study, we designed and validated a derivative of ARN726 as the first activity-based protein profiling (ABPP) probe for the in vivo detection of NAAA. The newly synthesized molecule 1 is an effective in vitro and in vivo click-chemistry activity based probe (ABP), which is able to capture the catalytically active form of NAAA in Human Embryonic Kidney 293 (HEK293) cells overexpressing human NAAA as well as in rat lung tissue. Competitive ABPP with 1 confirmed that ARN726 and ARN077 inhibit NAAA in vitro and in vivo. Compound 1 is a useful new tool to identify activated NAAA both in vitro and in vivo and to investigate the physiological and pathological roles of this enzyme.