The endocannabinoid anandamide is a precursor for the signaling lipid N-arachidonoyl glycine by two distinct pathways

Bradshaw, Heather B.; Rimmerman, Neta; Hu, Sherry Shu Jung; Benton, Valery M.; Stuart, Jordyn; Masuda, Kim; Cravatt, Benjamin F.; O'Dell, David K.; Walker, J. Michael

doi:10.1186/1471-2091-10-14

Cited by 111 publications

(131 citation statements)

References 27 publications

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“…Consistent with these earlier results, decreased expression of PAM resulted in the accumulation of N-oleoylglycine and a decrease in oleamide levels relative to endogenous amounts the conjugation of the resulting acyl-CoA with glycine. It is known that long-chain fatty acid amides can be produced by more than one route; there is evidence for their biosynthesis by the sequential oxidation of N-acylethanolamines (16)(17)(18)20). There is evidence that this alternative pathway does take place in the N 18 TG 2 cells (28).…”

Section: Sirna Knockdown Of Glyatl3 Results In Decreased Levels Of N-mentioning

confidence: 99%

“…There are two proposed pathways for N-acylgycine biosynthesis: a) sequential oxidation of an N-acylethanolamine by alcohol dehydrogenase and aldehyde dehydrogenase (16)(17)(18)(19); and b) activation of a fatty acid by an acyl-CoA synthetase followed by the conjugation with glycine via a long-chain specific glycine N-acyltransferase (GLYAT) (Fig. 1) (5,9,12,19,20).…”

Section: N-oleoylglycine N-palmitoylglycine N-arachidonoylglycine-dmentioning

confidence: 99%

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Glycine N-acyltransferase-like 3 is responsible for long-chain N-acylglycine formation in N18TG2 cells

Jeffries

Dempsey²,

Farrell³

et al. 2016

Journal of Lipid Research

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The long-chain fatty acid amides are an emerging family of bioactive lipids with members that include N-acyl amino acids, primary fatty acid amides (PFAMs), N-acylarylalkylamides, N-acylethanolamines, and N-monoacylpolyamines. Fatty acid amides were first identified from biological sources over 50 years ago with the isolation and identification of N-palmitoylethanolamine from egg yolk in 1957 (1) and, in 1965, N-palmitoylethanolamine and N-stearoylethanolamine in several tissues from rat and guinea pig (2). The discovery of N-arachidonoylethanolamine (anandamide) as the endogenous ligand for the mammalian brain cannabinoid receptor CB 1 sparked a dramatic interest in the fatty acid amides (3). Since these early discoveries, a diversity of long-chain fatty acid amides have been identified in mammals and, more recently, in invertebrates as well (4)(5)(6)(7)(8).The N-fatty acylglycines, a subclass of the N-fatty acyl amino acids, are an important class of cell signaling lipids that are distributed throughout the central nervous system and the rest of the body (6, 7, 9). Identification of glycine conjugates dates back to the 1820s with the identification of N-benzoylglycine (hippurate) as a mammalian metabolite (10). N-arachidonoylglycine was the first longchain N-acylglycine identified from a mammalian source and was determined to have anti-nociceptive and antiinflammatory effects in rat models of pain (11). Since

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Section: Sirna Knockdown Of Glyatl3 Results In Decreased Levels Of N-mentioning

confidence: 99%

Section: N-oleoylglycine N-palmitoylglycine N-arachidonoylglycine-dmentioning

confidence: 99%

Glycine N-acyltransferase-like 3 is responsible for long-chain N-acylglycine formation in N18TG2 cells

Jeffries

Dempsey²,

Farrell³

et al. 2016

Journal of Lipid Research

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“…Npalmitoyl-ethanolamide and, particularly, N-oleoyl-and Nlinoleoyl-ethanolamide, by acting as alternative substrates for FAAH [35], can retard the degradation of anandamide, and the same is true for some unsaturated N-acyl-amino acids, particularly N-arachidonoyl-glycine [36,37], and N-acyl-taurines [38]. Furthermore, N-palmitoyl-ethanolamide can reduce the expression of FAAH after prolonged exposure of human breast cancer cells [39].…”

Section: Other Ways Through Which Non-thc Plant Cannabinoids Influencmentioning

confidence: 99%

The Endocannabinoid System and its Modulation by Phytocannabinoids

2015

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The endocannabinoid system is currently defined as the ensemble of the two 7-transmembrane-domain and G protein-coupled receptors for Δ 9 -tetrahydrocannabinol (but not for most other plant cannabinoids or phytocannabinoids)-cannabinoid receptor type-1 (CB 1 R) and cannabinoid receptor type-2 (CB 2 R); their two most studied endogenous ligands, the "endocannabinoids" N-arachidonoylethanolamine (anandamide) and 2-arachidonoylglycerol (2-AG); and the enzymes responsible for endocannabinoid metabolism. However, anandamide and 2-AG, and also the phytocannabinoids, have more molecular targets than just CB 1 R and CB 2 R. Furthermore, the endocannabinoids, like most other lipid mediators, have more than just one set of biosynthetic and degrading pathways and enzymes, which they often share with "endocannabinoid-like" mediators that may or may not interact with the same proteins as Δ 9 -tetrahydrocannabinol and other phytocannabinoids. In some cases, these degrading pathways and enzymes lead to molecules that are not inactive and instead interact with other receptors. Finally, some of the metabolic enzymes may also participate in the chemical modification of molecules that have very little to do with endocannabinoid and cannabinoid targets. Here, we review the whole world of ligands, receptors, and enzymes, a true "endocannabinoidome", discovered after the cloning of CB 1 R and CB 2 R and the identification of anandamide and 2-AG, and its interactions with phytocannabinoids.

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“…3A , C ). There is evidence that the NAEs can serve as precursors to the N -fatty acylglycines and the PFAMs (44)(45)(46); this is the fi rst evidence that such chemistry can take place in the N 18 TG 2 cells. Palmitamide was the most abundant PFAM after incubation of the N 18 TG 2 cells with palmitic acid.…”

Section: Analysis Of Background Pfamsmentioning

confidence: 99%

“…Given there are multiple pathways known for the biosynthesis of the NAEs (44)(45)(46), it is likely that there are also multiple routes for the in vivo production of the N -fatty acylglycines and the PFAMs ( 29,30 ). In fact, Bradshaw et al ( 46 ) have shown that the N -fatty acylglycines are produced in the C6 glioma cells via the glycine-dependent and NAE-dependent reactions shown in Fig. 1 .…”

Section: Use Of Bsa As a Fatty Acid Carriermentioning

confidence: 99%

Primary fatty acid amide metabolism: conversion of fatty acids and an ethanolamine in N18TG2 and SCP cells

Farrell¹,

Chen

Barazanji

et al. 2012

Journal of Lipid Research

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ceramides and sphingolipids ( 1, 2 ). Primary fatty acid amides (PFAM), R-CO-NH 2 with R being a long-chain fatty acid, were fi rst identifi ed from a biological source in 1989 with the identifi cation of palmitamide, palmitoleamide, oleamide, elaidamide, and linoleamide in luteal phase plasma ( 3 ). At the time of their discovery, the biological function of these mammalian PFAMs was unknown. Interest in the PFAMs dramatically intensifi ed with the discoveries that oleamide accumulated in the cerebrospinal fl uid (CSF) of sleep-deprived cats, that it is a natural component of the CSF in the cat, rat, and human, and that the administration of synthetic oleamide induced physiological sleep in rats ( 4 ). Intriguingly, later studies found that oleamide levels in the brain of the ground squirrel were ‫ف‬ 2.5-fold higher in hibernating animals relative to those found in nonhibernating animals ( 5 ). Other functions ascribed to oleamide, since its discovery as a sleep-inducing PFAM, include the ability to modulate gap junction communication in glial cells ( 6, 7 ), tracheal epithelial cells ( 8 ), seminiferous tubule cells ( 9 ), and fi broblasts ( 10 ); to allosterically activate the GABA A receptors and specifi c subtypes of the serotonin receptor ( 11-13 ); to affect memory processes ( 14 ); to increase food intake ( 15 ); to reduce anxiety and pain ( 16,17 ); to depress body temperature and locomotor activity ( 17,18 ); to stimulate Ca(II) release ( 19 ); and to relax blood vessels ( 20,21 ).Although much of the research regarding the PFAMs has focused on oleamide, studies show that some of the other known PFAMs are bioactive. Palmitamide is weakly anticonvulsant ( 22 ); linoleamide regulates Ca(II) fl ux ( 23 ) and inhibits the erg current ( 24 ); and erucamide stimulates Abstract Primary fatty acid amides (PFAM) are important signaling molecules in the mammalian nervous system, binding to many drug receptors and demonstrating control over sleep, locomotion, angiogenesis, and many other processes. Oleamide is the best-studied of the primary fatty acid amides, whereas the other known PFAMs are signifi cantly less studied. Herein, quantitative assays were used to examine the endogenous amounts of a panel of PFAMs, as well as the amounts produced after incubation of mouse neuroblastoma N 18 TG 2 and sheep choroid plexus (SCP) cells with the corresponding fatty acids or N -tridecanoylethanolamine. Although fi ve endogenous primary amides were discovered in the N 18 TG 2 and SCP cells, a different pattern of relative amounts were found between the two cell lines. Higher amounts of primary amides were found in SCP cells, and the conversion of N -tridecanoylethanolamine to tridecanamide was observed in the two cell lines. The data reported here show that the N 18 TG 2 and SCP cells are excellent model systems for the study of PFAM metabolism. Furthermore, the data support a role for the N -acylethanolamines as precursors for the PFAMs and provide valuable new kinetic results useful in modeling the metabolic fl ux throug...

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The endocannabinoid anandamide is a precursor for the signaling lipid N-arachidonoyl glycine by two distinct pathways

Cited by 111 publications

References 27 publications

Glycine N-acyltransferase-like 3 is responsible for long-chain N-acylglycine formation in N18TG2 cells

Glycine N-acyltransferase-like 3 is responsible for long-chain N-acylglycine formation in N18TG2 cells

The Endocannabinoid System and its Modulation by Phytocannabinoids

Primary fatty acid amide metabolism: conversion of fatty acids and an ethanolamine in N18TG2 and SCP cells

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