An N-acylethanolamine (NAE) is a type of fatty acid amide formed when one of several types of acyl group is linked to the nitrogen atom of ethanolamine. These amides conceptually can be formed from a fatty acid and ethanolamine with the release of a molecule of water, but the known biological synthesis uses a specific phospholipase D to cleave the phospholipid unit from N-acylphosphatidylethanolamines. Another route relies on the transesterification of acyl groups from phosphatidylcholine by an N-acyltransferase (NAT) activity. The suffixes -amine and -amide in these names each refer to the single nitrogen atom of ethanolamine that links the compound together: it is termed "amine" in ethanolamine because it is considered as a free terminal nitrogen in that subunit, while it is termed "amide" when it is considered in association with the adjacent carbonyl group of the acyl subunit. Names for these compounds may be encountered with either "amide" or "amine" varying by author.
Examples of N-acylethanolamines include:
- Anandamide (N-arachidonoylethanolamine; NAE) or arachidonoylethanolamine (AEA: C22H37NO2; 20:4, ω-6) is the amide of arachidonic acid (C20H32O2; 20:4, ω-6) and ethanolamine (MEA: C2H7NO). It is the ligand of both cannabinoid receptors and vanilloid receptor that attenuates pain sensation.
- N-Palmitoylethanolamine (PEA: C18H37NO2; 16:0) is the amide of palmitic acid (C16H32O2; 16:0) and ethanolamine. It is a ligand at CB2 receptors. It has anti-inflammatory activity and also attenuates pain sensation in mammals. NAE 16:0 has also been identified in plants including corn, and seeds of cotton, okra, tomato, castor bean, soya bean and peanuts, but its physiological functions remain unknown,
- N-Oleoylethanolamine (OEA: C20H39NO2; 18:1, ω-9) is the amide of oleic acid (C18H34O2; 18:1) and ethanolamine. It has anorexic effects and enables fat breakdown by stimulating PPAR-alpha. In plants, NAE 18:1 is present abundantly in dry seeds and levels decline during seed imbibition, but its physiological functions are yet to be elucidated. In humans, plasma OEA levels are also found positively correlated with positive mood and emotions.
- N-Stearoylethanolamine (SEA: C20H41NO2; 18:0) is the amide of stearic acid (C18H36O2) and ethanolamine. It has pro-apoptotic activity. It operates independently of the known cannabinoid and vanilloid receptors targeted by anandamide. It is an inhibitor of the sphingolipid signaling pathway, via specific ceramidase inhibition (ceramidase converts ceramide to sphingosine) and blocks the effects of TNF- and arachidonic acid on intracellular Ca2+ concentration.
- N-Docosahexaenoylethanolamine (C24H37NO2; 22:6,ω-10), "synaptamide", is the amide of docosahexaenoic acid (DHA: C22H32O2; 22:6, ω-3) and ethanolamine. It has anti-proliferative effects on prostate cancer cell lines and promotes synaptogenesis, neurogenesis and neuritogenesis, and as an endogenous metabolite of DHA, it promotes brain development and function.
- N-Docosatetraenoylethanolamine (DEA: C24H41NO2; 22:4,ω-6) act on the CB1 receptor, and possible CB2.
- N-homo-gamma-linolenoylethanolamine, or Anandamide (20:3,n-6) (HGLEA: C22H39NO2; 20:3,ω-6).
All are members of the endocannabinoidome, a complex lipid signaling system composed of more than 100 of fatty acid-derived mediators and their receptors, its anabolic and catabolic enzymes of more than 50 proteins, which are deeply involved in the control of energy metabolism and its pathological deviations, as well as immunosuppression.
Beyond vertebrates NAEs are also found to have signaling roles in more primitive organism, implicated as metabolic signals that coordinate nutrient status and lifespan determination in Caenorhabditis elegans, and detected in organisms as diverse as yeast (Saccharomyces cerevisiae), freshwater fish (Esox lucius and Cyprinus carpio), bivalve mollusc (Mytilus galloprovincialis), protists (Tetrahymena thermophila), slime mold (Dictyostelium discoideum), microbes such as bacteria, fungi, and viruses, are all organisms that appear to regulate their endogenous NAE levels via similar enzymatic machinery as mammalian vertebrates, show a widespread occurrence of NAEs, from single-celled organisms to humans, and a highly conserved role for this group of lipids in cell signaling.
As the euphoric feeling described after running, called the "runners high" is, at least in part, due to increased circulating endocannabinoids (eCBs), and these lipid signaling molecules are involved in reward, appetite, mood, memory and neuroprotection, an analysis of endocannabinoid concentrations and moods after singing, dancing, exercise and reading in healthy volunteers, showed that singing increased plasma levels of anandamide (AEA) by 42%, palmitoylethanolamine (PEA) by 53% and oleoylethanolamine (OEA) by 34%, and improved positive mood and emotions. Dancing did not affect eCB levels, but decreased negative mood and emotions. Cycling increased OEA levels by 26%, and reading increased OEA levels by 28%. All the ethanolamines were positively correlated with heart rate. As so, the plasma OEA levels were positively correlated with positive mood and emotions, and AEA levels were seen positively correlated with satiation.
It is found, that the 20:4 NAE (AEA) increase, only appear in response to medium-intensity workout, and the 16:0 NAE (PEA) and 18:1 NAE (OEA) also increases during and after this workout, but are more responsive to lower intensity than 20:4 NAE (AEA). In mice that exercise, show an increase of 20:4 NAE (AEA) and 18:1 NAE (OEA) levels, in association with decreased GABAergic neuron CB1-dependent anxiety.
In exercise addicts, which have increased negative mood in response to exercise deprivation, is found to have lower basal circulating 20:4 NAE (AEA) levels than non-addicted regular runners, and exercise withdrawal and reintroduction only decreases and increases these levels, respectively, in non-addicts, and the lack of response of 20:4 NAE (AEA) in exercise addicts is suggested, that their increased amount of exercise is a homeostatic attempt to increase the endocannabinoide and NAE-tone, with its subsequently activation of related receptors.
Metabolic production of NAEs
Diets in mammals, containing 20:4,n−6 and 22:6,n−3, are found to increase several biologically active NAEs in brain homogenates as metabolic products, like 20:4,n−6 NAE (4-fold), 20:5,n−3 NAE (5-fold), and 22:5,n−3 and 22:6,n−3 NAE (9- to 10-fold). The increase in all of the metabolic NAEs is regarded biologically important, because NAEs having fatty acids with at least 20 carbons and three double bonds bind to CB1 receptors, and endogenously released NAE 20:4 and 2-arachidonylglycerol (2-AG: C23H38O4; 20:4,n-6) are also found to activate CB2 receptors in addition.
The hydrolysis of NAE to free fatty acid (FFA) and ethanolamine (MEA) in animals, is catalyzed by fatty acid amide hydrolase (FAAH) or by a N-acylethanolamine-hydrolyzing acid amidase (NAAA), and the polyunsaturated NAEs such as NAE 18:2, NAE 18:3, or NAE 20:4 can also be oxygenated via lipoxygenase (LOX) or cyclooxygenase (COX), to produce ethanolamide oxylipins, like prostaglandin ethanolamides (prostamide) by COX-2, with various potential bioactivities that may have enhanced affinity with cannabinoid receptors in comparison to their respective non-oxygenated NAEs, as well as to oxygenated eicosanoid ethanolamides, prostaglandins, and leukotrienes, all believed to be important signaling compounds.
The major COX-2 derived prostanoid product from NAE 20:4 (AEA) are prostaglandin E2 (PGE2) ethanolamide (PGE2-EA; prostamide E2) and PGD2 ethanolamide (PGD2-EA; prostamide D2), might have many important functions, as PGE2 and PGD2 are pro-inflammatory mediators responsible for the induction of inflammation, PGE2-EA and PGD2-EA are contrary both growth inhibitory and can induce apoptosis, as well as that NAE 20:4 (AEA) and/or its prostamide metabolites in the renal medulla, may represent medullipin and function as a regulator of body fluid and the mean arterial pressure (MAP).
In addition to metabolism by FAAH, COX-2 and LOXs, NAE 20:4 (AEA) can also undergo oxidation by several of human cytochrome P450 (CYPs) enzymes, resulting in various oxidized lipid species, some of which have biological relevance as CYP-derived epoxides, that can act as a potent agonist of CB2 receptors.
NAEs in plants
N-acylethanolamines (NAEs), constitute a class of lipid compounds naturally present in both animal and plant membranes, as constituents of the membrane-bound phospholipid, N-acylphosphatidylethanolamine (NAPE). NAPE is composed of a third fatty acid moiety linked to the amino head group of the commonly occurring membrane phospholipid, phosphatidylethanolamine.
It is found, that the levels of NAEs increases 10- to 50-fold in tobacco (Nicotiana tabacum) leaves treated with fungal elicitors, as a protection against it, by producing the N-myristoylethanolamine (Myristamide-MEA: C16H33NO2; NAE 14:0), that specific binds to a protein in tobacco membranes with biochemical properties appropriate for the physiological responses, and it do not show identical binding properties to NAE-binding proteins in intact tobacco microsomes, compared to non-intact microsomes. In addition to this, antagonists of mammalian CB receptors was seen to block both of the biological activities previously attributed to NAE 14:0, this endogenous NAE that is accumulated in tobacco cell suspensions and leaves after pathogen elicitor perception, is why it is proposed, that plants possess an NAE-signaling pathway with functional similarities to the “endocannabinoid” pathway of animal systems, and this pathway, in part, participates in xylanase elicitor perception in the tobacco plant, as well as in the Arabidopsis and Medicago truncatula plant tissues.
N-acylethanolamines (NAEs), with its cell-protective and stress-combating action-response of organisms, have showed promise as therapeutic potential in treating bacterial, fungal, and viral infections, as NAEs also exhibit anti-inflammatory, antibacterial, and antiviral properties, which have considerable application potential.
- Pain in amphibians
- Retrograde signaling
- Endocannabinoid system
- Evolutionary history of life
- Evolutionary history of plants
- Okamoto, Y.; Morishita, J.; Tsuboi, K.; Tonai, T.; Ueda, N. (2004). "Molecular characterization of a phospholipase D generating anandamide and its congeners". The Journal of Biological Chemistry. 279 (7): 5298–5305. doi:10.1074/jbc.M306642200. PMID 14634025.
- For example, note synonyms in PubChem for oleoylethanolamine.
- The list and references provided are based on background discussion in Okamoto Y, Morishita J, Tsuboi K, Tonai T, Ueda N (February 2004). "Molecular characterization of a phospholipase D generating anandamide and its congeners". J. Biol. Chem. 279 (7): 5298–305. doi:10.1074/jbc.M306642200. PMID 14634025.
- WA Devane, L Hanus, A Breuer, RG Pertwee, LA Stevenson, G Griffin, D Gibson, A Mandelbaum, A Etinger, and R Mechoulam; Hanus; Breuer; Pertwee; Stevenson; Griffin; Gibson; Mandelbaum; Etinger; Mechoulam (1992). "Isolation and structure of a brain constituent that binds to the cannabinoid receptor". Science. 258 (5090): 1946–1949. Bibcode:1992Sci...258.1946D. doi:10.1126/science.1470919. PMID 1470919.CS1 maint: multiple names: authors list (link)
- Di Marzo (1998). "'Endocannabinoids' and other fatty acid derivatives with cannabimimetic properties: biochemistry and possible physiopathological relevance". Biochimica et Biophysica Acta (BBA) - Lipids and Lipid Metabolism. 1392 (2–3): 153–75. doi:10.1016/s0005-2760(98)00042-3. PMID 9630590.
- Di Marzo; De Petrocellis, L; Fezza, F; Ligresti, A; Bisogno, T (2002). "Anandamide receptors". Prostaglandins, Leukotrienes, and Essential Fatty Acids. 66 (2–3): 377–91. doi:10.1054/plef.2001.0349. PMID 12052051.
- Calignano; La Rana, G; Giuffrida, A; Piomelli, D (1998). "Control of pain initiation by endogenous cannabinoids". Nature. 394 (6690): 277–81. Bibcode:1998Natur.394..277C. doi:10.1038/28393. PMID 9685157.
- Stella, Nephi; Möller, Thomas; Witting, Anke; Franklin, Allyn; Walter, Lisa (2002-06-07). "Astrocytes in Culture Produce Anandamide and Other Acylethanolamides". Journal of Biological Chemistry. 277 (23): 20869–20876. doi:10.1074/jbc.M110813200. ISSN 0021-9258. PMID 11916961.
- Swamy, Musti J.; Kamlekar, Ravi Kanth (2006-07-01). "Molecular packing and intermolecular interactions in two structural polymorphs of N-palmitoylethanolamine, a type 2 cannabinoid receptor agonist". Journal of Lipid Research. 47 (7): 1424–1433. doi:10.1194/jlr.M600043-JLR200. ISSN 0022-2275. PMID 16609146.
- Lambert; Vandevoorde, S; Jonsson, KO; Fowler, CJ (2002). "The palmitoylethanolamide family: a new class of anti-inflammatory agents?". Current Medicinal Chemistry. 9 (6): 663–74. doi:10.2174/0929867023370707. PMID 11945130.
- Rahman, Iffat Ara Sonia; Tsuboi, Kazuhito; Uyama, Toru; Ueda, Natsuo (2014-08-01). "New players in the fatty acyl ethanolamide metabolism". Pharmacological Research. Lipid amide signaling: regulation, physiological roles and pathological implications. 86: 1–10. doi:10.1016/j.phrs.2014.04.001. PMID 24747663.
- Chapman, Kent; Venables, Barney; Markovic, Robert; Blair Jr, Raymond; Bettinger, Chris (1999). "N-Acylethanolamines in Seeds. Quantification of Molecular Species and Their Degradation upon Imbibition". Plant Physiology. 120 (4): 1157–1164. doi:10.1104/pp.120.4.1157. PMC 59349. PMID 10444099.
- Motes, Christy M.; Pechter, Priit; Yoo, Cheol Min; Wang, Yuh-Shuh; Chapman, Kent D.; Blancaflor, Elison B. (2005-12-12). "Differential effects of two phospholipase D inhibitors, 1-butanol and N-acylethanolamine, on in vivo cytoskeletal organization and Arabidopsis seedling growth". Protoplasma. 226 (3–4): 109–123. doi:10.1007/s00709-005-0124-4. ISSN 0033-183X. PMID 16333570.
- Rodríguez De Fonseca; Navarro, M; Gómez, R; Escuredo, L; Nava, F; Fu, J; Murillo-Rodríguez, E; Giuffrida, A; Loverme, J (2001). "An anorexic lipid mediator regulated by feeding". Nature. 414 (6860): 209–12. Bibcode:2001Natur.414..209R. doi:10.1038/35102582. PMID 11700558.
- Kilaru, Aruna; Tamura, Pamela; Isaac, Giorgis; Welti, Ruth; Venables, Barney J.; Seier, Edith; Chapman, Kent D. (2012-06-07). "Lipidomic analysis of N-acylphosphatidylethanolamine molecular species in Arabidopsis suggests feedback regulation by N-acylethanolamines". Planta. 236 (3): 809–824. doi:10.1007/s00425-012-1669-z. ISSN 0032-0935. PMC 3579225. PMID 22673881.
- Stone, Nicole L.; Millar, Sophie A.; Herrod, Philip J. J.; Barrett, David A.; Ortori, Catharine A.; Mellon, Valerie A.; O’Sullivan, Saoirse E. (2018-11-26). "An Analysis of Endocannabinoid Concentrations and Mood Following Singing and Exercise in Healthy Volunteers". Frontiers in Behavioral Neuroscience. 12: 269. doi:10.3389/fnbeh.2018.00269. ISSN 1662-5153. PMC 6275239. PMID 30534062. Material was copied from this source, which is available under a Creative Commons Attribution 4.0 International License.
- Tripathy, Swati; Kleppinger-Sparace, Kathryn; Dixon, Richard A.; Chapman, Kent D. (2003). "N-Acylethanolamine Signaling in Tobacco Is Mediated by a Membrane-Associated, High-Affinity Binding Protein". Plant Physiology. 131 (4): 1781–1791. doi:10.1104/pp.102.014936. ISSN 0032-0889. PMC 166934. PMID 12692337.
- Hofmann, Ulrich; Domeier, Erik; Frantz, Stefan; Laser, Martin; Weckler, Barbara; Kuhlencordt, Peter; Heuer, Stefan; Keweloh, Boris; Ertl, Georg (2003-06-01). "Increased myocardial oxygen consumption by TNF-α is mediated by a sphingosine signaling pathway". American Journal of Physiology. Heart and Circulatory Physiology. 284 (6): H2100–H2105. doi:10.1152/ajpheart.00888.2002. ISSN 0363-6135. PMID 12560208.
- Amadou, Aïssata; Nawrocki, Artur; Best-Belpomme, Martin; Pavoine, Catherine; Pecker, Françoise (2002-06-01). "Arachidonic acid mediates dual effect of TNF-α on Ca2+ transients and contraction of adult rat cardiomyocytes". American Journal of Physiology. Cell Physiology. 282 (6): C1339–C1347. doi:10.1152/ajpcell.00471.2001. ISSN 0363-6143. PMID 11997249.
- Brown I, Cascio MG, Wahle KW, Smoum R, Mechoulam R, Ross RA, et al. (2010). "Cannabinoid receptor-dependent and -independent anti-proliferative effects of omega-3 ethanolamides in androgen receptor-positive and -negative prostate cancer cell lines". Carcinogenesis. 31 (9): 1584–91. doi:10.1093/carcin/bgq151. PMC 2930808. PMID 20660502.
- Kim HY, Spector AA, Xiong ZM (2011). "A synaptogenic amide N-docosahexaenoylethanolamide promotes hippocampal development". Prostaglandins Other Lipid Mediat. 96 (1–4): 114–20. doi:10.1016/j.prostaglandins.2011.07.002. PMC 3215906. PMID 21810478.
- Lee, Ji-Won; Huang, Bill X.; Kwon, HeungSun; Rashid, Md Abdur; Kharebava, Giorgi; Desai, Abhishek; Patnaik, Samarjit; Marugan, Juan; Kim, Hee-Yong (2016-10-19). "Orphan GPR110 (ADGRF1) targeted by N-docosahexaenoylethanolamine in development of neurons and cognitive function". Nature Communications. 7: 13123. doi:10.1038/ncomms13123. ISSN 2041-1723. PMC 5075789. PMID 27759003.
- Stella, Nephi; Mackie, Ken; Kunos, George; Xie, Yiheng; Wade, Christian; Witting, Anke; Franklin, Allyn; Walter, Lisa (2003-02-15). "Nonpsychotropic Cannabinoid Receptors Regulate Microglial Cell Migration". Journal of Neuroscience. 23 (4): 1398–1405. doi:10.1523/JNEUROSCI.23-04-01398.2003. ISSN 0270-6474. PMC 6742252. PMID 12598628.
- Magotti P, Bauer I, Igarashi M, Babagoli M, Marotta R, Piomelli D, Garau G (Dec 2014). "Structure of Human N-Acylphosphatidylethanolamine-Hydrolyzing Phospholipase D: Regulation of Fatty Acid Ethanolamide Biosynthesis by Bile Acids". Structure. 23 (3): 598–604. doi:10.1016/j.str.2014.12.018. PMC 4351732. PMID 25684574.
- Silvestri, Cristoforo; Di Marzo, Vincenzo (2019-08-20). "Lifestyle and Metabolic Syndrome: Contribution of the Endocannabinoidome". Nutrients. 11 (8). 1956. doi:10.3390/nu11081956. PMC 6722643. PMID 31434293.
- Surowiec, Izabella; Gouveia-Figueira, Sandra; Orikiiriza, Judy; Lindquist, Elisabeth; Bonde, Mari; Magambo, Jimmy; Muhinda, Charles; Bergström, Sven; Normark, Johan (2017-09-08). "The oxylipin and endocannabidome responses in acute phase Plasmodium falciparum malaria in children". Malaria Journal. 16 (1): 358. doi:10.1186/s12936-017-2001-y. ISSN 1475-2875. PMC 5591560. PMID 28886714.
- Blancaflor, Elison B.; Kilaru, Aruna; Keereetaweep, Jantana; Khan, Bibi Rafeiza; Faure, Lionel; Chapman, Kent D. (2014). "N-Acylethanolamines: lipid metabolites with functions in plant growth and development". The Plant Journal. 79 (4): 568–583. doi:10.1111/tpj.12427. ISSN 1365-313X. PMID 24397856.
- Cite error: The named reference
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- Berger, Alvin; Crozier, Gayle; Bisogno, Tiziana; Cavaliere, Paolo; Innis, Sheila; Di Marzo, Vincenzo (2001-05-22). "Anandamide and diet: Inclusion of dietary arachidonate and docosahexaenoate leads to increased brain levels of the corresponding N-acylethanolamines in piglets". Proceedings of the National Academy of Sciences of the United States of America. 98 (11): 6402–6406. doi:10.1073/pnas.101119098. ISSN 0027-8424. PMC 33480. PMID 11353819.
- Dyall, Simon C. (2017). "Interplay Between n-3 and n-6 Long-Chain Polyunsaturated Fatty Acids and the Endocannabinoid System in Brain Protection and Repair". Lipids. 52 (11): 885–900. doi:10.1007/s11745-017-4292-8. ISSN 0024-4201. PMC 5656721. PMID 28875399.
- Gaitán, Adriana V; Wood, JodiAnne T; Solomons, Noel W; Donohue, Juliana A; Ji, Lipin; Liu, Yingpeng; Nikas, Spyros P; Zhang, Fan; Allen, Lindsay H (2019-03-27). "Endocannabinoid Metabolome Characterization of Milk from Guatemalan Women Living in the Western Highlands". Current Developments in Nutrition. 3 (6): nzz018. doi:10.1093/cdn/nzz018. ISSN 2475-2991. PMC 6517780. PMID 31111118.
- Keereetaweep, Jantana; Chapman, Kent D. (2016). "Lipidomic Analysis of Endocannabinoid Signaling: Targeted Metabolite Identification and Quantification". Neural Plasticity. 2016: 2426398. doi:10.1155/2016/2426398. ISSN 2090-5904. PMC 4709765. PMID 26839710.
- Ramesha, Chakkodabylu S.; Ives, Danial; Yu, Ming (1997-08-22). "Synthesis of Prostaglandin E2 Ethanolamide from Anandamide by Cyclooxygenase-2". Journal of Biological Chemistry. 272 (34): 21181–21186. doi:10.1074/jbc.272.34.21181. ISSN 0021-9258. PMID 9261124.
- Patsos, H A; Hicks, D J; Dobson, R R H; Greenhough, A; Woodman, N; Lane, J D; Williams, A C; Paraskeva, C (2005). "The endogenous cannabinoid, anandamide, induces cell death in colorectal carcinoma cells: a possible role for cyclooxygenase 2". Gut. 54 (12): 1741–1750. doi:10.1136/gut.2005.073403. ISSN 0017-5749. PMC 1774787. PMID 16099783.
- Ritter, Joseph K.; Li, Cao; Xia, Min; Poklis, Justin L.; Lichtman, Aron H.; Abdullah, Rehab A.; Dewey, William L.; Li, Pin-Lan (2012). "Production and Actions of the Anandamide Metabolite Prostamide E2 in the Renal Medulla". The Journal of Pharmacology and Experimental Therapeutics. 342 (3): 770–779. doi:10.1124/jpet.112.196451. ISSN 0022-3565. PMC 3422528. PMID 22685343.
- Stelt, Marcelis van der; Noordermeer, Minke A.; Kiss, Tünde; Zadelhoff, Guus van; Merghart, Ben; Veldink, Gerrit A.; Vliegenthart, Johannes F. G. (2000). "Formation of a new class of oxylipins from N-acyl(ethanol)amines by the lipoxygenase pathway". European Journal of Biochemistry. 267 (7): 2000–2007. doi:10.1046/j.1432-1327.2000.01203.x. hdl:1874/5348. ISSN 1432-1033. PMID 10727939.
- Gachet, María Salomé; Schubert, Alexandra; Calarco, Serafina; Boccard, Julien; Gertsch, Jürg (2017-01-25). "Targeted metabolomics shows plasticity in the evolution of signaling lipids and uncovers old and new endocannabinoids in the plant kingdom". Scientific Reports. 7: 41177. doi:10.1038/srep41177. ISSN 2045-2322. PMC 5264637. PMID 28120902.
- N-Acylphosphatidylethanolamines (NAPEs), N-acylethanolamines (NAEs) and Other Acylamides: Metabolism, Occurrence and Functions in Plants; Center for Plant Lipid Research, Department of Biological Sciences, University of North Texas, Denton, TX, USA