N-Acylamides

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Amide.svg

N-acyl amides are a general class of endogenous fatty acid compounds characterized by a fatty acyl group linked to a primary amine metabolite by an amide bond. Broadly speaking, N-acyl amides fall into several categories: amino acid conjugates (e.g., N-arachidonoyl-glycine), neurotransmitter conjugates (e.g., N-arachidonoyl-serotonin), ethanolamine conjugates (e.g., anandamide), and taurine conjugates (e.g., N-palmitoyl-taurine). N-acyl amides have pleiotropic signaling functions in physiology, including in cardiovascular function, metabolic homeostasis, memory, cognition, pain, motor control and others. [1] Initial attention focused on N-acyl amides present in mammalian organisms, however recently lipid signaling systems consisting of N-acyl amides have also been found to be present in invertebrates, such as Drosophila melanogaster. [2] N-acyl amides play important roles in many biochemical pathways involved in a variety of physiological and pathological processes, as well as the metabolic enzymes, transporters, and receptors that regulate their signaling.

Contents

Compounds

ClassCommon Name
2-acyl glycerols 2-oleoyl glycerol †#
2-linoleoyl glycerol †# *
2-arachidonoyl glycerol †
N-acyl alanineN-palmitoyl alanine †#
N-stearoyl alanine †#
N-oleoyl alanine †#
N-linoleoyl alanine #
N-arachidonoyl alanine †
N-docosahexaenoyl alanine †
N-acyl ethanolamine N-lauroylethanolamine *
N-myristoylethanolamine *
N-palmitoyl ethanolamine †# *
N-stearoyl ethanolamine †#
N-oleoyl ethanolamine †#
N-linoleoyl ethanolamine †#
N-arachidonoyl ethanolamine †
N-docosahexaenoyl ethanolamine †
N-acyl dopamineN-palmitoyl dopamine †
N-stearoyl dopamine †
N-oleoyl dopamine †
N-arachidonoyl dopamine †
N-acyl GABAN-palmitoyl GABA †
N-stearoyl GABA †
N-oleoyl GABA †#
N-linoleoyl GABA #
N-arachidonoyl GABA †
N-docosahexaenoyl GABA †
N-acyl glycineN-palmitoyl glycine †#
N-stearoyl glycine †#
N-oleoyl glycine †#
N-linoleoyl glycine †#
N-arachidonoyl glycine †
N-docosahexaenoyl glycine †
N-acyl leucineN-palmitoyl leucine †#
N-stearoyl leucine #
N-oleoyl leucine †#
N-linoleoyl leucine #
N-docosahexaenoyl leucine †
N-acyl methionineN-palmitoyl methionine †#
N-stearoyl methionine †
N-oleoyl methionine †#
N-linoleoyl methionine #
N-arachidonoyl methionine †
N-docosahexaenoyl methionine †
N-acyl phenylalanineN-palmitoyl phenylalanine †#
N-stearoyl phenylalanine †#
N-oleoyl phenylalanine †#
N-linoleoyl phenylalanine #
N-arachidonoyl phenylalanine †
N-docosahexaenoyl phenylalanine †
N-acyl prolineN-palmitoyl proline †#
N-stearoyl proline †#
N-oleoyl proline †#
N-linoleoyl proline #
N-arachidonoyl proline †
N-docosahexaenoyl proline †
N-acyl serotoninN-palmitoyl serotonin †
N-stearoyl serotonin †
N-oleoyl serotonin †
N-eicosapentaenoyl serotonin †
N-arachidonoyl serotonin †
N-docosahexaenoyl serotonin †
N-acyl serineN-palmitoyl serine †#
N-stearoyl serine †#
N-oleoyl serine †#
N-linoleoyl serine #
N-arachidonoyl serine †
N-docosahexaenoyl serine †
N-acyl taurineN-palmitoyl taurine †
N-stearoyl taurine †
N-arachidonoyl taurine †
N-acyl tryptophanN-palmitoyl tryptophan †#
N-stearoyl tryptophan †#
N-oleoyl tryptophan †#
N-linoleoyl tryptophan #
N-arachidonoyl tryptophan †
N-docosahexaenoyl tryptophan †
N-acyl tyrosineN-palmitoyl tyrosine †#
N-stearoyl tyrosine †#
N-oleoyl tyrosine †#
N-linoleoyl tyrosine #
N-arachidonoyl tyrosine †
N-docosahexaenoyl tyrosine †
N-acyl valineN-palmitoyl valine †#
N-stearoyl valine †#
N-oleoyl valine †#
N-nervonoyl valine †
N-linoleoyl valine #
N-docosahexaenoyl valine †

†-Compound found in mammalian species [2] [3] [4] [5] [6] [7] [8] [9] [10] [11]

#-Compound found in invertebrate (Drosophila melanogaster) species [2] [12] [13] [14]

*-Compound found in plant species [15] [16] [17] [18]

Enzymatic biosynthesis and degradation

The enzymatic biosynthesis of the N-acyl amide class of metabolites is a topic of active research with various pathways being discovered for specific N-acyl amides. For example, a proposed biosynthetic pathway for the N-acyl ethanolamines (NAEs) has been the hydrolysis of an unusual phospholipid precursor, N-acyl-phosphatidylethanolamine (NAPE), by a phospholipase D activity to liberate NAE and, as a byproduct, phosphatidic acid. Mice deficient in the enzyme NAPE-PLD show decreased in a subset of brain NAEs, providing genetic evidence for this proposal, at least for a subset of the NAEs. Other biosynthetic pathways do exist and are currently being elucidated. Two possible alternative routes are via lysoNAPE or phosphate-NAE.

The degradation of NAEs in vivo is largely mediated by an enzyme called fatty acid amide hydrolase (FAAH), which catalyzes the hydrolysis of NAEs into fatty acids and ethanolamine. Mice deficient in FAAH show complete loss of NAE degradation activity in tissues and dramatic elevations in tissue levels of NAEs.

FAAH also mediates the degradation of a separate class of N-acyl amides, the N-acyl taurines (NATs). FAAH knockout mice also show dramatic increases in tissue and blood NATs. The enzymatic biosynthesis of NATs remains unknown.

A distinct circulating enzyme, peptidase M20 domain containing 1 (PM20D1), can catalyze the bidirectional the condensation and hydrolysis of a variety of N-acyl amino acids in vitro. In vivo, PM20D1 overexpression increases the levels of various N-acyl amino acids in blood, demonstrating that this enzyme can contribute to N-acyl amino acid biosynthesis. [19] PM20D1 knockout mice have complete loss of N-acyl amino acid hydrolysis activity in blood and tissues with concomitant bidirectional dysregulation of endogenous N-acyl amino acids. [20]

Biological activity

N-acyl amides have been shown to play an important role in a variety of physiological functions as lipid signaling molecule. Apart from the aforementioned roles in cardiovascular function, memory, cognition, pain, and motor control, the compounds have also been shown to play a role in cell migration, inflammation and certain pathological conditions such as diabetes, cancer, neurodegenerative disease, and obesity. [11]

In a more general sense, one of the key characteristics of the N-acyl amide group of compounds is their ubiquitous nature. Research has shown the presence of the compounds in mice, Drosophila melanogaster, Arabidopsis, C. Elegans, Cerevisiae (yeast), Pseudomonas Syringae, olive oil and PYD media [21] . This diverse presence of N-acyl amides attests to their importance in multiple biological systems and also shows that the detected presence of specific N-acyl amides in a number of species, including humans, may be endogenous or exogenous.

N-acyl amides are primarily involved in cell-to-cell communication in biological systems. An example of this is the lipid signaling system involving transient receptor potential channels (TRP), which interact with N-acyl amides such as N-arachidonoyl ethanolamide (Anandamide), N-arachidonoyl dopamine and others in an opportunistic fashion. [22] This signaling system has been shown to play a role in the physiological processes involved in inflammation. [23] Other N-acyl amides, including N-oleoyl-glutamine, have also been characterized as TRP channel antagonists. [20]

An application of N-acyl amides that is currently at the forefront of related research is the correlation between oleoyl serine and bone remodeling. Recent research has shown that oleoyl serine, an N-acyl amide found in olive oil amongst other sources, plays a role in the proliferation of osteoblast activity and the inhibition of osteoclast activity. [24] Further research regarding this application of oleoyl serine is set to take place to explore the possible correlation between the consumption of the compound by individuals at risk for osteoporosis.

Certain N-acyl amino acids can act as chemical uncouplers and directly stimulate mitochondrial respiration. These N-acyl amino acids are characterized by medium chain, unsaturated fatty acyl chains and neutral amino acid head groups. [25] Administration of these N-acyl amino acids to mice elevates energy expenditure leading to profound body weight loss and improvement of glucose homeostasis. [26]

Overall, the applications of N-acyl amides in biological settings are abundant. As mentioned, their importance in cell signaling in a variety systems leading to various physiological roles and in turn therapeutic capabilities, which gives all the more reason to continue the extensive research being conducted on the compounds today.

Several N-acyl amides have been demonstrated to physiologically activate G-protein coupled receptors. Anandamide activates the cannabinoid receptors CB1 and CB2. FAAH knockout mice show increased anandamide levels in vivo and cannabinoid-receptor dependent behaviors including antinociception and anxiolysis. GPR18, GPR55, GPR92 have also been proposed to be activated by various N-acyl amides, though the physiological relevance of these assignments remains unknown.

Related Research Articles

<span class="mw-page-title-main">Anandamide</span> Chemical compound (fatty acid neurotransmitter)

Anandamide (ANA), also known as N-arachidonoylethanolamine (AEA), an N-acylethanolamine (NAE), is a fatty acid neurotransmitter. Anandamide was the first endocannabinoid to be discovered: it participates in the body's endocannabinoid system by binding to cannabinoid receptors, the same receptors that the psychoactive compound THC in cannabis acts on. Anandamide is found in nearly all tissues in a wide range of animals. Anandamide has also been found in plants, including small amounts in chocolate. The name 'anandamide' is taken from the Sanskrit word ananda, which means "joy, bliss, delight", plus amide.

<span class="mw-page-title-main">URB597</span> Chemical compound

URB597 (KDS-4103) is a relatively selective and irreversible inhibitor of the enzyme fatty acid amide hydrolase (FAAH). FAAH is the primary degradatory enzyme for the endocannabinoid anandamide and, as such, inhibition of FAAH leads to an accumulation of anandamide in the CNS and periphery where it activates cannabinoid receptors. URB597 has been found to elevate anandamide levels and have activity against neuropathic pain in a mouse model.

Fatty acid desaturases are a family of enzymes that convert saturated fatty acids into unsaturated fatty acids and polyunsaturated fatty acids. For the common fatty acids of the C18 variety, desaturases convert stearic acid into oleic acid. Other desaturases convert oleic acid into linolenic acid, which is the precursor to alpha-linolenic acid, gamma-linolenic acid, and eicosatrienoic acid.

The endocannabinoid system (ECS) is a biological system composed of endocannabinoids, which are endogenous lipid-based retrograde neurotransmitters that bind to cannabinoid receptors (CBRs), and cannabinoid receptor proteins that are expressed throughout the vertebrate central nervous system and peripheral nervous system. The endocannabinoid system remains under preliminary research, but may be involved in regulating physiological and cognitive processes, including fertility, pregnancy, pre- and postnatal development, various activity of immune system, appetite, pain-sensation, mood, and memory, and in mediating the pharmacological effects of cannabis. The ECS plays an important role in multiple aspects of neural functions, including the control of movement and motor coordination, learning and memory, emotion and motivation, addictive-like behavior and pain modulation, among others.

<span class="mw-page-title-main">Fatty-acid amide hydrolase 1</span>

Fatty-acid amide hydrolase 1 or FAAH-1(EC 3.5.1.99, oleamide hydrolase, anandamide amidohydrolase) is a member of the serine hydrolase family of enzymes. It was first shown to break down anandamide (AEA), an N-acylethanolamine (NAE) in 1993. In humans, it is encoded by the gene FAAH. FAAH also regulate the contents of NAE's in Dictyostelium discoideum, as they modulate their NAE levels in vivo through the use of a semispecific FAAH inhibitor.

<span class="mw-page-title-main">TRPV1</span> Human protein for regulating body temperature

The transient receptor potential cation channel subfamily V member 1 (TRPV1), also known as the capsaicin receptor and the vanilloid receptor 1, is a protein that, in humans, is encoded by the TRPV1 gene. It was the first isolated member of the transient receptor potential vanilloid receptor proteins that in turn are a sub-family of the transient receptor potential protein group. This protein is a member of the TRPV group of transient receptor potential family of ion channels. And a receptor being clearly present in bacteria, the oldest organisms on Earth known to express phosphatidylethanolamine, the precursor to endocannabinoids, in their cytoplasmic membranes, and fatty acid metabolites with affinity for this CB receptor are produced by cyanobacteria, which diverged from eukaryotes at least 2000 million years ago (MYA).

<span class="mw-page-title-main">AM404</span> Active metabolite of paracetamol

AM404, also known as N-arachidonoylphenolamine, is an active metabolite of paracetamol (acetaminophen), responsible for all or part of its analgesic action and anticonvulsant effects. Chemically, it is the amide formed from 4-aminophenol and arachidonic acid.

<span class="mw-page-title-main">Oleamide</span> Chemical compound

Oleamide is an organic compound with the formula CH3(CH2)7CH=CH(CH2)7CONH2. It is the amide derived from the fatty acid oleic acid. It is a colorless waxy solid and occurs in nature. Sometimes labeled as a fatty acid primary amide (FAPA), it is biosynthesized from N-oleoylglycine.

<span class="mw-page-title-main">NAGly receptor</span> Protein-coding gene in the species Homo sapiens

N-Arachidonyl glycine receptor, also known as G protein-coupled receptor 18 (GPR18), is a protein that in humans is encoded by the GPR18 gene. Along with the other previously "orphan" receptors GPR55 and GPR119, GPR18 has been found to be a receptor for endogenous lipid neurotransmitters, several of which also bind to cannabinoid receptors. It has been found to be involved in the regulation of intraocular pressure.

<span class="mw-page-title-main">GPR119</span> Protein-coding gene in humans

G protein-coupled receptor 119 also known as GPR119 is a G protein-coupled receptor that in humans is encoded by the GPR119 gene.

<i>N</i>-Arachidonoyl dopamine Chemical compound

N-Arachidonoyl dopamine (NADA) is an endocannabinoid that acts as an agonist of the CB1 receptor and the transient receptor potential V1 (TRPV1) ion channel. NADA was first described as a putative endocannabinoid (agonist for the CB1 receptor) in 2000 and was subsequently identified as an endovanilloid (agonist for TRPV1) in 2002. NADA is an endogenous arachidonic acid based lipid found in the brain of rats, with especially high concentrations in the hippocampus, cerebellum, and striatum. It activates the TRPV1 channel with an EC50 of approximately of 50 nM which makes it the putative endogenous TRPV1 agonist.

<span class="mw-page-title-main">Oleoylethanolamide</span> Chemical compound

Oleoylethanolamide (OEA) is an endogenous peroxisome proliferator-activated receptor alpha (PPAR-α) agonist. It is a naturally occurring ethanolamide lipid that regulates feeding and body weight in vertebrates ranging from mice to pythons.

N-acyl phosphatidylethanolamine phospholipase D (NAPE-PLD) is an enzyme that catalyzes the release of N-acylethanolamine (NAE) from N-acyl-phosphatidylethanolamine (NAPE). This is a major part of the process that converts ordinary lipids into chemical signals like anandamide and oleoylethanolamine. In humans, the NAPE-PLD protein is encoded by the NAPEPLD gene.

<i>N</i>-Acylethanolamine Class of chemical compounds

An N-acylethanolamine (NAE) is a type of fatty acid amide where one of several types of acyl groups is linked to the nitrogen atom of ethanolamine, and highly metabolic formed by intake of essential fatty acids through diet by 20:4, n-6 and 22:6, n-3 fatty acids, and when the body is physically and psychologically active,. The endocannabinoid signaling system (ECS) is the major pathway by which NAEs exerts its physiological effects in animal cells with similarities in plants, and the metabolism of NAEs is an integral part of the ECS, a very ancient signaling system, being clearly present from the divergence of the protostomian/deuterostomian, and even further back in time, to the very beginning of bacteria, the oldest organisms on Earth known to express phosphatidylethanolamine, the precursor to endocannabinoids, in their cytoplasmic membranes. Fatty acid metabolites with affinity for CB receptors are produced by cyanobacteria, which diverged from eukaryotes at least 2000 million years ago (MYA), by brown algae which diverged about 1500 MYA, by sponges, which diverged from eumetazoans about 930 MYA, and a lineages that predate the evolution of CB receptors, as CB1 – CB2 duplication event may have occurred prior to the lophotrochozoan-deuterostome divergence 590 MYA. Fatty acid amide hydrolase (FAAH) evolved relatively recently, either after the evolution of fish 400 MYA, or after the appearance of mammals 300 MYA, but after the appearance of vertebrates. Linking FAAH, vanilloid receptors (VR1) and anandamide implies a coupling among the remaining ‘‘older’’ parts of the endocannabinoid system, monoglyceride lipase (MGL), CB receptors, that evolved prior to the metazoan-bilaterian divergence, but were secondarily lost in the Ecdysozoa, and 2-Arachidonoylglycerol (2-AG).

Palmitoylethanolamide (PEA) is an endogenous fatty acid amide, and lipid modulator PEA has been studied in in vitro and in vivo systems using exogenously added or dosed compound; there is evidence that it binds to a nuclear receptor, through which it exerts a variety of biological effects, some related to chronic inflammation and pain.

<span class="mw-page-title-main">Arachidonoyl serotonin</span> Chemical compound

Arachidonoyl serotonin is an endogenous lipid signaling molecule. It was first described in 1998 as being an inhibitor of fatty acid amide hydrolase (FAAH). In 2007, it was shown to have analgesic properties and to act as an antagonist of the TRPV1 receptor. In 2011, it was shown to be present in the ileum and jejunum of the gastrointestinal tract and modulate glucagon-like peptide-1 (GLP-1) secretion. In addition to this, in 2016, AA-5-HT was also found to affect the signaling mechanisms responsible for anxiety, by inhibiting dopamine release from the Basolateral amygdala following fear behavior. In 2017, AA-5-HT was tested in its effects on the sleep wake cycle, where it was found to affect the sleep homeostasis when used in conjunction with molecules and chemicals that affect wake-related neurotransmitters.

<i>N</i>-Arachidonylglycine Chemical compound

N-Arachidonylglycine (NAGly) is a carboxylic metabolite of the endocannabinoid anandamide (AEA). Since it was first synthesized in 1996, NAGly has been a primary focus of the relatively contemporary field of lipidomics due to its wide range of signaling targets in the brain, the immune system and throughout various other bodily systems. In combination with 2‐arachidonoyl glycerol (2‐AG), NAGly has enabled the identification of a family of lipids often referred to as endocannabinoids. Recently, NAGly has been found to bind to G-protein coupled receptor 18 (GPR18), the putative abnormal cannabidiol receptor. NaGly is an endogenous inhibitor of fatty acid amide hydrolase (FAAH) and thereby increases the ethanolamide endocannabinoids AEA, oleoylethanolamide (OEA) and palmitoylethanolamide (PEA) levels. NaGly is found throughout the body and research on its explicit functions is ongoing.

<span class="mw-page-title-main">Vanilloids</span> Chemical compounds containing a vanillyl group

The vanilloids are compounds which possess a vanillyl group. They include vanillyl alcohol, vanillin, vanillic acid, acetovanillon, vanillylmandelic acid, homovanillic acid, capsaicin, etc. Isomers are the isovanilloids.

The endocannabinoid transporters (eCBTs) are transport proteins for the endocannabinoids. Most neurotransmitters are water-soluble and require transmembrane proteins to transport them across the cell membrane. The endocannabinoids on the other hand, are non-charged lipids that readily cross lipid membranes. However, since the endocannabinoids are water immiscible, protein transporters have been described that act as carriers to solubilize and transport the endocannabinoids through the aqueous cytoplasm. These include the heat shock proteins (Hsp70s) and fatty acid-binding proteins for anandamide (FABPs). FABPs such as FABP1, FABP3, FABP5, and FABP7 have been shown to bind endocannabinoids. FABP inhibitors attenuate the breakdown of anandamide by the enzyme fatty acid amide hydrolase (FAAH) in cell culture. One of these inhibitors (SB-FI-26), isolated from a virtual library of a million compounds, belongs to a class of compounds that act as an anti-nociceptive agent with mild anti-inflammatory activity in mice. These truxillic acids and their derivatives have been known to have anti-inflammatory and anti-nociceptive effects in mice and are active components of a Chinese herbal medicine used to treat rheumatism and pain in human. The blockade of anandamide transport may, at least in part, be the mechanism through which these compounds exert their anti-nociceptive effects.

N-acylethanolamine acid amide hydrolase (NAAA) EC 3.5.1.- is a member of the choloylglycine hydrolase family, a subset of the N-terminal nucleophile hydrolase superfamily. NAAA has a molecular weight of 31 kDa. The activation and inhibition of its catalytic site is of medical interest as a potential treatment for obesity and chronic pain. While it was discovered within the last decade, its structural similarity to the more familiar acid ceramidase (AC) and functional similarity to fatty acid amide hydrolase (FAAH) allow it to be studied extensively.

References

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  24. ↑ Smoum R, Bar A, Tan B, Milman G, Attar-Namdar M, Ofek O, Stuart JM, Bajayo A, Tam J, Kram V, O'Dell D, Walker MJ, Bradshaw HB, Bab I, Mechoulam R (October 2010). "Oleoyl serine, an endogenous N-acyl amide, modulates bone remodeling and mass". Proceedings of the National Academy of Sciences of the United States of America. 107 (41): 17710–5. Bibcode:2010PNAS..10717710S. doi: 10.1073/pnas.0912479107 . PMC   2955099 . PMID   20876113.
  25. ↑ Lin H, Long JZ, Roche AM, Svensson KJ, Dou FY, Chang MR, Strutzenberg T, Ruiz C, Cameron MD, Novick SJ, Berdan CA, Louie SM, Nomura DK, Spiegelman BM, Griffin PR, Kamenecka TM (April 2018). "Discovery of Hydrolysis-Resistant Isoindoline N-Acyl Amino Acid Analogues that Stimulate Mitochondrial Respiration". Journal of Medicinal Chemistry. 61 (7): 3224–3230. doi:10.1021/acs.jmedchem.8b00029. PMC   6335027 . PMID   29533650.
  26. ↑ Long JZ, Svensson KJ, Bateman LA, Lin H, Kamenecka T, Lokurkar IA, et al. (July 2016). "The Secreted Enzyme PM20D1 Regulates Lipidated Amino Acid Uncouplers of Mitochondria". Cell. 166 (2): 424–435. doi:10.1016/j.cell.2016.05.071. PMC   4947008 . PMID   27374330.
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