N-Acylethanolamine

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,^[1][2] and when the body is physically and psychologically active,.^[3][4] 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,^[5] a very ancient signaling system, being clearly present from the divergence of the protostomian/deuterostomian,^[6][7] 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 (NAE 20:4) 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 (ie, between extant Hydra and leech), but were secondarily lost in the Ecdysozoa, and 2-Arachidonoylglycerol (2-AG).^[8]

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.^[9] Another route relies on the transesterification of acyl groups from phosphatidylcholine by an N-acyltransferase (NAT) activity.^{[citation needed]} 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.^[10]

N-acylethanolamines (NAEs) are broken down, or hydrolysed, by fatty acid amide hydrolase (FAAH) to ethanolamine (MEA) and their corresponding fatty acid, arachidonic acid. FAAH is activated during stress exposure circumstances, which also raises the neuronal excitability in the amygdala, a critical brain area that mediates anxiety, and the anxiolytic outcome of CB1 receptor activation.^[11] Inhibition of FAAH has been shown to increase the levels of NAEs in vivo and to produce desirable phenotypes, that produce analgesic, anxiolytic, neuroprotective, and anti-inflammatory effects,^[12] like in high-level performance athletes (i.e., elite athletes) that present an extraordinary interindividual variability of physical, but also mental traits, that greatly influence their sports accomplishments and their career longevity, by an FAAH genetic polymorphism that produce the SNP rs324420 (C385A allele), associated with a higher sensitivity of FAAH to proteolytic degradation and a shorter half-life, as compared to the C variant, as the A variant displays normal catalytic properties, but an enhanced sensitivity to degradation, leading to increased NAE and anandamide (AEA) signaling.^[11] Activation of the cannabinoid receptor CB1 or CB2 in different tissues, including skin, inhibit FAAH, and thereby increases endocannabinoid levels.^[13]