Fatty-acid amide hydrolase 1

(Redirected from Fatty acid amide hydrolase)

Fatty-acid amide hydrolase 1 or FAAH-1[5](EC, 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.[6] In humans, it is encoded by the gene FAAH.[7][8][9] 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.[10]

AliasesFAAH, fatty acid amide hydrolase, FAAH-1, PSAB
External IDsOMIM: 602935 MGI: 109609 HomoloGene: 68184 GeneCards: FAAH
RefSeq (mRNA)



RefSeq (protein)



Location (UCSC)Chr 1: 46.39 – 46.41 MbChr 4: 115.82 – 115.88 Mb
PubMed search[3][4]
View/Edit HumanView/Edit Mouse

The FAAH protein, involved in the metabolism of endocannabinoids, is encoded by the FAAH gene, which also contains 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 the proteolytic degradation, and shorter half-life, leading to increased N-acylethanolamine (NAE) and anandamide (AEA) signaling at the CB1 receptor etc., and which accounts for the protein’s lower amounts seen in high-level performance athletes (i.e., elite athletes), that present an extraordinary interindividual variability of physical, but also mental traits, which greatly influence their sports accomplishments and their career longevity. However, the role of the C385A variant in athletic performance is not consensual, as other evidence suggesting, that the A polymorphism allele genotype is underrepresented in the Polish elite athletes, regardless of metabolic characteristics of their sport disciplines, where it seems to affect the elite athletic performance negatively.[11][12]

Function Edit

FAAH is an integral membrane hydrolase with a single N-terminal transmembrane domain. In vitro, FAAH has esterase and amidase activity.[13] In vivo, FAAH is the principal catabolic enzyme for a class of bioactive lipids called the fatty acid amides (FAAs). Members of the FAAs include:

FAAH knockout mice display highly elevated (>15-fold) levels of N-acylethanolamines and N-acyltaurines in various tissues. Because of their significantly elevated anandamide levels, FAAH KOs have an analgesic phenotype, showing reduced pain sensation in the hot plate test, the formalin test, and the tail flick test.[19] Finally, because of their impaired ability to degrade anandamide, FAAH KOs also display supersensitivity to exogenous anandamide, a cannabinoid receptor (CB) agonist.[14]

Due to the ability of FAAH to regulate nociception, it is currently viewed as an attractive drug target for the treatment of pain.[20][21][22]

A Scottish woman with a previously unreported genetic mutation (dubbed FAAH-OUT) in her FAAH gene with resultant elevated anandamide levels was reported in 2019 to be immune to anxiety, unable to experience fear, and insensitive to pain. The frequent burns and cuts she suffered due to her hypoalgesia healed quicker than average.[23][24][25]

A 2017 study found a strong correlation between national percentage of very happy people (as measured by the World Values Survey) and the presence of the A allele in the FAAH gene variant rs324420 in citizens' genetic make-up.[26]

A mutation in FAAH was initially provisionally linked to drug abuse and dependence but this was not borne out in subsequent studies.[27]

Studies in cells and animals and genetic studies in humans have shown that inhibiting FAAH may be a useful strategy to treat anxiety disorders,[27][28][29] as inhibition produce analgesic, anxiolytic, neuroprotective, and anti-inflammatory effects by elevated N-acylethanolamines (NAE's) and their activation of cannabinoid receptors.[10]

Inhibitors and inactivators Edit

Activation of the cannabinoid receptor CB1 or CB2 in different tissues, including skin, inhibit FAAH, and thereby increases endocannabinoid levels.[30]

Based on the hydrolytic mechanism of fatty acid amide hydrolase, a large number of irreversible and reversible inhibitors of this enzyme have been developed.[31][32][33][34][35][36][37][38]

Some of the more significant compounds are listed below;

Inhibition and binding Edit

Structural and conformational properties that contribute to enzyme inhibition and substrate binding imply an extended bound conformation, and a role for the presence, position, and stereochemistry of a delta cis double bond.[54]

Enhancements of FAAH and its activity Edit

Insulin medication and intraoperative doses of insulin increase the production and activity of fatty acid amide hydrolase, which, beside of other N-acylethanolamines (NAE's), degrade the endocannabinoid NAE 20:4 (AEA: C22H37NO2; 20:4, ω-6),[55] also suggest that insulin may play a key role in the obesity-linked dysregulation of the adipose ECS at the gene level,[56] is possible why the European Medicines Agency (EMA), in 2023 are investigating several reports from European countries about suicidal thoughts and thoughts of self-harm in patients who have been treated with Novo Nordisk's popular medicines for obesity and diabetes, revealed by the danish newspaper Belingske,[57] an outcome also seen in the CB1 receptor blocker rimonabant, an anorectic antiobesity drug that was first approved in Europe in 2006, but several years later was withdrawn worldwide due to serious psychiatric side effects,[58][59][60] and happening at the same time as BT reveal that EMA also has raised a safety alert for Wegovy, and the companies diabetes medication Ozempic, based on a study that suggests that the active substance in the two preparations, can increase the risk of thyroid cancer in patients with type 2 diabetes.[61]

The phytocannabinoid Δ9-tetrahydrocannabinol, that can mimic endocannabinoid activation at CB1 and CB2 receptors in different tissues, thereby inhibit FAAH,[30] is found to induce apoptosis in different cancer cells by increased de novo synthesized ceramide levels in a CB2 dependent manner, and moreover, cannabinoid administration selectively increased apoptosis in pancreatic tumor cells, but not in normal tissue.[62][63]

And by its cannabinoid receptor activation, the influence of cannabis on insulin observed in an human study, is in line with the established role of the endocannabinoid system (ECS) in regulating glucose metabolism and, at large, energy balance, an homeostatic function that is carried out via interactions between ECS and multiple central and peripheral pathways (e.g., brain, pancreas, liver). And through autocrine, paracrine, and endocrine mechanisms, endocannabinoids modulate pancreatic β-cells function, proliferation, and survival, as well as insulin production, secretion, and resistance, through CB1 and CB2 receptors also widely expressed in islets of Langerhans, but the direction and magnitude of the relationship between cannabinoids and insulin is not linear, and may depend of duration and frequency of exposure, as chronic cannabis use (daily consumption) reduces the risk of obesity, insulin resistance, and diabetes mellitus (DM), where acute cannabis administration in cannabis users also blunt the insulin spike secondary to a brownie intake, and the found activation of cannabinoid receptors expressed by pancreatic β-cells, can stimulate insulin secretion and, therefore, may be beneficial in treating impaired glucose tolerance and diabetes mellitus,[64][65] as the lower odds of DM among marijuana users is found significant,[66] as well as former and, to a greater extent, chronic (daily) cannabis use, is consistently associated with smaller waist circumference, lower BMI, and lower risks of overweight, obesity, and central obesity in patients with chronic hepatitis C virus (HCV) infection,[67] where obesity is found with various diseases and conditions, particularly cardiovascular diseases, type 2 diabetes, obstructive sleep apnea, certain types of cancer, and osteoarthritis.

Assays Edit

The enzyme is typically assayed making use of a radiolabelled anandamide substrate, which generates free labelled ethanolamine, although alternative LC-MS methods have also been described.[68][69]

Structures Edit

The first crystal structure of FAAH was published in 2002 (PDB code 1MT5).[9] Structures of FAAH with drug-like ligands were first reported in 2008, and include non-covalent inhibitor complexes and covalent adducts.[70]

See also Edit

References Edit

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External links Edit