Fatty-acid amide hydrolase 1 explained

Fatty-acid amide hydrolase 1 (FAAH)[1] 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.[2] In humans, it is encoded by the gene FAAH.[3] [4] [5]

Function

FAAH is an integral membrane hydrolase with a single N-terminal transmembrane domain. In vitro, FAAH has esterase and amidase activity.[6] 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.[12] Finally, because of their impaired ability to degrade anandamide, FAAH KOs also display supersensitivity to exogenous anandamide, a cannabinoid receptor (CB) agonist.[7]

Due to the ability of FAAH to regulate nociception, it is currently viewed as an attractive drug target for the treatment of pain.[13] [14] [15]

Studies in cells and animals and genetic studies in humans have shown that inhibiting FAAH may be a useful strategy to treat anxiety disorders,[16] [17] as inhibition produce analgesic, anxiolytic, neuroprotective, and anti-inflammatory effects by elevated N-acylethanolamines (NAE's) and their activation of cannabinoid receptors.

Inhibitors and inactivators

Activation of the cannabinoid receptor CB1 or CB2 in different tissues, including skin, inhibit FAAH, and thereby increases endocannabinoid levels.[18]

Based on the hydrolytic mechanism of fatty acid amide hydrolase, a large number of irreversible and reversible inhibitors of this enzyme have been developed.[19] [20] [21] [22] [23] [24] [25] [26]

Some of the more significant compounds are listed below;

Inhibition and binding

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.[40]

Enhancement of FAAH activity

Insulin medication increases the production and activity of FAAH.[41]

Genetic variants

rs324420

Rsid:324420
Name 1:C385A
Name 2:c.385C>A
Name 3:p.Pro129Thr
Gene:FAAH
Chromosome:1
Region:Exon

The FAAH gene contains a single nucleotide polymorphism (SNP) called rs324420. The variant allele, C385A, is associated with a higher sensitivity of FAAH to proteolytic degradation and a shorter half-life compared to the standard C variant. As a result, carriers of the A variant has increased N-acylethanolamine (NAE) levels and anandamide (AEA) signaling at the cannabinoid receptors. The A variant may be responsible for lower levels of the FAAH protein seen in high-performing athletes, providing increased physical and mental fitness.[42] However, among elite Polish athletes, the A variant is under-represented regardless of metabolic characteristics of their sport disciplines; this seems to suggest an opposite role for the A variant.[43]

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 rs324420 C385A allele in citizens' genetic make-up.[44]

The C385A allele was initially provisionally linked to drug abuse and dependence but this was not borne out in subsequent studies. According to later studies, carriers of the A allele are more likely to try cannabis, but less likely to become dependent.[45]

microdeletion

See main article: Jo Cameron.

FAAH-OUT is a pseudogene downstream of the FAAH coding region. It expresses a long non-coding RNA (lncRNA) that increases the expression of FAAH.[46] In 2019, a Scottish woman named Jo Cameron was found to have both a previously unreported microdeletion mutation in FAAH-OUT and a rs324420 C385A mutation. The result is extreme disruption of FAAH function leading to elevated anandamide levels. She was immune to anxiety, unable to experience fear, and insensitive to pain. The frequent burns and cuts suffered due to her hypoalgesia healed quicker than average with little or no scarring.[47] [48] [49] Her son, who shares the FAAH-OUT deletion but has no C385A mutation, has a lesser degree of pain insensitivity.[47]

A 2023 study looks further into the functions of FAAH-OUT using transcriptomic analyses of cell models, some created anew using CRISPR-Cas9, others obtained from the 2019 patient. The study confirms that FAAH-OUT increases the expression of FAAH, both via its lncRNA product and through an intronic enhancer called FAAH-AMP. Loss of FAAH-OUT also changes the expression of a wide network of genes beyond FAAH itself. For example, although the pain insensitivity is mostly due to loss of FAAH function (via increased endocannabinoid levels and reduced ACKR3 expression), lack of depression and anxiety is instead due to a non-canonical Wnt pathway upregulating BDNF. The increased wound healing is due to both pathways: loss of FAAH function increases N-acyltaurine levels; the non-canonical Wnt pathway is also beneficial to healing.[46]

Assays

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.[50] [51]

Structures

The first crystal structure of FAAH was published in 2002 (PDB code 1MT5).[5] Structures of FAAH with drug-like ligands were first reported in 2008, and include non-covalent inhibitor complexes and covalent adducts.[52]

Regulation

In slime molds

The slime mold Dictyostelium discoideum produces a semispecific FAAH inhibitor. By controlling the levels of FAAH activity, they modulate endogenous N-acylethanolamine levels.[53]

Enzyme classification

In the Enzyme Commission numbering scheme, "fatty acid amide hydrolase" is . The number applies to all enzymes that have the chemical activity; in humans it covers both the genes FAAH and FAAH2. The systematic name is "fatty acylamide amidohydrolase". Recorded synonyms include "oleamide hydrolase", "anandamide amidohydrolase".[54]

See also

External links

Notes and References

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