Fatty-acid amide hydrolase 1

Fatty-acid amide hydrolase 1 (FAAH)^[5] 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]

Function

FAAH is an integral membrane hydrolase with a single N-terminal transmembrane domain. In vitro, FAAH has esterase and amidase activity.^[10] 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:

• endocannabinoid^[11]
• 2-arachidonoylglycerol (2-AG), an endocannabinoid.^[12]
• Other
  N-acylethanolamines, such as N-oleoylethanolamine and N-palmitoylethanolamine^[13]
• The sleep-inducing lipid oleamide^[14]
• The N-acyltaurines, which are agonists of the
  transient receptor potential (TRP) family of calcium channels.^[15]

Due to the ability of FAAH to regulate nociception, it is currently viewed as an attractive drug target for the treatment of pain.^[17][18][19]

Studies in cells and animals and genetic studies in humans have shown that inhibiting FAAH may be a useful strategy to treat

Based on the hydrolytic mechanism of fatty acid amide hydrolase, a large number of irreversible and reversible inhibitors of this enzyme have been developed.^{[25][26][27][28][29][30][31][32]}

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.^[48]

Enhancement of FAAH activity

Insulin medication increase the production and activity of fatty acid amide hydrolase.^[49]

Genetic variants

rs324420

The FAAH gene contains a

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.^[52]

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.^{[20]: § 5.6}

FAAH-OUT microdeletion

FAAH-OUT is a

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.^[59]

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.^[23]

Enzyme classification

In the Enzyme Commission numbering scheme, "fatty acid amide hydrolase" is EC 3.5.1.99. 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".^[60]

See also

• Endocannabinoid enhancer
• Endocannabinoid reuptake inhibitor
• Monoacylglycerol lipase

References