Fatty acid amide hydrolase

Fatty acid amide hydrolase or FAAH (, oleamide hydrolase, anandamide amidohydrolase) is a member of the serine hydrolase family of enzymes. It was first shown to break down anandamide in 1993. In humans, it is encoded by the gene "FAAH".
Function.
FAAH is an integral membrane hydrolase with a single "N"-terminal transmembrane domain. "In vitro", FAAH has esterase and amidase activity. "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. Finally, because of their impaired ability to degrade anandamide, "FAAH" KOs also display supersensitivity to exogenous anandamide, a cannabinoid receptor (CB) agonist.
Due to the ability of FAAH to regulate nociception, it is currently viewed as an attractive drug target for the treatment of pain.
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.
A mutation in FAAH was initially provisionally linked to drug abuse and dependence but this was not borne out in subsequent studies.
Studies in cells and animals and genetic studies in humans have shown that inhibiting FAAH may be a useful strategy to treat anxiety disorders.
Inhibitors and inactivators.
Based on the hydrolytic mechanism of fatty acid amide hydrolase, a large number of irreversible and reversible inhibitors of this enzyme have been developed.
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.
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.
Structures.
The first crystal structure of FAAH was published in 2002 (PDB code 1MT5). Structures of FAAH with drug-like ligands were first reported in 2008, and include non-covalent inhibitor complexes and covalent adducts.