Fatty acid amide hydrolase or FAAH (, oleamide hydrolase, anandamide amidohydrolase) is a member of the
serine hydrolase family of
enzyme
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products ...
s. It was first shown to break down
anandamide
Anandamide (ANA), also known as ''N''-arachidonoylethanolamine (AEA), is a fatty acid neurotransmitter. Anandamide was the first endocannabinoid to be discovered: it participates in the body's endocannabinoid system by binding to cannabinoid r ...
in 1993.
In humans, it is encoded by the
gene
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...
''FAAH''.
[; ]
Function
FAAH is an integral membrane
hydrolase with a single
''N''-terminal transmembrane domain
A transmembrane domain (TMD) is a membrane-spanning protein domain. TMDs generally adopt an alpha helix topological conformation, although some TMDs such as those in porins can adopt a different conformation. Because the interior of the lipid bi ...
. ''In vitro'', FAAH has
esterase
An esterase is a hydrolase enzyme that splits esters into an acid and an alcohol in a chemical reaction with water called hydrolysis.
A wide range of different esterases exist that differ in their substrate specificity, their protein structure ...
and
amidase
In enzymology, an amidase (, ''acylamidase'', ''acylase (misleading)'', ''amidohydrolase (ambiguous)'', ''deaminase (ambiguous)'', ''fatty acylamidase'', ''N-acetylaminohydrolase (ambiguous)'') is an enzyme that catalyzes the hydrolysis of an amid ...
activity.
''In vivo'', FAAH is the principal
catabolic
Catabolism () is the set of metabolic pathways that breaks down molecules into smaller units that are either oxidized to release energy or used in other anabolic reactions. Catabolism breaks down large molecules (such as polysaccharides, lip ...
enzyme
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products ...
for a class of bioactive
lipid
Lipids are a broad group of naturally-occurring molecules which includes fats, waxes, sterols, fat-soluble vitamins (such as vitamins A, D, E and K), monoglycerides, diglycerides, phospholipids, and others. The functions of lipids in ...
s called the fatty acid amides (FAAs). Members of the FAAs include:
*
Anandamide
Anandamide (ANA), also known as ''N''-arachidonoylethanolamine (AEA), is a fatty acid neurotransmitter. Anandamide was the first endocannabinoid to be discovered: it participates in the body's endocannabinoid system by binding to cannabinoid r ...
(''N''-arachidonoylethanolamine), an
endocannabinoid
Cannabinoids () are several structural classes of compounds found in the cannabis plant primarily and most animal organisms (although insects lack such receptors) or as synthetic compounds. The most notable cannabinoid is the phytocannabinoid tet ...
*
2-arachidonoylglycerol (2-AG), an endocannabinoid.
* Other
''N''-acylethanolamines, such as
''N''-oleoylethanolamine and
''N''-palmitoylethanolamine
* The sleep-inducing lipid
oleamide
Oleamide is an organic compound with the formula CH3(CH2)7CH=CH(CH2)7CONH2(. It is the amide derived from the fatty acid oleic acid. It is a colorless waxy solid and occurs in nature. Sometimes labeled as a fatty acid primary amide (FAPA), it ...
* The ''N''-acyltaurines, which are agonists of the
transient receptor potential
Transient receptor potential channels (TRP channels) are a group of ion channels located mostly on the plasma membrane of numerous animal cell types. Most of these are grouped into two broad groups: Group 1 includes TRPC ( "C" for canonical), TR ...
(TRP) family of calcium channels.
''FAAH''
knockout mice
A knockout mouse, or knock-out mouse, is a genetically modified mouse (''Mus musculus'') in which researchers have inactivated, or "knocked out", an existing gene by replacing it or disrupting it with an artificial piece of DNA. They are importan ...
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
The tail flick test is a test of the pain response in animals, similar to the hot plate test. It is used in basic pain research and to measure the effectiveness of analgesics, by observing the reaction to heat. It was first described by D'Amour ...
.
Finally, because of their impaired ability to degrade anandamide, ''FAAH'' KOs also display supersensitivity to
exogenous
In a variety of contexts, exogeny or exogeneity () is the fact of an action or object originating externally. It contrasts with endogeneity or endogeny, the fact of being influenced within a system.
Economics
In an economic model, an exogen ...
anandamide, a cannabinoid receptor (CB) agonist.
Due to the ability of FAAH to regulate
nociception
Nociception (also nocioception, from Latin ''nocere'' 'to harm or hurt') is the Somatosensory system, sensory nervous system's process of encoding Noxious stimulus, noxious stimuli. It deals with a series of events and processes required for an org ...
, 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 2017 study found a strong correlation between national percentage of very happy people (as measured by the
World Values Survey
The World Values Survey (WVS) is a global research project that explores people's values and beliefs, how they change over time, and what social and political impact they have. Since 1981 a worldwide network of social scientists have conducte ...
) and the presence of the A allele in the FAAH gene variant rs324420 in citizens' genetic make-up.
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
Anxiety disorders are a cluster of mental disorders characterized by significant and uncontrollable feelings of anxiety and fear such that a person's social, occupational, and personal function are significantly impaired. Anxiety may cause physi ...
.
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.Portugal
Portugal, officially the Portuguese Republic ( pt, República Portuguesa, links=yes ), is a country whose mainland is located on the Iberian Peninsula of Southwestern Europe, and whose territory also includes the Atlantic archipelagos of th ...
) has been linked to severe adverse events affecting 5 patients in a drug trial in Rennes, France, and at least one death, in January 2016. Many other pharmaceutical companies have previously taken other FAAH inhibitors into clinical trials without reporting such adverse events.
* BMS-469908Cannabidiol
Cannabidiol (CBD) is a phytocannabinoid discovered in 1940. It is one of 113 identified cannabinoids in cannabis plants, along with tetrahydrocannabinol (THC), and accounts for up to 40% of the plant's extract. , clinical research on CBD in ...
osteoarthritis
Osteoarthritis (OA) is a type of degenerative joint disease that results from breakdown of joint cartilage and underlying bone which affects 1 in 7 adults in the United States. It is believed to be the fourth leading cause of disability in the ...
carbamate
In organic chemistry, a carbamate is a category of organic compounds with the general formula and structure , which are formally derived from carbamic acid (). The term includes organic compounds (e.g., the ester ethyl carbamate), formall ...
-based mechanism, and appears in one report as a somewhat selective, though it also inactivates other serine hydrolases (e.g., carboxylesterases) in peripheral tissues.
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
Stereochemistry, a subdiscipline of chemistry, involves the study of the relative spatial arrangement of atoms that form the structure of molecules and their manipulation. The study of stereochemistry focuses on the relationships between stereoi ...
of a delta cis double bond
In chemistry, a double bond is a covalent bond between two atoms involving four bonding electrons as opposed to two in a single bond. Double bonds occur most commonly between two carbon atoms, for example in alkenes. Many double bonds exist betwee ...
.
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).[; ]
See also
* Endocannabinoid enhancer
* Endocannabinoid reuptake inhibitor
* Monoacylglycerol lipase
* FAAH2
References
External links
*
Proteopedia FAAH entry
- interactive structure (JMOL) of inhibitor-bound FAAH
Fatty acid amide hydrolase (FAAH1) Human Protein Atlas
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EC 3.5.1
Integral membrane proteins