FAAH
Encyclopedia
Fatty acid amide hydrolase or FAAH is a member of the serine hydrolase
family of enzyme
s. It was first shown to breakdown anandamide in 1993 . In humans, it is encoded by the gene
FAAH.
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.
have been described. Examples of non-selective inhibitors include PMSF
(phenylmethylsulfonylfluoride) , MAFP , and ATMK (arachidonoyltrifluoromethylketone). URB597
is a relatively selective, irreversible, carbamate-based inhibitor, though it also inhibits other serine hydrolases, such as carboxylesterases, in peripheral tissues. Urea-based inhibitors such as PF-622 and PF-750 are more potent and more selective inhibitors of FAAH than URB597.
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.
Serine hydrolase
The serine hydrolase superfamily is one of the largest known enzyme families comprising approximately ~200 enzymes or 1% of the genes in the human proteome. A characteristic defining feature of this superfamily is the presence of an active site nucleophilic serine that is used for the hydrolysis of...
family of enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
s. It was first shown to breakdown anandamide in 1993 . In humans, it is encoded by the gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
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:- AnandamideAnandamideAnandamide, also known as N-arachidonoylethanolamide or AEA, is an endogenous cannabinoid neurotransmitter. The name is taken from the Sanskrit word ananda, which means "bliss, delight", and amide. It is synthesized from N-arachidonoyl phosphatidylethanolamine by multiple pathways...
(N-arachidonoylethanolamine), an endocannabinoid
- Other N-acylethanolamines, such as N-oleoylethanolamineOleoylethanolamideOleoylethanolamine is an endogenous peroxisome proliferator-activated receptor alpha agonist. It is a naturally occurring ethanolamide lipid that regulates feeding and body weight in vertebrates ranging from mice to pythons....
and N-palmitoylethanolaminePalmitoylethanolamidePalmitoylethanolamide is an endogenous fatty acid amide, belonging to the class of endocannabinoids. PEA has been demonstrated to bind to a receptor in the cell-nucleus and exerts a great variety of biological functions related to chronic pain and inflammation. The main target is thought to be...
- The sleep-inducing lipid oleamideOleamideOleamide is an amide of the fatty acid oleic acid. It is an endogenous substance: it occurs naturally in the body of animals. It accumulates in the cerebrospinal fluid during sleep deprivation and induces sleep in animals...
- The N-acyltaurines, which are agonists of the transient receptor potentialTransient receptor potentialTransient receptor potential channels are a group of ion channels located mostly on the plasma membrane of numerous human and animal cell types. There are about 28 TRP channels that share some structural similarity to each other...
(TRP) family of calcium channels.
FAAH knockout mice
Knockout mouse
A knockout mouse is a genetically engineered mouse in which researchers have inactivated, or "knocked out," an existing gene by replacing it or disrupting it with an artificial piece of DNA...
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
Hot plate test
The hot plate test is a test of the pain response in animals. It is used in basic pain research and in testing the effectiveness of analgesics by observing the reaction to pain caused by heat. It was proposed by Eddy and Leimbach in 1953....
, the formalin test, and the tail flick test
Tail flick test
The tail flick test is a test of the pain response in animals. It is used in basic pain research and to measure the effectiveness of analgesics, by observing the reaction to intense heat. It was first described by D'Amour and Smith in 1941....
. Finally, because of their impaired ability to degrade anandamide, FAAH KOs also display supersensitivity to exogenous
Exogenous
Exogenous refers to an action or object coming from outside a system. It is the opposite of endogenous, something generated from within the system....
anandamide, a cannabinoid receptor (CB) agonist.
Due to the ability of FAAH to regulate nociception
Nociception
Nociception is defined as "the neural processes of encoding and processing noxious stimuli." It is the afferent activity produced in the peripheral and central nervous system by stimuli that have the potential to damage tissue...
, it is currently viewed as an attractive drug target for the treatment of pain.
Inhibitors and assays
Both non-selective and selective inhibitors of the enzymeEnzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
have been described. Examples of non-selective inhibitors include PMSF
PMSF
In biochemistry, PMSF is a serine protease inhibitor commonly used in the preparation of cell lysates. PMSF does not inhibit all serine proteases. It is rapidly degraded in water and stock solutions are usually made up in anhydrous ethanol, isopropanol, corn oil, or DMSO...
(phenylmethylsulfonylfluoride) , MAFP , and ATMK (arachidonoyltrifluoromethylketone). URB597
URB597
URB597 is a relatively selective inhibitor of the enzyme fatty acid amide hydrolase . FAAH is the primary degradatory enzyme for the endocannabinoid anandamide and, as such, inhibition of FAAH leads to an accumulation of anandamide in the CNS and periphery where it activates cannabinoid receptors...
is a relatively selective, irreversible, carbamate-based inhibitor, though it also inhibits other serine hydrolases, such as carboxylesterases, in peripheral tissues. Urea-based inhibitors such as PF-622 and PF-750 are more potent and more selective inhibitors of FAAH than URB597.
The enzyme is typically assayed making use of a radiolabelled anandamide substrate
Substrate (biochemistry)
In biochemistry, a substrate is a molecule upon which an enzyme acts. Enzymes catalyze chemical reactions involving the substrate. In the case of a single substrate, the substrate binds with the enzyme active site, and an enzyme-substrate complex is formed. The substrate is transformed into one or...
, which generates free labelled ethanolamine
Ethanolamine
Ethanolamine, also called 2-aminoethanol or monoethanolamine , is an organic chemical compound that is both a primary amine and a primary alcohol . Like other amines, monoethanolamine acts as a weak base...
, although alternative LC-MS methods have also been described.
External links
- Proteopedia FAAH entry - interactive structure (JMOL) of inhibitor-bound FAAH