Fatty acid amide hydrolase

"FAAH" redirects here. For other uses, see FAAH (disambiguation).

Fatty acid amide hydrolase
Fatty acid amide hydrolase (FAAH) dimer shown with covalent inhibitor (MAFP, yellow) bound in the active site.
Identifiers
Symbol	FAAH
Entrez	2166
HUGO	3553
OMIM	602935
PDB	1MT5
RefSeq	NM_001441
UniProt	O00519
Other data
EC number	3.5.1.99
Locus	Chr. 1 p35-p34

Fatty acid amide hydrolase or FAAH (EC 3.5.1.99, 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:

• Anandamide (N-arachidonoylethanolamine), an endocannabinoid

• Other N-acylethanolamines, such as N-oleoylethanolamine and N-palmitoylethanolamine

• The sleep-inducing lipid oleamide

• The N-acyltaurines, which are agonists of the transient receptor potential (TRP) family of calcium channels.

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 mutation in FAAH has been linked to drug abuse and dependence. Individuals with the mutation have higher levels of anandamide, the so-called "bliss" molecule, because of lower levels of FAAH, which may reduce anxiety and post-traumatic stress disorder.

Inhibitors and assays

Both non-selective and selective inhibitors of the enzyme 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.

Structure

The first crystal structure of FAAH was published in 2002 (PDB ID: 1mt5). Structures of FAAH with drug-like ligands were first reported in 2008, and include covalent (e.g. 2vya, 2wap, 2wj1, 3qkv) and non-covalent (e.g. 3qj9, 4do3) inhibitors.

See also

• Anandamide
• URB597
• NSAID

External links

• fatty-acid amide hydrolase at the US National Library of Medicine Medical Subject Headings (MeSH)
• Proteopedia FAAH entry - interactive structure (JMOL) of inhibitor-bound FAAH