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FAAH2

Official Full Name
fatty acid amide hydrolase 2
Organism
Homo sapiens
GeneID
158584
Background
This gene encodes a fatty acid amide hydrolase that shares a conserved protein motif with the amidase signature family of enzymes. The encoded enzyme is able to catalyze the hydrolysis of a broad range of bioactive lipids, including those from the three main classes of fatty acid amides; N-acylethanolamines, fatty acid primary amides and N-acyl amino acids. This enzyme has a preference for monounsaturated acyl chains as a substrate. Alternate splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Jul 2017]
Synonyms
AMDD;

Detailed Information

Lipid transmitters are composited by a majority of fatty acid amides including endogenous cannabinoids and sleep-inducing substances. The duration and magnitude of fatty acid amides signal transmission is modulated by innate enzyme hydrolysis. Mammal's fatty acid amides activity is mainly attributed to single integral membrane enzyme. Here what reported second membrane-related protein found in the human functional proteomic discovery displaying FAAH activity, and the genes responsible for encoding the second FAAH enzyme are widely distributed in distantly related vertebrates but not in placental mammals. FAAH-1 and FAAH-2, those two human FAAH enzymes shared 20 sequence identity, both were sensitive to FAAH inhibitors synthesized to date, including O-ary carbamates and α-keto heterocycles. Sensitivity to inhibitors coupled with wide distribution in different tissues manifests those two enzymes may be collaborated to control metabolition of fatty acid amide. Biological fatty acid amide lipids family can be divided into three chemical categories including N-acylethanolamines, fatty acid primary amides, and N-acyl amino acids. Pain, feeding and memory, those three neurobehavioral processes may be under the control of N-acylethanolamines acting as a central cannabinoid receptor (CBI) agonist. Oleamide is sleep-inducing lipid occupying in the cerebrospinal fluid of sleep-deprived animals. Several receptors, including serotonin, GABA, and cannabinoid, may be affiliated by oleamide, or at least subunits of those receptors may be vital mediation of oleamide' hypnotic effect.

The Variable Distribution of FAAH-2 Among Placental Mammals

FAAH is a widely-distributed membrane protein in mammal tissue, belonged to an enzyme family sharing highly conserved 130 amino acid motif designated as "amidase signature (AS) enzyme". Among the 130 amino acid, serine-serine-lysine composited catalytic trimer function to accelerate hydrolysis of amide bond. Most AS enzymes identified till now is originated from bacterial or fungal, FAAH is a unique member constituting in mammals of the AS enzyme family. Cravatt provided the proteomic evidence supporting the existence of the second enzyme with FAAH activity (known as FAAH-2) in mammals, which showed difference in tissue distribution, substrate selectivity, and inhibitor sensitivity but some overlappings in other characterizations compared with FAAH1. Genome analysis of FAAH-2 reminded the complexity of fatty acid amide catabolism across mammalian species, for the revelation of its presence in primates and related vertebrates while not murids (mice and rats).

Lipid Droplets Act as New Sites for Hydrolysis of N-Acylethanolamine by FAAH-2

FAAH-2 is a human enzyme capable of deactivating N-Acylethanolamine. Further, Martin Kaczocha group explored its capability to hydrolyze N-Acylrthanolamine in cell based on biological characterization of FAAH-2. And FAAH-2 performed 5% and 20% hydrolysis activity of FAAH on Anandamide (AEA) and palmitoylethanolamide (PEA) respectively in homogenate activity assays. However, hydrolysis rate of FAAH-2 turning to be almost 30-40% of FAAH-2 is underlining greater contribution toward NAE catabolism in vivo. Immunofluorescence revealed lipid droplet localization of FAAH-2 against the previous conception endoplasmic reticulum-localized FAAH. The identification of N-terminal hydrophobic region of FAAH-2 further supports this distribution model. Exclusion from lipid droplets may eclipse N-Acylethanolamine deactivation activity of FAAH-2.

The endocannabinoids work as intercellular signals in the nervous systemFig 1. The endocannabinoids work as intercellular signals in the nervous system (Bradley E.Alger et al. 2004)

References:

  1. Vincenzo Di Marzo, Mauro Maccarrone. (2008) 'FAAH and anandamide: is 2-AG really the odd one out? Trends in Pharmacological Sciences, doi: 10.1016/j.tips.2008.03.001.
  2. Martin Kaczocha, Sherrye T. Glaser , Janiper Chae. (2009) 'Lipid Droplets Are Novel Sites of N-Acylethanolamine Inactivation by Fatty Acid Amide Hydrolase-2, Journal of Biological Chemistry, doi: 10.1074/jbc.M109.058461
  3. Bradley E. Alger. (2004) 'Endocannabinoids: Getting the message across, PNAS,doi: 10.1073/pnas.0402935101
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