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J Biol Chem DOI:10.1074/jbc.M606646200

A second fatty acid amide hydrolase with variable distribution among placental mammals.

Publication TypeJournal Article
Year of Publication2006
AuthorsWei, BQ, Mikkelsen, TS, McKinney, MK, Lander, ES, Cravatt, BF
JournalJ Biol Chem
Date Published2006 Dec 01
KeywordsAmidohydrolases, Amino Acid Sequence, Animals, Arachidonic Acids, Cell Line, Tumor, Cercopithecus aethiops, COS Cells, Endocannabinoids, Fatty Acids, Humans, Hydrolysis, Mice, Molecular Sequence Data, Placenta, Polyunsaturated Alkamides, Rats, Sequence Homology, Amino Acid, Signal Transduction, Tissue Distribution

Fatty acid amides constitute a large and diverse class of lipid transmitters that includes the endogenous cannabinoid anandamide and the sleep-inducing substance oleamide. The magnitude and duration of fatty acid amide signaling are controlled by enzymatic hydrolysis in vivo. Fatty acid amide hydrolase (FAAH) activity in mammals has been primarily attributed to a single integral membrane enzyme of the amidase signature (AS) family. Here, we report the functional proteomic discovery of a second membrane-associated AS enzyme in humans that displays FAAH activity. The gene that encodes this second FAAH enzyme was found in multiple primate genomes, marsupials, and more distantly related vertebrates, but, remarkably, not in a number of lower placental mammals, including mouse and rat. The two human FAAH enzymes, which share 20% sequence identity and are referred to hereafter as FAAH-1 and FAAH-2, hydrolyzed primary fatty acid amide substrates (e.g. oleamide) at equivalent rates, whereas FAAH-1 exhibited much greater activity with N-acyl ethanolamines (e.g. anandamide) and N-acyl taurines. Both enzymes were sensitive to the principal classes of FAAH inhibitors synthesized to date, including O-aryl carbamates and alpha-keto heterocycles. These data coupled with the overlapping, but distinct tissue distributions of FAAH-1 and FAAH-2 suggest that these proteins may collaborate to control fatty acid amide catabolism in primates. The apparent loss of the FAAH-2 gene in some lower mammals should be taken into consideration when extrapolating genetic or pharmacological findings on the fatty acid amide signaling system across species.


Alternate JournalJ. Biol. Chem.
PubMed ID17015445
Grant ListDA015197 / DA / NIDA NIH HHS / United States
CA087660 / CA / NCI NIH HHS / United States
R01 DA015197 / DA / NIDA NIH HHS / United States
R01 CA087660-06 / CA / NCI NIH HHS / United States
DA017259 / DA / NIDA NIH HHS / United States
P01 DA017259 / DA / NIDA NIH HHS / United States
R01 CA087660 / CA / NCI NIH HHS / United States
P01 DA017259-03 / DA / NIDA NIH HHS / United States
R01 DA015197-04 / DA / NIDA NIH HHS / United States