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The Fatty Acid Amide Hydrolase (FAAH)

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The Fatty Acid Amide Hydrolase (FAAH) Chemistry and Physics of Lipids 108 (2000) 107–121 www.elsevier.com/locate/chemphyslip Review The fatty acid amide hydrolase (FAAH) Natsuo Ueda a, Robyn A. Puffenbarger b, Shozo Yamamoto a, Dale G. Deutsch b,* a Department of Biochemistry, School of Medicine, Uni6ersity of Tokushima, Kuramoto-cho, Tokushima 770-8503, Japan b Department of Biochemistry and Cell Biology, State Uni6ersity of New York at Stony Brook, Stony Brook, NY 11794-5215, USA Received 3 May 2000; received in revised form 5 June 2000; accepted 5 June 2000 Abstract The topic of this review is fatty acid amide hydrolase (FAAH), one of the best-characterized enzymes involved in the hydrolysis of bioactive lipids such as anandamide, 2-arachidonoylglycerol (2-AG), and oleamide. Herein, we discuss the nomenclature, the various assays that have been developed, the relative activity of the various substrates and the reversibility of the enzyme reactions catalyzed by FAAH. We also describe the cloning of the enzyme from rat and subsequent cDNA isolation from mouse, human, and pig. The proteins and the mRNAs from different species are compared. Cloning the enzyme permitted the purification and characterization of recombinant FAAH. The conserved regions of FAAH are described in terms of sequence and function, including the amidase domain which contains the serine catalytic nucleophile, the hydrophobic domain important for self association, and the proline rich domain region, which may be important for subcellular localization. The distribution of FAAH in the major organs of the body is described as well as regional distribution in the brain and its correlation with cannabinoid receptors. Since FAAH is recognized as a drug target, a large number of inhibitors have been synthesized and tested since 1994 and these are reviewed in terms of reversibility, potency, and specificity for FAAH and cannabinoid receptors. © 2000 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Fatty acid amide hydrolase; Anandamide; 2-Arachidonoylglycerol; Oleamide; Amidase; Amidohydrolase 1. Introduction The fatty acid amide hydrolase (FAAH) plays an important role in terminating the signaling of * Corresponding author. Tel.: +1-631-6328595; fax: +1- the endocannabinoids and oleamide in the central 631-6328575. E-mail address: [email protected] (D.G. nervous system and in peripheral tissues. For the Deutsch). endocannabinoids, the action of both anandamide 0009-3084/00/$ - see front matter © 2000 Elsevier Science Ireland Ltd. All rights reserved. PII: S0009-3084(00)00190-0 108 N. Ueda et al. / Chemistry and Physics of Lipids 108 (2000) 107–121 and 2-arachidonoylglycerol (2-AG) are terminated the remaining anandamide by thin-layer chro- by the hydrolysis of the amide or ester bonds after matography (Deutsch and Chin, 1993; Hillard et being taken up into the cell. This research area al., 1995; Ueda et al., 1995; Cravatt et al., 1996) has been covered to some extent as part of recent or high-performance liquid chromatography reviews on the endocannabinoids (Deutsch and (Maccarrone et al., 1999a). Alternatively, when Makriyannis, 1997; Di Marzo and Deutsch, 1998; [14C] or [3H]anandamide labeled on the Di Marzo et al., 1999b). Although the role of ethanolamine moiety was hydrolyzed by FAAH, FAAH in hydrolyzing anandamide was first re- the water-soluble radioactive ethanolamine ported in 1993, where it was called an amidase product was separated from anandamide by open (Deutsch and Chin, 1993), the enzyme has an bed column chromatography (Desarnaud et al., interesting history. An enzyme activity was de- 1995; Maurelli et al., 1995) or by chloroform scribed in the 1960s, which catalyzed the forma- extraction (Omeir et al., 1995). tion of fatty acid amides of ethanolamine and this When non-labeled anandamide was employed enzyme showed tissue specificity similar to FAAH as the substrate, the arachidonic acid product was since it was not present in heart muscle and separated and quantified by high-performance liq- skeletal muscle (Bachur and Udenfriend, 1966). In uid chromatography by monitoring absorption at the 1980s an enzyme, called an amidohydrolase, 204 or 205 nm (Lang et al., 1996; Goparaju et al., was well characterized in terms of the N- 1998) or by gas chromatography of its methyl acylethanolamine substrates hydrolyzed, pH ester (Watanabe et al., 1998). Alternatively, the profile, inhibition by detergents and sulfhydryl ethanolamine product was derivatized with o-ph- reagents, and reversibility (Schmid et al., 1985). thaldialdehyde, and the derivative was quantified Many breakthroughs and exciting discoveries by high-performance liquid chromatography have been reported since these early days. FAAH monitoring absorbance at 230 nm (Qin et al., was also shown to have an esterase activity with 1998). A fluorescence displacement assay has also the ability to hydrolyze 2-AG (Di Marzo et al., been reported (Thumser et al., 1997). 1998; Goparaju et al., 1998) and an amidase for oleamide (Maurelli et al., 1995). An important 2.2. Enzyme purification advance in our understanding of FAAH was the study where it was cloned and shown to belong to FAAH is a membrane-bound protein found a family of amidases with similar domains in the predominantly in microsomal and mitochondrial catalytic site (Cravatt et al., 1996). In this review, fractions (Schmid et al., 1985; Desarnaud et al., the first devoted solely to FAAH, we describe the 1995; Hillard et al., 1995; Ueda et al., 1995). The enzymological and molecular properties of the enzyme can be solubilized from the membrane enzyme, its distribution in organs and tissues, and with the aid of detergents such as sodium tau- the inhibitors that have been developed for rodeoxycholate (Schmid et al., 1985) and Triton FAAH. X-100 (Ueda et al., 1995; Cravatt et al., 1996). The enzyme solubilized from porcine brain micro- somes was purified 22-fold by hydrophobic chro- 2. Catalytic properties matography using a Phenyl-5PW column (Ueda et al., 1995). The enzyme solubilized from rat liver 2.1. Assays plasma membrane was purified approximately 20- fold by a combination of DEAE, organomercu- For the detection of the anandamide hydrolyz- rial, and heparin columns (Cravatt et al., 1996). ing activity, radioactive anandamide is generally The latter enzyme preparation was further used as substrate. When [arachidonoyl-1-14C] or purified by affinity chromatography using oleyl [arachidonoyl-5,6,8,9,11,12,14,15-3H] anandamide trifluoromethyl ketone as a ligand, and was uti- was used as substrate, the radioactive arachidonic lized for amino acid sequencing of the enzyme acid produced by hydrolysis was separated from (Cravatt et al., 1996). N. Ueda et al. / Chemistry and Physics of Lipids 108 (2000) 107–121 109 Recently, recombinant rat FAAH was highly anandamide (Cravatt et al., 1996; Giang and Cra- purified. The enzyme with a hexahistidine tag was vatt, 1997; Kurahashi et al., 1997; Goparaju et al., overexpressed in Escherichia coli (Patricelli et al., 1999). The enzyme can hydrolyze not only 1998a) or in a baculovirus-Sf9 insect cell system oleamide but also primary amides of other fatty (Katayama et al., 1999) and these enzyme prepa- acids (Cravatt et al., 1996; Giang and Cravatt, rations were purified by cobalt- or nickel-charged 1997). Their hydrolytic rates were in the order of \ \ resin. The kcat value of the recombinant enzyme oleamide myristamide palmitamide. Arachi- was 7.1 s−1 (E. coli, oleamide substrate) or 6.5 donamide (primary amide of arachidonic acid) s−1 (baculovirus system, anandamide substrate). was later shown to be hydrolyzed at the highest m The Km for anandamide was 2–67 M depending rate (Kurahashi et al., 1997; Lang et al., 1999). upon the enzyme preparations and assay condi- Various synthetic anandamide derivatives were tions (Desarnaud et al., 1995; Hillard et al., 1995; also tested as substrates for FAAH by reverse- Maurelli et al., 1995; Omeir et al., 1995; Ueda et phase high performance liquid chromatography al., 1995; Bisogno et al., 1997a; Katayama et al., (Lang et al., 1999). It should be noted that (R)- 1999; Maccarrone et al., 1999a). The optimum pH methanandamide, an anandamide analogue resis- was 8.5–10 (Hillard et al., 1995; Maurelli et al., tant to the hydrolysis by FAAH, showed 1995; Omeir et al., 1995; Ueda et al., 1995; long-lasting biological activity in vivo (Romero et Bisogno et al., 1997a; Goparaju et al., 1998; al., 1996). Katayama et al., 1999). In addition to its amidase activity, FAAH also has an esterase activity for monoacylglycerols (Di 2.3. Substrate specificity Marzo et al., 1998; Goparaju et al., 1998, 1999) and methyl esters of fatty acids (Kurahashi et al., The relative reactivities of FAAH with various 1997; Goparaju et al., 1999; Patricelli and Cra- substrates are shown in Table 1. Although the vatt, 1999). 2-AG is another endogenous agonist first report of anandamide acting as a substrate for the cannabinoid receptor (Mechoulam et al., for this enzyme was made in 1993 (Deutsch 1995; Sugiura et al., 1995) and was hydrolyzed at and Chin, 1993) there was an earlier report of a rate several-fold faster than anandamide by this activity breaking down other N-acyl- recombinant rat and porcine FAAH (Goparaju et ethanolamines (Schmid et al., 1985). As the chain al., 1998, 1999). 1(3)-Arachidonoylglycerol was as length of saturated fatty acids was varied between active as 2-AG while 1-oleoylglycerol was less C12 and C18, the rat liver enzyme hydrolyzed active. 2-AG and racemic 1-arachidonoylglycerol N-acylethanolamines of shorter-chain fatty acids were also shown to be excellent FAAH substrates faster than those of longer-chain fatty acids. in rat brain microsomal fractions (Lang et al., Amides of propanolamine or higher homologs (up 1999) while 1,2-diacylglycerol was inactive (Go- to C6) were hydrolyzed at drastically slower rates paraju et al., 1998). than the amides of ethanolamine (Schmid et al., 1985).
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