Anandamide degradation

Maccarrone M, Attina M, Bari M, Cartoni A, Ledent C, Finazzi-Agro A (2001) Anandamide degradation and N-acylethanolamines level in wild-type and CBi cannabinoid receptor knockout mice of different ages. J Neurochem 78 339-348... 

Ruiz-Llorente L, Ortega- Gutierrez S, Viso A, Sdnchez MG, Sanchez AM, Fernandez C, Ramos JA, Hillard C, Lasuncidn MA, Ldpez-Rodrfguez ML, Diaz-Laviada I (2004) Characterization of an anandamide degradation system in prostate epithelial PC-3 cells synthesis of new transporter inhibitors as tools for this study. Br J Pharmacol 141 457-467... 

Once antibodies to the anandamide-degrading enzyme, namely fatty acid amide hydrolase (FAAH), became available, it was apparent that in many regions FAAH and CBl expression is reciprocal in nature (Egertova et al. 1998, 2003 Tsou et al. 1998b). For example, FAAH, but not CBi is highly expressed in the somata and proximal dendrites of hippocampal pyramidal cells and cerebellar Purkinje neurons. These neurons are, in turn, densely innervated by CBi-positive fibers. Thus, it has been proposed that anandamide, despite its possible presynaptic site... 

Boger DL, Sato H, Lerner AE, Hedrick MP, Fesik RA, Miyauchi H, Wilkie GD, Austin BJ, Patricelli MP, Cravatt BF. Exceptionally potent inhibitors of fatty acid amide hydrolase the enzyme responsible for degradation of endogenous oleamide and anandamide. Proc Natl Acad Sci USA 2000 97 5044-5049. 

Multiple lipid pathways take part in anandamide biosynthesis and degradation (Fig. 1). Here, we review the lipid components that constitute such networks and how they might interact to regulate anandamide metabolism. 

Anandamide is a member of the FAE family (also called jV-acylethanolamides, NAEs) (Fig. 4), which include both cannabimimetic and noncannabimimetic compounds present in most mammalian tissues. These molecules, which only differ in length and degree of unsaturation of their acyl chains, share common biosynthetic and degradative enzymes. 

Anandamide amidohydrolase is likely to play an important role in the physiological degradation of anandamide. Three lines of evidence support this possibility. First, anandamide amidohydrolase is highly selective. Second, anandamide amidohydrolase is discretely distributed in the central nervous system, where its localization parallels that of cannabinoid receptors. 

Deutsch, D. G. and Chin, S. A., Enzymatic Synthesis and Degradation of Anandamide, A Cannabinoid Receptor Agonist, Biochemical Pharmacology, 46(5) 791-796 (1993). 

Oleamide, a lipid originally named cerebrodiene, was first iso lated from partially sleep-deprived cats (Lerner et al 1994). The molecule, with the chemical formula C18H35NO, is a long-chain base structurally related to sphingosine and sphinganine (Lerner et al 1994). Oleamide, or cerebrodiene, is chemically characterized as cis-9,10-octadecenoamide (Cravatt et al 1995). Oleamide is degraded by the brain enzyme fatty acid amide hydrolase (FAAH), which also degrades anandamide (Cravatt et al. Nature 1996). 

Soon after the discovery of anandamide, enzymatic activities responsible for its degradation (an amidase, also called an amidohydrolase) and s mthesis (synthase) were described (DiMarzo et al. 1994 Desamaud et al. 1995 Ueda et al. 1995 Deutsch and Chin 1993 Kruszka and Gross 1994 Devane and Axelrod 1994). Phenylmethylsulfonyl fluoride (PMSF) was discovered to be a potent inhibitor of the enzymatic breakdown of arachidonoylethanolamide (Deutsch and Chin 1993). A series of anandamide analogs was synthesized (trifluoromethyl ketone, -keto ester, and -keto amide derivatives) and tested in vitro and in intact cells as amidase inhibitors (Koutek et al. 1994). The trifluoromethyl ketones (e.g., arachidonyltrifluoromethyl ketone) were found to be potent inhibitors in the low micromolar (M) range. Most recently, a potent irreversible inhibitor of anandamide hydrolysis (AM 374) has... 

The reaction for the degradation of anandamide to arachidonic acid and ethanolamine is shown below. 

Deutsch, D.G., and Chin, S.A. Enzymatic synthesis and degradation of anandamide, a cannabinoid receptor agonist. Biochem Pharmacol A6 5) J9l-6, 1993. 

Sugiura T, Kobayashi Y, Oka S, Waku K (2002) Biosynthesis and degradation of anandamide and 2-arachidonoylglycerol and their possible physiological significance. Prostaglandins Leukot Essent Fatty Acids 66 173-192... 

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