Fatty acid amide hydrolase

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. 

Cravatt BF, Demarest K, Patricelli MP, Bracey MH, Giang DK, Martin BR and Lichtman AH (2001). Supersensitivity to anandamide and enhanced endogenous cannabinoid signaling in mice lacking fatty acid amide hydrolase. Proceedings of the National Academy of Science, 98, 9371-9376. 

A competitive version of ABPP identifies the target(s) and assesses the selectivity of an enzyme inhibitor in biological systems by gauging how well the inhibitor slows the enzyme s reaction with an ABP. For example, fluorophosphonate ABP 3 was used to profile the selectivity of fatty acid amide hydrolase (FAAH) inhibitors within the serine hydrolase superfamily [27] (FAAH hydrolyzes endocannabinoids such as anandamide). Serine hydrolases that exhibited reduced labeling by the probe in the presence of inhibitor were scored as targets of the inhibitor. Urea FAAH inhibitors exemplified by PF-3845 (5) that covalently modify the active-site serine nucleophile of FAAH were found to be exquisitely selective for FAAH in brain and liver... 

Key Fatty acid amide hydrolase (FAAH) /V-a-PEA = /V-arachidonoyl-phosphatidylethanolamine. 

Both anandamide and 2-AG are inactivated by enzymatic hydrolysis (Goparaju et al. 1998). Fatty acid amide hydrolase (FAAH) is an enzyme that catalyses their hydrolysis. High concentrations of FAAH were found in the cerebellum, hippocampus and neocortex of rat brain, which are also rich in cannabinoid receptors. Further, there is a complementary pattern of distribution of FAAH and the CBl receptor. For example, in the cerebellum, FAAH is found in the cell bodies of Purkinje cells and the CBl receptor is found in the axons of granule cells and basket cells, which are presynaptic to Purkinje cells. 2-AG may also be inactivated by direct esterification into membrane phospholipids. Cannabinoid Receptors... 

Egertova M, Giang DK, Cravatt BF, Elphick MR. (1998). A new perspective on cannabinoid signalling complementary localization of fatty acid amide hydrolase and the CBl receptor in rat brain. Proc Royal Soc London B Biol Sci. 265(1410) 2081-85. 

Functional interactions between the nicotinic and cannabinoid systems have been proposed (Cohen et al. 2002) and several studies have tested the applicability of these ideas to nicotine discrimination. However cannabinoid agonists acting at cannabinoid CBi and CB2 receptors have failed to generalise with nicotine (Zaniewska et al. 2006). Results with the anandamide uptake and fatty acid amide hydrolase inhibitors AM-404 and URB 597, that elevate brain concentrations of endogenous cannabinoids, were also negative. Furthermore, neither the CBi receptor... 

Mitchell, and M. Glass. Identification of the CBl cannabinoid receptor and CS337 fatty acid amide hydrolase (FAAH) in the human placenta. Placenta 2003 ... 

Boger, D.L., Miyauchi, H., Hedrick, M.P. a-Keto Heterocycle Inhibitors of Fatty Acid Amide Hydrolase Carbonyl Group Modification and a-Substitution, Bioorg. Med. Chem. Lett. 2001, 11,1517-1520. 

The fatty acid amides are destroyed by an integral membrane protein, a fatty acid amide hydrolase.321 322... 

Lichtman AH, Hawkins EG, Griffin G, Cravatt BF (2002) Pharmacological activity of fatty add amides is regulated, but not mediated, by fatty acid amide hydrolase in vivo. J Pharmacol Exp Ther 302(l) 73-9... 

Mackie K. (2006) Mechanisms of CB1 receptor signaling endocannabinoid modulation of synaptic strength. Int. J. Obes. (Lond.) 30 Suppl 1 S 19-23 Mckinney MK, Cravatt, BP (2005) Structure and function of fatty acid amide hydrolase. Annu Rev Biochem 74 411-32... 

Wei BQ, Mikkelsen TS, McKinney MK, Lander ES, Cravatt BF (2006) A second fatty acid amide hydrolase with variable distribution among placental mammals. J Biol Chem 281(48) 36569-78... 

Fig. 1. Targeted lipidomics of anandamide metabolism. Postulated pathways of anandamide metabolism. Abbreviations PC, phosphatidylcholine PE, phosphatidylethanolamine NAT, JV-acyl transferase LPA, lysophosphatidic acid PA, phosphatidic acid NAPE, jV-acyl-phosphatidylethanolamine Lyso-NAPE, l-lyso,2-acyl-OT-glycero-3-phosphoethanolamine-JV-acyl ABHD-4, a//3 hydrolase-4 GP-anandamide, glycerophospho-anandamide PAEA, phospho-anandamide PLA, phospholipase A NAPE-PLD, NAPE phospholipase D PLC, phospholipase C FAAH, fatty acid amide hydrolase P, phosphatase COX, cyclooxygenase LOX, lipoxygenase CYP450, cytochrome P450 PDE, phosphodiesterase.

Anandamide can be hydrolyzed to arachidonic acid and ethanolamine by fatty acid amide hydrolase (FAAH) (Cravatt et al., 1996 Wei et al., 2006) (Fig. 1). FAAH is highly expressed in the brain, where it is expressed at high concentrations in neuronal cell bodies and dendrites that are juxtaposed to axon terminals containing CB receptors. This suggests that anandamide hydrolysis occurs post-synaptically (Piomelli, 2003). 

Fegley, D., Kathuria, S., Mercier, R., Li, C., Goutopoulos, A., Makriyannis, A., and Piomelli, D. (2004). Anandamide transport is independent of fatty-acid amide hydrolase activity and is blocked by the hydrolysis-resistant inhibitor AMI 172. Proc. Natl. Acad. Sci. USA 101, 8756—8761. 

Justinova, Z., Manieri, R. A., Bortolato, M., Chefir, S. I., Mukhin, A. G., Clipper, J. R., King, A. R., Redhi, G. H., Yasar, S., Pomelli, D., and Goldberg, S. R. (2008). Fatty acid amide hydrolase inhibition heightens anandamide signaling without producing reinforcing effects in primates. 

Varvel, S. A., Wise, L. E., Niyuhire, F., Cravatt, B. F., and Lichtman, A. H. (2007). Inhibition of fatty-acid amide hydrolase accelerates acquisition and extinction rates in a spatial memory task. Neuropsychopharmacology 32, 1032-1041. 

Jhaveri, M. D., Richardson, D., Robinson, I., Garle, M. J., Patel, A., Sun, Y., Sagar, D. R., Bennett, A. J., Alexander, S. P., Kendall, D. A., Barrett, D. A., and Chapman, V. (2008). Inhibition of fatty acid amide hydrolase and cyclooxygenase-2 increases levels of endocannabi-noid related molecules and produces analgesia via peroxisome proliferator-activated receptor-alpha in a model of inflammatory pain. Neuropharmacology 55, 85—93. 

Insights into the mechanism and inhibition of fatty acid amide hydrolase from quantum mechanics/molecular mechanics (QM/ MM) modelling. Biochem Soc Trans 37(Pt 2) 363-367... 

LodolaA, MMor, JC Hermann, GTarzia, DPiomelli, AJ Mulholland (2005) QM/MM modelling of oleamide hydrolysis in fatty acid amide hydrolase (FAAH) reveals a new mechanism of nucleophile activation. Chem. Comm. (35) 43994 401... 

Anandamide is rapidly hydrolysed enzymatically to arachidonic acid and ethanol-amine by a fatty acid amide hydrolase (FAAH) [50], The molecular characterization, cloning and expression of FAAH have been reported in a recent study [51]. FAAH can be blocked with either the general serine protease inhibitor phenyl methy(sulphonyl fluoride [38] or with the highly efficient methyl arachidonyl fluorophsphonate [52], The non-steroidal antiinflammatory ibuprofen in therapeutic doses, but not aspirin, sulindac or acetaminophen, also inhibits anandamide metabolism [53], This observation may have therapeutic implications. 

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