Anandamide hydrolase

Maccarone M, Yalenise H, Bari M, Lazzarin N, Romani C, Finazzi-Agro A. Relationship between decreased anandamide hydrolase concentrations in human lymphocytes and miscarriage. Lancet 2000 235 1326-1329. 

Maccarrone M, De Fehci M, Bari M, Klinger E, Siracusa G, Einazzi-Agro A (2000b) Down-regulation of anandamide hydrolase in mouse uterus by sex hormones. Eur J Biochem 267 2991-2997... 

Maccarrone M, Di Rienzo M, Finazzi-Agro A, Rossi A (2003b) Leptin activates the anandamide hydrolase promoter in human T lymphocytes through STAT3. J Biol Chem 278 13318-13324... 

Maccarrone M, DeFelici M, Klinger FG, Battista N, Fezza F, Dainese E, Siracusa G, Finazzi-Agro A (2004) Mouse blastocysts release a lipid which activates anandamide hydrolase in intact uterus. Mol Hum Reprod 10 215-221... 

Maccarrone M, Valensise H, Bari M, Lazzarin N, Romanini C, Finazzi-Agrd A (2001) Progesterone up-regulates anandamide hydrolase in human lymphocytes role of cytokines and implications for fertility. J Immunol 166 7183-7189... 

Maccarrone, M. and Finazzi-Agro, A., Anandamide hydrolase a guardian angel of human reproduction , Trends Pharmacol Sci, 25 (2004a) 353-357. 

Once inside the cell, anandamide is hydrolyzed by a specific hydrolase, anandamide amidase (AEAase) or fatty acid amidohydrolase (FAAH) (Desarnaud, 1995 Deutsch, 1993). This enzyme is membrane associated and shows significant specificity for anandamide (Desarnaud, 1995 Lang, 1999). 

Anandamide amidase recognizes and hydrolyzes 2-AG (Goparaju, 1999 Di Marzo, 1999 Lang, 1999) however, there is evidence for the existence of another specific hydrolase [monoacylglycerol (MAG) lipase] that hydrolyzes 2-AG (D. Piomelli and A. Makriyannis, 2000, personal communication). In addition to this pathway, 2-AG diffuses rapidly into the cell membrane where it could be either hydrolyzed to arachidonic acid and glycerol or esterified back to phosphoglycerides (Di Marzo, 1999b). 

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... 

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... 

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... 

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. 

As an example of the application of metabolomics, we will refer to the substrates of the enzyme fatty acyl amide hydrolase (FAAH) that regulates several brain lipids that have interesting pharmacological properties including effects on the control of pain. It is well known that some fatty acyl amides of ethanolamine are substrates of FAAH, such as the ethanolamide of arachidonic acid (anandamide), which is an endogenous ligand of cannabinoid receptors. 

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. 

Wise LE, Shelton CC, Cravatt BE, Martin BR, Lichtman AH (2007) Assessment of anandamide s pharmacological effects in mice deficient of both fatty acid amide hydrolase and cannabinoid CBl receptors. Eur J Pharmacol 557 44-48... 

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