The principle endocannabinoids are 2-arachidonoylglycerol (2AG) and anandamide (N-arachidonoylethanolamine, AEA), thought to be generated on demand rather than stored. For 2-arachidonoylglycerol, the key enzyme involved is diacylglycerol lipase (DGL), whilst several routes for anandamide synthesis have been described, the best characterized of which involves N-acylphosphatidylethanolamine-phospholipase D (NAPE-PLD, [14]). Inactivation of these endocannabinoids appears to occur predominantly through monoacylglycerol lipase (MGL) and fatty acid amide hydrolase (FAAH) for 2-arachidonoylglycerol and anandamide, respectively. In vitro experiments indicate that the endocannabinoids are also substrates for oxidative metabolism via cyclooxygenase, lipoxygenase and cytochrome P450 enzyme activities [3,6,15].
Unless otherwise stated all data refer to the human proteins. Gene information is provided for human (Hs), mouse (Mm) and rat (Rn).
Enzymes 
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Diacylglycerol lipase α Show »« Hide
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Diacylglycerol lipase β Show »« Hide
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N-Acylphosphatidylethanolamine-phospholipase D Show »« Hide
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Monoacylglycerol lipase Show »« Hide
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Fatty acid amide hydrolase-1 Show »« Hide
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Fatty acid amide hydrolase-2 Show »« Hide
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N-Acylethanolamine acid amidase Show »« Hide
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Alexander, SP; Kendall, DA. (2007) The complications of promiscuity: endocannabinoid action and metabolism. Br. J. Pharmacol., 152 (5): 602-23. [PMID:17876303]
Bisogno, T. (2008) Endogenous cannabinoids: structure and metabolism. J. Neuroendocrinol., 20 Suppl 1: 1-9. [PMID:18426492]
Di Marzo, V; Bisogno, T; De Petrocellis, L. (2007) Endocannabinoids and related compounds: walking back and forth between plant natural products and animal physiology. Chem. Biol., 14 (7): 741-56. [PMID:17656311]
Di Marzo, V; Petrosino, S. (2007) Endocannabinoids and the regulation of their levels in health and disease. Curr. Opin. Lipidol., 18 (2): 129-40. [PMID:17353660]
Farrell, EK; Merkler, DJ. (2008) Biosynthesis, degradation and pharmacological importance of the fatty acid amides. Drug Discov. Today, 13 (13-14): 558-68. [PMID:18598910]
Fowler, CJ. (2007) The contribution of cyclooxygenase-2 to endocannabinoid metabolism and action. Br. J. Pharmacol., 152 (5): 594-601. [PMID:17618306]
Fowler, CJ; Naidu, PS; Lichtman, A; Onnis, V. (2009) The case for the development of novel analgesic agents targeting both fatty acid amide hydrolase and either cyclooxygenase or TRPV1. Br. J. Pharmacol., 156 (3): 412-9. [PMID:19226258]
Hwang, J; Adamson, C; Butler, D; Janero, DR; Makriyannis, A; Bahr, BA. (2010) Enhancement of endocannabinoid signaling by fatty acid amide hydrolase inhibition: a neuroprotective therapeutic modality. Life Sci., 86 (15-16): 615-23. [PMID:19527737]
Savinainen, JR; Saario, SM; Laitinen, JT. (2012) The serine hydrolases MAGL, ABHD6 and ABHD12 as guardians of 2-arachidonoylglycerol signalling through cannabinoid receptors. Acta Physiol (Oxf), 204 (2): 267-76. [PMID:21418147]
Simon, GM; Cravatt, BF. (2010) Characterization of mice lacking candidate N-acyl ethanolamine biosynthetic enzymes provides evidence for multiple pathways that contribute to endocannabinoid production in vivo. Mol Biosyst, 6 (8): 1411-8. [PMID:20393650]
Snider, NT; Walker, VJ; Hollenberg, PF. (2010) Oxidation of the endogenous cannabinoid arachidonoyl ethanolamide by the cytochrome P450 monooxygenases: physiological and pharmacological implications. Pharmacol. Rev., 62 (1): 136-54. [PMID:20133390]
Wang, J; Ueda, N. (2009) Biology of endocannabinoid synthesis system. Prostaglandins Other Lipid Mediat., 89 (3-4): 112-9. [PMID:19126434]
Yates, ML; Barker, EL. (2009) Inactivation and biotransformation of the endogenous cannabinoids anandamide and 2-arachidonoylglycerol. Mol. Pharmacol., 76 (1): 11-7. [PMID:19389920]
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3. Alexander, SP; Kendall, DA. (2007) The complications of promiscuity: endocannabinoid action and metabolism. Br. J. Pharmacol., 152 (5): 602-23. [PMID:17876303]
4. Bisogno, T; Howell, F; Williams, G; Minassi, A; Cascio, MG; Ligresti, A; Matias, I; Schiano-Moriello, A; Paul, P; Williams, EJ; et al.. (2003) Cloning of the first sn1-DAG lipases points to the spatial and temporal regulation of endocannabinoid signaling in the brain. J. Cell Biol., 163 (3): 463-8. [PMID:14610053]
5. Blankman, JL; Simon, GM; Cravatt, BF. (2007) A comprehensive profile of brain enzymes that hydrolyze the endocannabinoid 2-arachidonoylglycerol. Chem. Biol., 14 (12): 1347-56. [PMID:18096503]
6. Fowler, CJ. (2007) The contribution of cyclooxygenase-2 to endocannabinoid metabolism and action. Br. J. Pharmacol., 152 (5): 594-601. [PMID:17618306]
7. Ghafouri, N; Tiger, G; Razdan, RK; Mahadevan, A; Pertwee, RG; Martin, BR; Fowler, CJ. (2004) Inhibition of monoacylglycerol lipase and fatty acid amide hydrolase by analogues of 2-arachidonoylglycerol. Br. J. Pharmacol., 143 (6): 774-84. [PMID:15492019]
8. Keith, JM; Apodaca, R; Xiao, W; Seierstad, M; Pattabiraman, K; Wu, J; Webb, M; Karbarz, MJ; Brown, S; Wilson, S; et al.. (2008) Thiadiazolopiperazinyl ureas as inhibitors of fatty acid amide hydrolase. Bioorg. Med. Chem. Lett., 18 (17): 4838-43. [PMID:18693015]
9. Li, W; Blankman, JL; Cravatt, BF. (2007) A functional proteomic strategy to discover inhibitors for uncharacterized hydrolases. J. Am. Chem. Soc., 129 (31): 9594-5. [PMID:17629278]
10. Liu, Q; Tonai, T; Ueda, N. (2002) Activation of N-acylethanolamine-releasing phospholipase D by polyamines. Chem. Phys. Lipids, 115 (1-2): 77-84. [PMID:12047899]
11. Long, JZ; Li, W; Booker, L; Burston, JJ; Kinsey, SG; Schlosburg, JE; Pavón, FJ; Serrano, AM; Selley, DE; Parsons, LH; et al.. (2009) Selective blockade of 2-arachidonoylglycerol hydrolysis produces cannabinoid behavioral effects. Nat. Chem. Biol., 5 (1): 37-44. [PMID:19029917]
12. Marrs, WR; Blankman, JL; Horne, EA; Thomazeau, A; Lin, YH; Coy, J; Bodor, AL; Muccioli, GG; Hu, SS; Woodruff, G; et al.. (2010) The serine hydrolase ABHD6 controls the accumulation and efficacy of 2-AG at cannabinoid receptors. Nat. Neurosci., 13 (8): 951-7. [PMID:20657592]
13. Petersen, G; Hansen, HS. (1999) N-acylphosphatidylethanolamine-hydrolysing phospholipase D lacks the ability to transphosphatidylate. FEBS Lett., 455 (1-2): 41-4. [PMID:10428468]
14. Simon, GM; Cravatt, BF. (2010) Characterization of mice lacking candidate N-acyl ethanolamine biosynthetic enzymes provides evidence for multiple pathways that contribute to endocannabinoid production in vivo. Mol Biosyst, 6 (8): 1411-8. [PMID:20393650]
15. Snider, NT; Walker, VJ; Hollenberg, PF. (2010) Oxidation of the endogenous cannabinoid arachidonoyl ethanolamide by the cytochrome P450 monooxygenases: physiological and pharmacological implications. Pharmacol. Rev., 62 (1): 136-54. [PMID:20133390]
16. Tsuboi, K; Hilligsmann, C; Vandevoorde, S; Lambert, DM; Ueda, N. (2004) N-cyclohexanecarbonylpentadecylamine: a selective inhibitor of the acid amidase hydrolysing N-acylethanolamines, as a tool to distinguish acid amidase from fatty acid amide hydrolase. Biochem. J., 379 (Pt 1): 99-106. [PMID:14686878]
17. Ueda, N; Yamanaka, K; Yamamoto, S. (2001) Purification and characterization of an acid amidase selective for N-palmitoylethanolamine, a putative endogenous anti-inflammatory substance. J. Biol. Chem., 276 (38): 35552-7. [PMID:11463796]
18. 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. [PMID:17015445]
19. Xie, S; Borazjani, A; Hatfield, MJ; Edwards, CC; Potter, PM; Ross, MK. (2010) Inactivation of lipid glyceryl ester metabolism in human THP1 monocytes/macrophages by activated organophosphorus insecticides: role of carboxylesterases 1 and 2. Chem. Res. Toxicol., 23 (12): 1890-904. [PMID:21049984]
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Many of the compounds described as inhibitors are irreversible and so potency estimates will vary with incubation time. FAAH2 is not found in rodents [18]. 2-arachidonoylglycerol has been reported to be hydrolysed by multiple enzyme activities from neural preparations, including ABHD6 (ENSG00000163686, [5]), ABHD12 (ENSG00000100997, [5]), neuropathy target esterase (PNPLA6, ENSG00000032444, [12]) and carboxylesterase 1 (CES1, ENSG00000198848, [19]). Although these have been incompletely defined, WWL70 has been described to inhibit ABHD6 selectively with a pIC50 value of 7.2 [9].