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Overview
The principle endocannabinoids are 2-acylglycerol esters, such as 2-arachidonoylglycerol (2-AG), and N-acylethanolamines, such as anandamide (N-arachidonoylethanolamine, AEA). The glycerol esters and ethanolamides are synthesised and hydrolysed by parallel, independent pathways. Mechanisms for release and re-uptake of endocannabinoids are unclear, although potent and selective inhibitors of facilitated diffusion of endocannabinoids across cell membranes have been developed [6]. FABP5 (Q01469) has been suggested to act as a canonical intracellular endocannabinoid transporter in vivo [4]. For the generation of 2-arachidonoylglycerol, the key enzyme involved is diacylglycerol lipase (DAGL), whilst several routes for anandamide synthesis have been described, the best characterized of which involves N-acylphosphatidylethanolamine-phospholipase D (NAPE-PLD, [11]). A transacylation enzyme which forms N-acylphosphatidylethanolamines has been identified as a cytosolic enzyme, PLA2G4E (Q3MJ16) [9]. In vitro experiments indicate that the endocannabinoids are also substrates for oxidative metabolism via cyclooxygenase, lipoxygenase and cytochrome P450 enzyme activities [1,5,12].
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Concise Guide to PHARMACOLOGY citation:
Alexander SPH, Fabbro D, Kelly E, Mathie A, Peters JA, Veale EL, Armstrong JF, Faccenda E, Harding SD, Pawson AJ, Sharman JL, Southan C, Davies JA; CGTP Collaborators. (2019) The Concise Guide to PHARMACOLOGY 2019/20: Enzymes. Br J Pharmacol. 176 Issue S1: S297-S396.
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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 [14] and only a few of the inhibitors described have been assessed at this enzyme activity. 2-Arachidonoylglycerol has been reported to be hydrolysed by multiple enzyme activities from neural preparations [2], including ABHD2 (P08910) [8], ABHD12 (Q8N2K0) [3] and carboxylesterase 1 (CES1, P23141 [15]). ABHD2 (P08910) has also been described as a triacylglycerol lipase and ester hydrolase [7], while ABHD12 (Q8N2K0) is also able to hydrolyse lysophosphatidylserine [13]. ABHD12 (Q8N2K0) has been described to be inhibited selectively by pentacyclic triterpenoids, such as oleanolic acid [10].