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Contents
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, Gibb AJ, Kelly E, Mathie AA, Peach CJ, Veale EL, Armstrong JF, Faccenda E, Harding SD, Southan C, Davies JA et al. (2025) The Concise Guide to PHARMACOLOGY 2025/26: Enzymes. Br J Pharmacol. 182: S307-S403.
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].