Anandamide biosynthesis

Multiple lipid pathways take part in anandamide biosynthesis and degradation (Fig. 1). Here, we review the lipid components that constitute such networks and how they might interact to regulate anandamide metabolism. 

Simon, G. M., and Cravatt, B. F. (2008). Anandamide biosynthesis catalyzed by the phosphodiesterase GDE1 and detection of glycerophospho-jV-acyl ethanolamine precursors in mouse brain. J. Biol. Chem. 283, 9341. 

Figure 10.6. The biosynthesis of endocannabinoids. Biosynthetic pathways for the biosynthesis of the major endocannabinoids anandamide and 2-arachidonoylglycerol (2-AG). Note that the enzymes N-acyltransferase in anandamide biosynthesis. The biosynthesis of 2-AG can proceed via two different routes and is also dependent on an increase in Ca. Figures reprinted from Piomelli (2003) with permission from Nature Publishing Group.

Burstein, S.H., and Hunter, S.A. Anandamide biosynthesis inN-18TG2 neuroblastoma cells is stimulated by THC. Biochem Pharmacol 1995. 

The Phylogenetic Distribution of Anandamide and Enzymes Involved in Anandamide Biosynthesis... 

Schmid, PC., Schwindenhammer, D., Krebsbach, R.J., and Schmid, H.H.O. (1998) Alternative pathways of anandamide biosynthesis in rat testes. Chemistry and Physics of Lipids 92 27-35. 

Szallasi, A. (2002). Vanilloid (capsaicin) receptors in health and disease. Am. J. Clin. Pathol., 118, 110-121. Ueda, N., Kurahashi, Y, Yamamoto, K., Yamamoto, S., and Tokunaga, T. (1996). Enzymes for anandamide biosynthesis and metabolism. J. Lipid Medial Cell Signal., 14, 57-61. 

The biosyntheses of anandamide and 2-AG have been studied in depth [10]. These compounds appear to be synthesised on demand in response to certain stimuli, rather than being stored in cells. Little is known regarding the biosynthesis of noladin ether, virodhamine or NADA. 

All the foregoing pharmacological effects of anandamide, in conjunction with the well-documented existence of specific systems for its biosynthesis, catabolism, and cellular reuptake to be discussed shortly, suggest that anandamide is indeed the endogenous cannabinoid ligand. The other two less studied A -acylethanolamide endocannabinoids and also 2-AG may serve similar functions. The differential roles of each of these four endocannabinoids are still unclear. 

As with the biosynthesis of anandamide, the biosynthesis of 2-AG is also triggered by increases of intracellular calcium ions that result from neuronal activity. High frequency stimulation of neurons produced a fourfold increase of 2-AG accumulation compared with controls, and this was prevented by sodium ion channel blocking or removal of calcium ions (Stella, 1997). The concentration of 2-AG in depolarized neurons reached 1 to 2 pM, significantly higher than anandamide and sufficient to substantially activate CB1 (Stella, 1997). 

Based on the pathways just proposed for the biosynthesis of anandamide and 2-AG, the formation of these endogenous ligands must also be dependent on the composition of the precursor lipids. This dependence is of greater importance for anandamide rather than for 2-AG because... 

Bisogno T, Delton-Vandenbroucke 1, Milone A, Lagarde M, Di Marzo V. Biosynthesis and inactivation of N-arachidonoylethanol-amine anandamide. and N-docosahexaenoylethanolamine in bovine retina. Arch Biochem. Biophys. 1999 370 300-307. 

Burstein and Hunter (1995) observed that THC stimulated the biosynthesis of anandamide in neuroblastoma cells employing either ethanolamine or arachidonic acid as the label. Anandamide bios5mthesis has also been shown to occur in primary cultures of rat brain neurons labelled with [H]-ethanolamine when stimulated with ionomycin, a Ca ionophore (Di Marzo et al. 1994). These authors proposed an alternate model for the biosynthesis of anandamide in which N-arachidonoyl phosphatidyl ethanolamine is cleaved by a phospholipase D activity to yield phosphatidic acid and ararchidonoylethanolamide. This model is based upon extensive studies undertaken by Schmid and collaborators (1990), who have shown that fatty acid ethanolamide formation results from the N-acylation of phosphatidyl ethanolamine by a transacylase to form N-acyl phosphatidylethanolamine. Possibly resulting from postmortem changes, this compound is subsequently hydrolyzed to the fatty acid ethanolamide and the corresponding phosphatide by a phosphodiesterase, phospholipase D. 

Sugiura T, Kobayashi Y, Oka S, Waku K (2002) Biosynthesis and degradation of anandamide and 2-arachidonoylglycerol and their possible physiological significance. Prostaglandins Leukot Essent Fatty Acids 66 173-192... 

Sun YX, Tsuboi K, Okamoto Y, Tonai T, Murakami M, Kudo 1, Ueda N (2004) Biosynthesis of anandamide and N-palmitoylethanolamine by sequential actions of phospholipase A2 and lysophospholipase D. Biochem J 380 749-756... 

Schmid HH (2000) Pathways and mechanisms of N-acylethanolamine biosynthesis can anandamide be generated selectively Chem Phys Lipids 108 71-87... 

To understand the regulation at the molecular level of the enzymes catalysing anandamide and 2-AG biosynthesis and inactivation... 

Bisogno T, Maurelli S, Melck D, De Petrocellis L, Di Marzo V (1997a) Biosynthesis, uptake, and degradation of anandamide and palmitoylethanolamide in leukocytes. J Biol Chem 272 3315-3323... 

Di Marzo V, De Petrocellis L, Sepe N, Buono A (1996a) Biosynthesis of anandamide and related acylethanolamides in mouse J774 macrophages and N18 neuroblastoma cells. Biochem J 316 977-984... 

Extensive studies on the endocannabinoid system have revealed a number of cannabinergic proteins involved in the inactivation and biosynthesis of endocannabinoids. These include fatty acid amide hydrolase (FAAH) (Di Marzo et al. 1994 Gaetani et al. 2003 Piomelli et al. 1999), monoglyceride lipase (MAG) (Dinh et al. 2002), and the anandamide transporter (ANT) (Beltramo et al. 1997 Di Marzo et al. 1994 Fegley et al. 2004 Hillard et al. 1997). The above three proteins and the two cannabinoid receptors have received considerable attention and show great promise as potential targets for the development of novel medications for various conditions, including pain, immunosuppression, peripheral vascular disease, appetite enhancement or suppression, and motor disorders. 

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