Biosynthesis of endocannabinoids

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.

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. 

Leung, D., Saghatelian, A., Simon, G. M. and Cravatt, B. F., Inactivation of N-acyl phos-phatidylethanolamine phospholipase D reveals multiple mechanisms for the biosynthesis of endocannabinoids. Biochemistry, 45 (2006) 4720 726. 

Biosynthesis of NADA and other endocannabinoids more questions than answers... 

Regulation of endocannabinoid levels what is the target, biosynthesis or degradation ... 

Bisogno T, Berrendero F, Ambrosino G, Cebeira M, Ramos JA, Fernandez-Ruiz 11, Di Marzo V (1999a) Brain regional disti ibution of endocannabinoids implications for their biosynthesis and biological function. Biochem Biophys Res Commun 256 377-380... 

Very little is known about the biosynthesis of the three most recently proposed endocannabinoids, 2-AGE, virodhamine and NADA. Regarding 2-AGE (noladin ether), this compound was previously identified in pig brain (Hanus et al. 2001) and in some rat tissues and brain areas (Fezza et al. 2002) by using mass-spectrometric (MS) methods coupled to chromatographic separations. However, a recent study cast some doubt on the actual existence of 2-AGE in mammalian brain tissue (Oka et al. 2003). At the time of this study it was already known that (1) the only acyl ethers to have been detected in animals before the discovery of 2-AGE were 2-acyl ethers (e.g. alkenyl ethers such as platelet activating factor and plasmalogens) (2) there was no evidence for the existence of any enzyme catalysing the formation... 

Fig. 4. Chemical structures of inhibitors of endocannabinoid biosynthesis or inactivation...

To develop selective and potent inhibitors of endocannabinoid biosynthesis and of 2-AG degradation that can be used in vivo... 

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