Anandamide biosynthesis and metabolism

Anandamide biosynthesis and metabolism

During anandamide biosynthesys 1-arachidonoyl-2-stearoyl-sn-glycerol 3-phospho ethanolamine and 1,2-diarachidonoylphosphatidylcholine pass to a transacylation reaction catalyzed by HRAS-like suppressor 5 (HRSL5) [1] and also by Arylamine N-acetyltransferase (NAT) that gives N,1-diarachidonoyl-2-stearoyl-sn-glycerol 3-phosphoethanolamine and either 2-arachidonoyl-glycerol 3-phosphocholine or 1-arachidonoyl-sn-glycero-3-phosphocholine as products.

N,1-Diarachidonoyl-2-stearoyl-sn-glycerol 3-phosphoethanolamine undergoes multiple transformations. It can either be hydrolyzed by N-acyl-phosphatidylethanolamine-hydrolyzing phospholipase D (NAPE PLD) to form directly Anandamide and also 1-arachidonoyl-2-stearoyl-glycerol 3-phosphate as a byproduct [2], [3], [4]; either can be hydrolyzed by the action of various phospholipases (Phospholipase A2 (PLA2(hGIIA)), Cytosolic phospholipase A2 (PA24A), Group 10 secretory phospholipase A2 precursor (PLA2G10), Calcium-dependent phospholipase A2 precursor (PLA2G5)) to form Arachidonic acid and N-arachidonoyl-2-stearoyl-sn-glycerol 3-phosphoethanolamine [5], [6], [7]. The same metabolite is formed in when HRSL5 catalyses the intramolecular transacylation of 1-arachidonoyl-2-stearoyl-sn-glycerol 3-phospho ethanolamine [1].

Another way is degradation under the action of Phospholipase A2 precursor (PLA2G1B) with N,1-diarachidonoyl-sn-glycerol 3-phosphoethanolamine metabolite and Stearic acid as a byproduct [5]. Ectonucleotide pyrophosphatase/phosphodiesterase family member 2 precursor (ENPP2) acts on N,1-diarachidonoyl-sn-glycerol 3-phosphoethanolamine causing its hydrolysis what leads to the production of Anandamide and 1-arachidonoyl-glycerol 3-phosphate [5]. 1-arachidonoyl-glycerol 3-phosphate can also be formed during ENPP2 catalyzed 1-arachidonoyl-glycerol 3-phosphate hydrolysis and 2-arachidonoyl-glycerol 3-phosphate is formed during an analogous process with 2-arachidonoyl-glycerol 3-phosphocholine as a substrate. Both processes give Choline as a byproduct [8], [9], [10], [11], [12].

Finally, N,1-diarachidonoyl-2-stearoyl-sn-glycerol 3-phosphoethanolamine can be hydrolyzed by a set of phospholipases (PLC-delta, PLC-gamma, phospholipase C, zeta 1 (PLC-zeta), PLC-beta, 1-phosphatidylinositol-4,5-bisphosphate phosphodiesterase epsilon-1 (PLC-epsilon)) to form 1-arachidonoyl-2-stearoyl-sn-glycerol and phosphoanandamide [13]. Phosphoanandamide is subjected to phosphatase activity of Tyrosine-protein phosphatase non-receptor type 22 (70Z-PEP) and Anandamide together with a phosphate unit are formed [13].

ENPP2 catalyzes the subsequent hydrolysis of N-arachidonoyl-2-stearoyl-sn-glycerol 3-phosphoethanolamine producing Anandamide and 2-stearoyl-sn-glycerol 3-phosphate as a byproduct [5].

Anandamide is metabolized by Fatty-acid amide hydrolase 1 (FAAH) and the products are Arachidonic acid and Ethanolamine [14], [15], [16].

References:

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