Multiple pathways involved in the biosynthesis of anandamide.
Endocannabinoids, including anandamide (arachidonoyl ethanolamide) have been implicated in the regulation of a growing number of physiological and pathological processes. Anandamide can be generated from its membrane phospholipid precursor N-arachidonoyl phosphatidylethanolamine (NAPE) through hydrolysis by a phospholipase D (NAPE-PLD). Recent evidence indicates, however, the existence of two additional, parallel pathways. One involves the sequential deacylation of NAPE by alpha,beta-hydrolase 4 (Abhd4) and the subsequent cleavage of glycerophosphate to yield anandamide, and the other one proceeds through phospholipase C-mediated hydrolysis of NAPE to yield phosphoanandamide, which is then dephosphorylated by phosphatases, including the tyrosine phosphatase PTPN22 and the inositol 5' phosphatase SHIP1. Conversion of synthetic NAPE to AEA by brain homogenates from wild-type and NAPE-PLD(-/-) mice can proceed through both the PLC/phosphatase and Abdh4 pathways, with the former being dominant at shorter (<10 min) and the latter at longer (60 min) incubations. In macrophages, the endotoxin-induced synthesis of anandamide proceeds uniquely through the phospholipase C/phosphatase pathway.
Liu
Jie
J
Laboratory of Physiologic Studies, NIAAA/NIH, 5625 Fishers Lane, MS-9413, Bethesda, MD 20892-9413, USA. jiel@mail.nih.gov
Wang
Lei
L
Harvey-White
Judith
J
Huang
Bill X
BX
Kim
Hee-Yong
HY
Luquet
Serge
S
Palmiter
Richard D
RD
Krystal
Gerald
G
Rai
Ravi
R
Mahadevan
Anu
A
Razdan
Raj K
RK
Kunos
George
G
D000818:Animals; D001095:Arachidonic Acids / Q000096:biosynthesis*; D002461:Cell Line, Transformed; D002851:Chromatography, High Pressure Liquid; D002855:Chromatography, Thin Layer; D004347:Drug Interactions; D063388:Endocannabinoids; D005994:Glycerophosphates / Q000378:metabolism; D006867:Hydrolases / Q000378:metabolism; D006868:Hydrolysis / Q000187:drug effects; D000072181:Inositol Polyphosphate 5-Phosphatases; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D053858:Metabolic Networks and Pathways / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009355:Neomycin / Q000494:pharmacology; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010739:Phospholipase D / Q000172:deficiency; D010744:Phosphoric Monoester Hydrolases / Q000172:deficiency; D053284:Polyunsaturated Alkamides; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22 / Q000172:deficiency; D034741:RNA, Small Interfering / Q000378:metabolism; D014162:Transfection / Q000379:methods; D010738:Type C Phospholipases / Q000378:metabolism
D001095:Arachidonic Acids; D063388:Endocannabinoids; D005994:Glycerophosphates; D006867:Hydrolases; D000072181:Inositol Polyphosphate 5-Phosphatases; D008070:Lipopolysaccharides; D009355:Neomycin; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010739:Phospholipase D; D010744:Phosphoric Monoester Hydrolases; D053284:Polyunsaturated Alkamides; D011500:Protein Synthesis Inhibitors; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22; D034741:RNA, Small Interfering; D010738:Type C Phospholipases; C516766:Ptpn22 protein, mouse; C000606433:Inpp5d protein, mouse; C506062:Napepld protein, mouse; C078814:anandamide