Pathway Map Details

Anandamide biosynthesis and metabolism

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3.1.4.39 , PLA2(hGIIA), 3.1.1.4, PLA2G1B, N,1-diarachidonoyl-2-stearoyl-sn-glycerol 3-phosphoethanolamine (NAPE), 2.3.1.- , PA24A, Phosphoanandamide, PLA2G5, 3.1.4.39/3.1.-.-, N-arachidonoyl-2-stearoyl-sn-glycerol 3-phosphoethanolamine (LysoNAPE), 1-arachidonoyl-sn-glycero-3-phosphocholine (LysoPC), PLC-gamma, 2-stearoyl-sn-glycerol 3-phosphate (LysoPA), 3.1.4.4 , NAPE PLD, 3.1.1.4, PLC-delta, FAAH, PLC-beta, 3.1.4.-, 2.3.1.- , 3.1.-.-, Arachidonic acid, 3.1.4.39, PLC-zeta, 1-arachidonoyl-2-stearoyl-sn-glycerol (DAG), stearic acid, 2-arachidonoyl-sn-glycero-3-phosphocholine (LysoPC), Anandamide, 3.1.3.48, 1-arachidonoyl-2-stearoyl-sn-glycerol 3-phosphate (PA), 1-arachidonoyl-2-stearoyl-sn-glycerol 3-phospho ethanolamine (PE), 2.3.-.-, 1-arachidonoyl-glycerol 3-phosphate (LysoPA), 2-arachidonoyl-glycerol 3-phosphate (LysoPA), HRSL5, 70Z-PEP, PLC-epsilon, Ethanolamine, choline extracellular region, N,1-diarachidonoyl-sn-glycerol 3-phosphoethanolamine (LysoNAPE), 3.1.4.39, PLA2G10, ENPP2, 1,2-diarachidonoyl-sn-glycero-3-phosphocholine (PC)

Description:

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:

1. Jin XH, Okamoto Y, Morishita J, Tsuboi K, Tonai T, Ueda N
   Discovery and characterization of a Ca2+-independent phosphatidylethanolamine N-acyltransferase generating the anandamide precursor and its congeners. The Journal of biological chemistry 2007 Feb 9;282(6):3614-23
2. Okamoto Y, Morishita J, Tsuboi K, Tonai T, Ueda N
   Molecular characterization of a phospholipase D generating anandamide and its congeners. The Journal of biological chemistry 2004 Feb 13;279(7):5298-305
3. Ueda N, Okamoto Y, Morishita J
   N-acylphosphatidylethanolamine-hydrolyzing phospholipase D: a novel enzyme of the beta-lactamase fold family releasing anandamide and other N-acylethanolamines. Life sciences 2005 Aug 19;77(14):1750-8
4. Wang J, Okamoto Y, Morishita J, Tsuboi K, Miyatake A, Ueda N
   Functional analysis of the purified anandamide-generating phospholipase D as a member of the metallo-beta-lactamase family. The Journal of biological chemistry 2006 May 5;281(18):12325-35
5. Sun YX, Tsuboi K, Okamoto Y, Tonai T, Murakami M, Kudo I, Ueda N
   Biosynthesis of anandamide and N-palmitoylethanolamine by sequential actions of phospholipase A2 and lysophospholipase D. The Biochemical journal 2004 Jun 15;380(Pt 3):749-56
6. Pruzanski W, Lambeau L, Lazdunsky M, Cho W, Kopilov J, Kuksis A
   Differential hydrolysis of molecular species of lipoprotein phosphatidylcholine by groups IIA, V and X secretory phospholipases A2. Biochimica et biophysica acta 2005 Sep 5;1736(1):38-50
7. Pruzanski W, Lambeau G, Lazdunski M, Cho W, Kopilov J, Kuksis A
   Hydrolysis of minor glycerophospholipids of plasma lipoproteins by human group IIA, V and X secretory phospholipases A2. Biochimica et biophysica acta 2007 Jan;1771(1):5-19
8. Tokumura A, Nishioka Y, Yoshimoto O, Shinomiya J, Fukuzawa K
   Substrate specificity of lysophospholipase D which produces bioactive lysophosphatidic acids in rat plasma. Biochimica et biophysica acta 1999 Feb 25;1437(2):235-45
9. Tokumura A
   Physiological and pathophysiological roles of lysophosphatidic acids produced by secretory lysophospholipase D in body fluids. Biochimica et biophysica acta 2002 May 23;1582(1-3):18-25
10. Tokumura A, Majima E, Kariya Y, Tominaga K, Kogure K, Yasuda K, Fukuzawa K
    Identification of human plasma lysophospholipase D, a lysophosphatidic acid-producing enzyme, as autotaxin, a multifunctional phosphodiesterase. The Journal of biological chemistry 2002 Oct 18;277(42):39436-42
11. Ferry G, Tellier E, Try A, Gres S, Naime I, Simon MF, Rodriguez M, Boucher J, Tack I, Gesta S, Chomarat P, Dieu M, Raes M, Galizzi JP, Valet P, Boutin JA, Saulnier-Blache JS
    Autotaxin is released from adipocytes, catalyzes lysophosphatidic acid synthesis, and activates preadipocyte proliferation. Up-regulated expression with adipocyte differentiation and obesity. The Journal of biological chemistry 2003 May 16;278(20):18162-9
12. Tokumura A, Kume T, Fukuzawa K, Tahara M, Tasaka K, Aoki J, Arai H, Yasuda K, Kanzaki H
    Peritoneal fluids from patients with certain gynecologic tumor contain elevated levels of bioactive lysophospholipase D activity. Life sciences 2007 Apr 10;80(18):1641-9
13. Liu J, Wang L, Harvey-White J, Osei-Hyiaman D, Razdan R, Gong Q, Chan AC, Zhou Z, Huang BX, Kim HY, Kunos G
    A biosynthetic pathway for anandamide. Proceedings of the National Academy of Sciences of the United States of America 2006 Sep 5;103(36):13345-50
14. Cravatt BF, Giang DK, Mayfield SP, Boger DL, Lerner RA, Gilula NB
    Molecular characterization of an enzyme that degrades neuromodulatory fatty-acid amides. Nature 1996 Nov 7;384(6604):83-7
15. Giang DK, Cravatt BF
    Molecular characterization of human and mouse fatty acid amide hydrolases. Proceedings of the National Academy of Sciences of the United States of America 1997 Mar 18;94(6):2238-42
16. Cravatt BF, Demarest K, Patricelli MP, Bracey MH, Giang DK, Martin BR, Lichtman AH
    Supersensitivity to anandamide and enhanced endogenous cannabinoid signaling in mice lacking fatty acid amide hydrolase. Proceedings of the National Academy of Sciences of the United States of America 2001 Jul 31;98(16):9371-6