Anandamide (an endocannabinoid) and other bioactive long-chain NAEs (N-acylethanolamines) are formed by direct release from N-acyl-PE (N-acyl-phosphatidylethanolamine) by a PLD (phospholipase D). However, the possible presence of a two-step pathway from N-acyl-PE has also been suggested previously, which comprises (1) the hydrolysis of N-acyl-PE to N-acyl-lysoPE by PLA1/PLA2 enzyme(s) and (2) the release of NAEs from N-acyllysoPE by lysoPLD (lysophospholipase D) enzyme(s). In the present study we report for the first time the characterization of enzymes responsible for this pathway. The PLA1/PLA2 activity for N-palmitoyl-PE was found in various rat tissues, with the highest activity in the stomach. This stomach enzyme was identified as group IB sPLA2 (secretory PLA2), and its product was determined as N-acyl-1-acyl-lysoPE. Recombinant group IB, IIA and V of sPLA2s were also active with N-palmitoyl-PE, whereas group X sPLA2 and cytosolic PLA2α were inactive. In addition, we found wide distribution of lysoPLD activity generating N-palmitoylethanolamine from N-palmitoyl-lysoPE in rat tissues, with higher activities in the brain and testis. Based on several lines of enzymological evidence, the lysoPLD enzyme could be distinct from the known N-acyl-PE-hydrolysing PLD. sPLA2-IB dose dependently enhanced the production of N-palmitoylethanolamine from N-palmitoyl-PE in the brain homogenate showing the lysoPLD activity. N-Arachidonoyl-PE and N-arachidonoyl-lysoPE as anandamide precursors were also good substrates of sPLA2-IB and the lysoPLD respectively. These results suggest that the sequential actions of PLA2 and lysoPLD may constitute another biosynthetic pathway for NAEs, including anandamide.
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Research Article|
June 15 2004
Biosynthesis of anandamide and N-palmitoylethanolamine by sequential actions of phospholipase A2 and lysophospholipase D
Yong-Xin SUN;
Yong-Xin SUN
*Department of Biochemistry, Kagawa University School of Medicine, 1750-1 Ikenobe, Miki, Kagawa 761-0793, Japan
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Kazuhito TSUBOI;
Kazuhito TSUBOI
*Department of Biochemistry, Kagawa University School of Medicine, 1750-1 Ikenobe, Miki, Kagawa 761-0793, Japan
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Yasuo OKAMOTO;
Yasuo OKAMOTO
*Department of Biochemistry, Kagawa University School of Medicine, 1750-1 Ikenobe, Miki, Kagawa 761-0793, Japan
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Takeharu TONAI;
Takeharu TONAI
†Department of Orthopedic Surgery and Clinical Research Institute, National Zentsuji Hospital, Zentsuji, Kagawa 765-0001, Japan
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Makoto MURAKAMI;
Makoto MURAKAMI
‡Department of Health Chemistry, School of Pharmaceutical Sciences, Showa University, Shinagawa-ku, Tokyo 142-8555, Japan
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Ichiro KUDO;
Ichiro KUDO
‡Department of Health Chemistry, School of Pharmaceutical Sciences, Showa University, Shinagawa-ku, Tokyo 142-8555, Japan
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Natsuo UEDA
Natsuo UEDA
1
*Department of Biochemistry, Kagawa University School of Medicine, 1750-1 Ikenobe, Miki, Kagawa 761-0793, Japan
1To whom corresponding should be addressed (e-mail [email protected]).
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Publisher: Portland Press Ltd
Received:
January 06 2004
Revision Received:
February 19 2004
Accepted:
March 03 2004
Accepted Manuscript online:
March 03 2004
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London ©2004
2004
Biochem J (2004) 380 (3): 749–756.
Article history
Received:
January 06 2004
Revision Received:
February 19 2004
Accepted:
March 03 2004
Accepted Manuscript online:
March 03 2004
Citation
Yong-Xin SUN, Kazuhito TSUBOI, Yasuo OKAMOTO, Takeharu TONAI, Makoto MURAKAMI, Ichiro KUDO, Natsuo UEDA; Biosynthesis of anandamide and N-palmitoylethanolamine by sequential actions of phospholipase A2 and lysophospholipase D. Biochem J 15 June 2004; 380 (3): 749–756. doi: https://doi.org/10.1042/bj20040031
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