Inactivation of N-Acyl Phosphatidylethanolamine Phospholipase D Reveals Multiple Mechanisms for the Biosynthesis of Endocannabinoids

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• 作者：Donmienne Leung ; Alan Saghatelian ; Gabriel M. Simon ; and Benjamin F. Cravatt
• 刊名：Biochemistry
• 出版年：2006
• 出版时间：April 18, 2006
• 年：2006
• 卷：45
• 期：15
• 页码：4720 - 4726
• 全文大小：389K
• 年卷期：v.45,no.15(April 18, 2006)
• ISSN：1520-4995

文摘

N-Acyl ethanolamines (NAEs) constitute a large and diverse class of signaling lipids thatincludes the endogenous cannabinoid anandamide. Like other lipid transmitters, NAEs are thought to bebiosynthesized and degraded on-demand rather than being stored in vesicles prior to signaling. Theidentification of enzymes involved in NAE metabolism is therefore imperative to achieve a completeunderstanding of this lipid signaling system and control it for potential therapeutic gain. Recently, anN-acyl phosphatidylethanolamine phospholipase D (NAPE-PLD) was identified as a candidate enzymeinvolved in the biosynthesis of NAEs. Here, we describe the generation and characterization of mice witha targeted disruption in the NAPE-PLD gene [NAPE-PLD(-/-) mice]. Brain tissue from NAPE-PLD(-/-) mice showed more than a 5-fold reduction in the calcium-dependent conversion of NAPEs toNAEs bearing both saturated and polyunsaturated N-acyl chains. However, only the former group ofNAEs was decreased in level in NAPE-PLD(-/-) brains, and these reductions were most dramatic forNAEs bearing very long acyl chains (C20). Further studies identified a calcium-independent PLD activityin brains from NAPE-PLD(-/-) mice that accepted multiple NAPEs as substrates, including theanandamide precursor C20:4 NAPE. The illumination of distinct enzymatic pathways for the biosynthesisof long chain saturated and polyunsaturated NAEs suggests a strategy to control the activity of specificsubsets of these lipids without globally affecting the function of the NAE family as a whole.