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J. Biol. Chem., Vol. 283, Issue 14, 9341-9349, April 4, 2008

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Anandamide Biosynthesis Catalyzed by the Phosphodiesterase GDE1 and Detection of Glycerophospho-N-acyl Ethanolamine Precursors in Mouse Brain^*

From the Skaggs Institute for Chemical Biology and the Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California 92037

Anandamide (AEA) is an endogenous ligand of cannabinoid receptors and a well characterized mediator of many physiological processes including inflammation, pain, and appetite. The biosynthetic pathway(s) for anandamide and its N-acyl ethanolamine (NAE) congeners remain enigmatic. Previously, we proposed an enzymatic route for producing NAEs that involves the double-O-deacylation of N-acyl phosphatidylethanolamines (NAPEs) by /β-hydrolase 4 (ABDH4 or Abh4) to form glycerophospho (GP)-NAEs, followed by conversion of these intermediates to NAEs by an unidentified phosphodiesterase. Here, we report the detection and measurement of GP-NAEs, including the anandamide precursor glycerophospho-N-arachidonoylethanolamine (GP-NArE), as endogenous constituents of mouse brain tissue. Inhibition of the phosphodiesterase-mediated degradation of GP-NAEs ex vivo resulted in a striking accumulation of these lipids in brain extracts, suggesting a rapid endogenous flux through this pathway. Furthermore, we identify the glycerophosphodiesterase GDE1, also known as MIR16, as a broadly expressed membrane enzyme with robust GP-NAE phosphodiesterase activity. Together, these data provide evidence for a multistep pathway for the production of anandamide in the nervous system by the sequential actions of Abh4 and GDE1.

Received for publication, September 18, 2007 , and in revised form, January 15, 2008.

^* This work was supported by National Institutes of Health Grants DA015197 and DA017259 and the ARCS Foundation and a Koshland Graduate Fellowship in Enzyme Biochemistry (to G. M. S.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. S1 and Table S1.

¹ To whom correspondence should be addressed: 10550 N. Torrey Pines Rd., La Jolla, CA 92037. Tel.: 858-784-8633; Fax: 858-784-8023; E-mail: cravatt{at}scripps.edu.

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