Chapter 1 Enzymatic Formation of Anandamide

doi:10.1016/S0083-6729(09)81001-7

Vitamins & Hormones

Volume 81, 2009, Pages 1-24

https://doi.org/10.1016/S0083-6729(09)81001-7 Get rights and content

Abstract

In animal tissues anandamide and other bioactive N‐acylethanolamines are principally produced from glycerophospholipids through the transacylation–phosphodiesterase pathway consisting of two enzymatic reactions. The first reaction is the generation of N‐acylphosphatidylethanolamine (NAPE) by transferring an acyl group esterified at sn‐1 position of glycerophospholipid to the amino group of phosphatidylethanolamine. This reaction is catalyzed by Ca²⁺‐dependent N‐acyltransferase. The discovery of Ca²⁺‐independent N‐acyltransferase revealed the existence of plural enzymes which are capable of catalyzing this reaction. The second reaction is the release of N‐acylethanolamine from NAPE catalyzed by NAPE‐hydrolyzing phospholipase D (NAPE‐PLD). The enzyme belongs to the metallo‐β‐lactamase family and specifically hydrolyzes NAPEs. Recent studies, including analysis of NAPE‐PLD‐deficient mice, led to the discovery of NAPE‐PLD‐independent pathways for the anandamide biosynthesis.

Section snippets

The Transacylation–Phosphodiesterase Pathway for Anandamide Formation

Ethanolamides of long‐chain fatty acids, referred to as N‐acylethanolamines (NAEs), comprise several bioactive compounds such as N‐arachidonoylethanolamine (anandamide), N‐palmitoylethanolamine, and N‐oleoylethanolamine. Anandamide was most extensively investigated (Di Marzo, 1998, Pacher et al., 2006) since the discovery in 1992 as the first endocannabinoid (endogenous ligand of cannabinoid receptors) (Devane et al., 1992). On the other hand, N‐palmitoylethanolamine and N‐oleoylethanolamine,

Ca‐NAT

NAT was first found in dog heart as an enzyme forming NAPE by PE N‐acylation (Natarajan et al., 1982, Reddy et al., 1983a, Reddy et al., 1983b, Reddy et al., 1984). Furthermore, NAT was isolated from other animal tissues such as dog brain (Natarajan et al., 1983), rat brain (Cadas et al., 1997, Natarajan et al., 1986, Sugiura et al., 1996a), and rat testis (Sugiura et al., 1996b) and crude or partially purified enzymes prepared from these tissues have been used for its characterization.

Earlier

Structure

Although NAPE‐PLD, as an enzyme to release NAEs from NAPEs in animal tissues, has been recognized for more than 20 years (Liu et al., 2002, Natarajan et al., 1984, Petersen et al., 2000, Schmid et al., 1983, Sugiura et al., 1996a, Sugiura et al., 1996b, Ueda et al., 2001a), information on this enzyme has been limited until recently. cDNA cloning of NAPE‐PLD by our group, however, enabled molecular biological approach to this enzyme (Okamoto et al., 2004).

We cloned NAPE‐PLD from human, rat, and

Alternative Pathways Forming NAEs from NAPEs

Apart from the physiological importance of NAPE‐PLD in the formation of bioactive NAEs, recent analysis of NAPE‐PLD^−/− mice revealed presence of other enzyme(s) or pathway(s) responsible for the formation of NAEs from NAPEs (Leung et al., 2006). Previously, Natarajan et al. (1984) discussed possible pathway(s) for the biosynthesis of NAEs and suggested a possibility that O‐acyl chain esterified at sn‐1 or sn‐2 position of NAPE or both acyl chains were first hydrolyzed to generate N‐acyl‐lyso‐PE

Conclusions

cDNA cloning of NAPE‐PLD and subsequent characterization of the recombinant enzyme demonstrated that NAPE‐PLD is a novel enzyme exclusively responsible for the transacylation–phosphodiesterase pathway and enabled molecular biological studies on this pathway for the first time. However, further studies, including analysis of NAPE‐PLD^−/− mice, revealed that the biosynthesis of anandamide and other NAEs is more complex than presumed before. Several enzymes involved in the NAPE‐PLD‐independent

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Chapter 1 Enzymatic Formation of Anandamide

Abstract

Section snippets

The Transacylation–Phosphodiesterase Pathway for Anandamide Formation

Ca‐NAT

Structure

Alternative Pathways Forming NAEs from NAPEs

Conclusions

Neurosci. Lett.

J. Lipid Res.

J. Lipid Mediat. Cell Signal.

Curr. Biol.

Neuroscience

Genomics

FEBS Lett.

Biochim. Biophys. Acta

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

Biochim. Biophys. Acta

Cell

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Biochim. Biophys. Acta

Chem. Phys. Lipids

J. Biol. Chem.

Biochim. Biophys. Acta

Biochim. Biophys. Acta

Arch. Biochem. Biophys.

Biochem. Biophys. Res. Commun.

Chem. Phys. Lipids

Neuropharmacology

Life Sci.

Gene

Biochim. Biophys. Acta

J. Lipid Res.

Comp. Biochem. Physiol. B Biochem. Mol. Biol.

Biochim. Biophys. Acta

Biochim. Biophys. Acta

J. Biol. Chem.

Cell Metab.

Vitam. Horm.

FEBS Lett.

J. Lipid Res.

Biochem. Biophys. Res. Commun.

Biochim. Biophys. Acta

Biochim. Biophys. Acta

Biochim. Biophys. Acta

J. Biol. Chem.

Life Sci.

Chem. Phys. Lipids

Chem. Phys. Lipids

J. Biol. Chem.