Endocannabinoid-related enzymes as drug targets with special reference to N-acylphosphatidylethanolamine-hydrolyzing phospholipase D.
Anandamide (N-arachidonoylethanolamine) is the first discovered endocannabinoid (endogenous ligand of cannabinoid receptors). In animal tissues, anandamide is principally formed together with other bioactive long-chain N-acylethanolamines from membrane glycerophospholipid by two enzyme reactions. The first reaction is the transfer of a fatty acyl chain from the sn-1 position of glycerophospholipid to phosphatidylethanolamine by calcium-dependent N-acyltransferase, resulting in the generation of N-acylphosphatidylethanolamine (NAPE). The second reaction is catalyzed by a phosphodiesterase of the phospholipase D (PLD)-type, which releases N-acylethanolamines from their corresponding NAPEs. The produced N-acylethanolamines are hydrolyzed to fatty acids and ethanolamine by fatty acid amide hydrolase or an amidase acting exclusively at acidic pH. Our recent cDNA cloning of the NAPE-hydrolyzing PLD (NAPE-PLD) from mouse, rat and human revealed that NAPE-PLD is a novel enzyme which has no homology with any known PLD enzymes, but belongs to the zinc metallo-hydrolase family of the beta-lactamase fold. The recombinant enzyme hydrolyzed various NAPEs, including the anandamide precursor N-arachidonoylphosphatidylethanolamine at similar rates, but was inactive with phosphatidylcholine and phosphatidylethanolamine. Considering cannabimimetic activities of anandamide, the enzymes involved in the biosynthesis and degradation of anandamide, including NAPE-PLD, may be promising targets for therapeutic agents.
Department of Biochemistry, Kagawa University School of Medicine, 1750-1 Ikenobe, Miki, Kagawa 761-0793, Japan. nueda@med.kagawa-u.ac.jp
Natsuo
N
Ueda
Yasuo
Y
Okamoto
Kazuhito
K
Tsuboi
D000595:Amino Acid Sequence; D000818:Animals; D063385:Cannabinoid Receptor Modulators / Q000378:metabolism; D002384:Catalysis; D063388:Endocannabinoids; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D008969:Molecular Sequence Data; D015394:Molecular Structure; D010714:Phosphatidylethanolamines / Q000737:chemistry / Q000378:metabolism; D010739:Phospholipase D / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D016415:Sequence Alignment; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D004791:Enzyme Inhibitors; D010714:Phosphatidylethanolamines; D010739:Phospholipase D