title: Calcium-dependent generation of N-acylethanolamines and lysophosphatidic acids by glycerophosphodiesterase GDE7.
abstract: N-Acylethanolamines form a class of lipid mediators and include an endocannabinoid arachidonoylethanolamide (anandamide), analgesic and anti-inflammatory palmitoylethanolamide, and appetite-suppressing oleoylethanolamide. In animal tissues, N-acylethanolamines are synthesized from N-acylated ethanolamine phospholipids directly by N-acylphosphatidylethanolamine-hydrolyzing phospholipase D or through multi-step pathways via N-acylethanolamine lysophospholipids. We previously reported that glycerophosphodiesterase (GDE) 4, a member of the GDE family, has lysophospholipase D (lysoPLD) activity hydrolyzing N-acylethanolamine lysophospholipids to N-acylethanolamines. Recently, GDE7 was shown to have lysoPLD activity toward lysophosphatidylcholine to produce lysophosphatidic acid (LPA). Here, we examined the reactivity of GDE7 with N-acylethanolamine lysophospholipids as well as the requirement of divalent cations for its catalytic activity. When overexpressed in HEK293 cells, recombinant GDE7 proteins of human and mouse showed lysoPLD activity toward N-palmitoyl, N-oleoyl, and N-arachidonoyl-lysophosphatidylethanolamines and N-palmitoyl-lysoplasmenylethanolamine to generate their corresponding N-acylethanolamines and LPAs. However, GDE7 hardly hydrolyzed glycerophospho-N-palmitoylethanolamine. Overexpression of GDE7 in HEK293 cells increased endogenous levels of N-acylethanolamines and LPAs. Interestingly, GDE7 was stimulated by micromolar concentrations of Ca2+but not by millimolar concentrations of Mg2+, while GDE4 was stimulated by Mg2+but was insensitive to Ca2+. GDE7 was widely distributed in various tissues of humans and mice with the highest levels in their kidney tissues. These results suggested that GDE7 is a novel Ca2+-dependent lysoPLD, which is involved in the generation of both N-acylethanolamines and LPAs.
authors.affiliation: Department of Biochemistry, Kagawa University School of Medicine, 1750-1 Ikenobe, Miki, Kagawa 761-0793, Japan.
authors.forename: Iffat Ara Sonia
authors.initials: IA
authors.lastname: Rahman
authors.affiliation: Department of Biochemistry, Kagawa University School of Medicine, 1750-1 Ikenobe, Miki, Kagawa 761-0793, Japan.
authors.forename: Kazuhito
authors.initials: K
authors.lastname: Tsuboi
authors.affiliation: Department of Biochemistry, Kagawa University School of Medicine, 1750-1 Ikenobe, Miki, Kagawa 761-0793, Japan.
authors.forename: Zahir
authors.initials: Z
authors.lastname: Hussain
authors.affiliation: Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima 770-8505, Japan.
authors.forename: Ryouhei
authors.initials: R
authors.lastname: Yamashita
authors.affiliation: Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima 770-8505, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Okamoto
authors.affiliation: Department of Biochemistry, Kagawa University School of Medicine, 1750-1 Ikenobe, Miki, Kagawa 761-0793, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Uyama
authors.affiliation: Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima 770-8505, Japan.
authors.forename: Naoshi
authors.initials: N
authors.lastname: Yamazaki
authors.affiliation: Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima 770-8505, Japan.
authors.forename: Tamotsu
authors.initials: T
authors.lastname: Tanaka
authors.affiliation: Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima 770-8505, Japan; Department of Life Sciences, Faculty of Pharmacy, Yasuda Women's University, Hiroshima 731-0153, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Tokumura
authors.affiliation: Department of Biochemistry, Kagawa University School of Medicine, 1750-1 Ikenobe, Miki, Kagawa 761-0793, Japan. Electronic address: nueda@med.kagawa-u.ac.jp.
authors.forename: Natsuo
authors.initials: N
authors.lastname: Ueda
mesh_terms: D000577:Amides; D000595:Amino Acid Sequence; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002384:Catalysis; D002460:Cell Line; D004983:Ethanolamines / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D008246:Lysophospholipids / Q000378:metabolism*; D008274:Magnesium / Q000378:metabolism; D051379:Mice; D010169:Palmitic Acids / Q000378:metabolism; D010714:Phosphatidylethanolamines / Q000378:metabolism; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D016415:Sequence Alignment
chemical_list: D000577:Amides; D004983:Ethanolamines; D008246:Lysophospholipids; C022203:N-acylethanolamines; C000609813:N-acylphosphatidylethanolamine; D010169:Palmitic Acids; D010714:Phosphatidylethanolamines; C008301:lysophosphatidylethanolamine; C021215:lysoplasmalogens; C005958:palmidrol; D010727:Phosphoric Diester Hydrolases; C038133:glycerophosphodiester phosphodiesterase; D008274:Magnesium; D002118:Calcium
keywords: Glycerophosphodiesterase; Lysophosphatidic acid; Lysophospholipase D; N-acylethanolamine; Phospholipid