title: Structure and biological function of ENPP6, a choline-specific glycerophosphodiester-phosphodiesterase.
abstract: Choline is an essential nutrient for all living cells and is produced extracellularly by sequential degradation of phosphatidylcholine (PC). However, little is known about how choline is produced extracellularly. Here, we report that ENPP6, a choline-specific phosphodiesterase, hydrolyzes glycerophosphocholine (GPC), a degradation product of PC, as a physiological substrate and participates in choline metabolism. ENPP6 is highly expressed in liver sinusoidal endothelial cells and developing oligodendrocytes, which actively incorporate choline and synthesize PC. ENPP6-deficient mice exhibited fatty liver and hypomyelination, well known choline-deficient phenotypes. The choline moiety of GPC was incorporated into PC in an ENPP6-dependent manner both in vivo and in vitro. The crystal structure of ENPP6 in complex with phosphocholine revealed that the choline moiety of the phosphocholine is recognized by a choline-binding pocket formed by conserved aromatic and acidic residues. The present study provides the molecular basis for ENPP6-mediated choline metabolism at atomic, cellular and tissue levels.
authors.affiliation: Department of Biological Sciences, Graduate School of Sciences, The University of Tokyo, 2-11-16, Yayoi, Bunkyo-ku, Tokyo, 113-0032, Japan.
authors.forename: Junko
authors.initials: J
authors.lastname: Morita
authors.affiliation: Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3, Aoba, Aramaki, Aoba-ku, Sendai, Miyagi, 980-8578, Japan.
authors.forename: Kuniyuki
authors.initials: K
authors.lastname: Kano
authors.affiliation: Department of Biological Sciences, Graduate School of Sciences, The University of Tokyo, 2-11-16, Yayoi, Bunkyo-ku, Tokyo, 113-0032, Japan.
authors.forename: Kazuki
authors.initials: K
authors.lastname: Kato
authors.affiliation: Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3, Aoba, Aramaki, Aoba-ku, Sendai, Miyagi, 980-8578, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Takita
authors.affiliation: Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1, Hongo, Bumkyo-ku, Tokyo, 113-0033, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Sakagami
authors.affiliation: Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3, Aoba, Aramaki, Aoba-ku, Sendai, Miyagi, 980-8578, Japan.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Yamamoto
authors.affiliation: Institute for Protein Research, Osaka University, 3-2, Yamadaoka, Suita-shi, Osaka, 565-0871, Japan.
authors.forename: Emiko
authors.initials: E
authors.lastname: Mihara
authors.affiliation: Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3, Aoba, Aramaki, Aoba-ku, Sendai, Miyagi, 980-8578, Japan.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Ueda
authors.affiliation: Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3, Aoba, Aramaki, Aoba-ku, Sendai, Miyagi, 980-8578, Japan.
authors.forename: Takanao
authors.initials: T
authors.lastname: Sato
authors.affiliation: Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3, Aoba, Aramaki, Aoba-ku, Sendai, Miyagi, 980-8578, Japan.
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Tokuyama
authors.affiliation: Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1, Hongo, Bumkyo-ku, Tokyo, 113-0033, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Arai
authors.affiliation: Center for Kampo Medicine, Keio University School of Medicine, 35, Shinanomachi, Shinjuku-ku, Tokyo, 160-0016, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Asou
authors.affiliation: Institute for Protein Research, Osaka University, 3-2, Yamadaoka, Suita-shi, Osaka, 565-0871, Japan.
authors.forename: Junichi
authors.initials: J
authors.lastname: Takagi
authors.affiliation: Department of Biological Sciences, Graduate School of Sciences, The University of Tokyo, 2-11-16, Yayoi, Bunkyo-ku, Tokyo, 113-0032, Japan.
authors.forename: Ryuichiro
authors.initials: R
authors.lastname: Ishitani
authors.affiliation: Department of Biological Sciences, Graduate School of Sciences, The University of Tokyo, 2-11-16, Yayoi, Bunkyo-ku, Tokyo, 113-0032, Japan.|PRESTO (Precursory Research for Embryonic Science and Technology), JST (Japan Science and Technology Agency), 4-1-8, Honcho, Kawaguchi, Saitama, 332-0012, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nishimasu
authors.affiliation: Department of Biological Sciences, Graduate School of Sciences, The University of Tokyo, 2-11-16, Yayoi, Bunkyo-ku, Tokyo, 113-0032, Japan.|AMED (Japan Agency for Medical Research and Development)-CREST (Core Research for Evolutional Science and Technology), 1-7-1, Otemachi, Chiyoda-ku, Tokyo, 100-0004, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Nureki
authors.affiliation: Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3, Aoba, Aramaki, Aoba-ku, Sendai, Miyagi, 980-8578, Japan.|AMED (Japan Agency for Medical Research and Development)-CREST (Core Research for Evolutional Science and Technology), 1-7-1, Otemachi, Chiyoda-ku, Tokyo, 100-0004, Japan.
authors.forename: Junken
authors.initials: J
authors.lastname: Aoki
mesh_terms: D000818:Animals; D018360:Crystallography, X-Ray; D042783:Endothelial Cells / Q000201:enzymology; D005234:Fatty Liver / Q000201:enzymology / Q000235:genetics; D008099:Liver / Q000201:enzymology; D051379:Mice; D018345:Mice, Knockout; D009836:Oligodendroglia / Q000201:enzymology; D009928:Organ Specificity; D010713:Phosphatidylcholines / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D010727:Phosphoric Diester Hydrolases / Q000737:chemistry* / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D010713:Phosphatidylcholines; D010727:Phosphoric Diester Hydrolases