Structure and biological function of ENPP6, a choline-specific glycerophosphodiester-phosphodiesterase

Junko Morita; Kuniyuki Kano; Kazuki Kato; Hiroyuki Takita; Hideki Sakagami; Yasuo Yamamoto; Emiko Mihara; Hirofumi Ueda; Takanao Sato; Hidetoshi Tokuyama; Hiroyuki Arai; Hiroaki Asou; Junichi Takagi; Ryuichiro Ishitani; Hiroshi Nishimasu; Osamu Nureki; Junken Aoki

doi:10.1038/srep20995

Structure and biological function of ENPP6, a choline-specific glycerophosphodiester-phosphodiesterase

Junko Morita, Kuniyuki Kano, Kazuki Kato, Hiroyuki Takita, Hideki Sakagami, Yasuo Yamamoto, Emiko Mihara, Hirofumi Ueda, Takanao Sato, Hidetoshi Tokuyama, Hiroyuki Arai, Hiroaki Asou, Junichi Takagi, Ryuichiro Ishitani, Hiroshi Nishimasu, Osamu Nureki, Junken Aoki

Research output: Contribution to journal › Article › peer-review

39 Citations (Scopus)

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.

Original language	English
Article number	20995
Journal	Scientific reports
Volume	6
DOIs	https://doi.org/10.1038/srep20995
Publication status	Published - 2016 Feb 18

ASJC Scopus subject areas

General

Access to Document

10.1038/srep20995

Cite this

Morita, J., Kano, K., Kato, K., Takita, H., Sakagami, H., Yamamoto, Y., Mihara, E., Ueda, H., Sato, T., Tokuyama, H., Arai, H., Asou, H., Takagi, J., Ishitani, R., Nishimasu, H., Nureki, O., & Aoki, J. (2016). Structure and biological function of ENPP6, a choline-specific glycerophosphodiester-phosphodiesterase. Scientific reports, 6, [20995]. https://doi.org/10.1038/srep20995

@article{186b0ec77d6042a9b3eb67803b2a2e90,

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.",

author = "Junko Morita and Kuniyuki Kano and Kazuki Kato and Hiroyuki Takita and Hideki Sakagami and Yasuo Yamamoto and Emiko Mihara and Hirofumi Ueda and Takanao Sato and Hidetoshi Tokuyama and Hiroyuki Arai and Hiroaki Asou and Junichi Takagi and Ryuichiro Ishitani and Hiroshi Nishimasu and Osamu Nureki and Junken Aoki",

note = "Funding Information: This work was supported in part by Grants-in-Aid for Scientific Research from the Ministry of Education, Science, Culture, Sports, and Technology (MEXT) of Japan, the Targeted Proteins Research Program from the MEXT, Japan Agency for Medical Research and Development–Core Research for Evolutional Science and Technology (AMED–CREST), Precursory Research for Embryonic Science and Technology (PRESTO) and the Platform Project for Supporting in Drug Discovery and Life Science Research (Platform for Drug Discovery, Informatics, and Structural Life Science) from the MEXT and AMED.",

year = "2016",

month = feb,

day = "18",

doi = "10.1038/srep20995",

language = "English",

volume = "6",

journal = "Scientific Reports",

issn = "2045-2322",

publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - Structure and biological function of ENPP6, a choline-specific glycerophosphodiester-phosphodiesterase

AU - Morita, Junko

AU - Kano, Kuniyuki

AU - Kato, Kazuki

AU - Takita, Hiroyuki

AU - Sakagami, Hideki

AU - Yamamoto, Yasuo

AU - Mihara, Emiko

AU - Ueda, Hirofumi

AU - Sato, Takanao

AU - Tokuyama, Hidetoshi

AU - Arai, Hiroyuki

AU - Asou, Hiroaki

AU - Takagi, Junichi

AU - Ishitani, Ryuichiro

AU - Nishimasu, Hiroshi

AU - Nureki, Osamu

AU - Aoki, Junken

N1 - Funding Information: This work was supported in part by Grants-in-Aid for Scientific Research from the Ministry of Education, Science, Culture, Sports, and Technology (MEXT) of Japan, the Targeted Proteins Research Program from the MEXT, Japan Agency for Medical Research and Development–Core Research for Evolutional Science and Technology (AMED–CREST), Precursory Research for Embryonic Science and Technology (PRESTO) and the Platform Project for Supporting in Drug Discovery and Life Science Research (Platform for Drug Discovery, Informatics, and Structural Life Science) from the MEXT and AMED.

PY - 2016/2/18

Y1 - 2016/2/18

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84959010450&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84959010450&partnerID=8YFLogxK

U2 - 10.1038/srep20995

DO - 10.1038/srep20995

M3 - Article

C2 - 26888014

AN - SCOPUS:84959010450

SN - 2045-2322

VL - 6

JO - Scientific Reports

JF - Scientific Reports

M1 - 20995

ER -

Structure and biological function of ENPP6, a choline-specific glycerophosphodiester-phosphodiesterase

Abstract

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this