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

• Published in: Scientific reports 2016-02, Vol.6 (1), p.20995-20995, Article 20995
• Main Authors: Morita, Junko, Kano, Kuniyuki, Kato, Kazuki, Takita, Hiroyuki, Sakagami, Hideki, Yamamoto, Yasuo, Mihara, Emiko, Ueda, Hirofumi, Sato, Takanao, Tokuyama, Hidetoshi, Arai, Hiroyuki, Asou, Hiroaki, Takagi, Junichi, Ishitani, Ryuichiro, Nishimasu, Hiroshi, Nureki, Osamu, Aoki, Junken
• Format: Article
• Language: English
• Subjects: 101/28; 101/58; 13/109; 13/51; 14/19; 631/45/535; 631/80/304; 82/1; 82/83; Animals; Choline; Crystal structure; Crystallography, X-Ray; Endothelial cells; Endothelial Cells - enzymology; Fatty liver; Fatty Liver - enzymology; Fatty Liver - genetics; Hepatocytes; Humanities and Social Sciences; Lecithin; Liver - enzymology; Metabolism; Mice; Mice, Knockout; multidisciplinary; Oligodendrocytes; Oligodendroglia - enzymology; Organ Specificity; Phosphatidylcholine; Phosphatidylcholines - chemistry; Phosphatidylcholines - genetics; Phosphatidylcholines - metabolism; Phosphocholine; Phosphodiesterase; Phosphoric Diester Hydrolases - chemistry; Phosphoric Diester Hydrolases - metabolism; Science; Science (multidisciplinary); Structure-Activity Relationship; Structure-function relationships; Substrate Specificity
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep20995

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.