Dataset Information

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.

SUBMITTER: Morita J

PROVIDER: S-EPMC4757880 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

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

Morita Junko J Kano Kuniyuki K Kato Kazuki K Takita Hiroyuki H Sakagami Hideki H Yamamoto Yasuo Y Mihara Emiko E Ueda Hirofumi H Sato Takanao T Tokuyama Hidetoshi H Arai Hiroyuki H Asou Hiroaki H Takagi Junichi J Ishitani Ryuichiro R Nishimasu Hiroshi H Nureki Osamu O Aoki Junken J

Scientific reports 20160218

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 olig ...[more]

PMID: 26888014

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Project description:Altered choline phospholipid metabolism is a hallmark of cancer, leading to malignant choline metabolite profiles consisting of low glycerophosphocholine (GPC) and high phosphocholine (PC) in human breast cancers. Glycerophosphocholine phosphodiesterase (GPC-PDE) catalyzes the degradation of GPC to free choline and glycerol-3-phosphate. The gene(s) encoding for the GPC-PDE(s) responsible for GPC degradation in breast cancers have not yet been identified. Here, we demonstrate for the first time that the GPC-PDE encoded by glycerophosphodiester phosphodiesterase domain containing 5 (GDPD5) is associated with breast cancer malignancy. Two human breast cancer cell lines (n = 8 and n = 10) and primary human breast tumor samples (n = 19) were studied with combined MRS and quantitative reverse transcription-polymerase chain reaction to investigate several isoforms of GDPD expression with respect to choline phospholipid metabolite levels. Of the five GDPDs tested, GDPD5 was found to be significantly overexpressed in highly malignant estrogen receptor negative (ER(-)) compared with weakly malignant estrogen receptor positive (ER(+)) human breast cancer cells (p = 0.027) and breast tumors from patients (p = 0.015). GDPD5 showed significantly positive correlations with PC (p < 0.001), total choline (tCho) (p = 0.007) and PC/GPC (p < 0.001) levels in human breast tumors. GDPD5 showed a trend towards a negative correlation with GPC levels (p = 0.130). Human breast cancers with malignant choline metabolite profiles consisting of low GPC and high PC levels highly co-expressed GDPD5, choline kinase alpha (CHKA) and phosphatidylcholine-specific phospholipase D1 (PLD1), whereas cancers containing high GPC and relatively low PC levels displayed low co-expression of GDPD5, CHKA and PLD1. GDPD5, CHKA and PLD1 were significantly overexpressed in highly malignant ER(-) tumors in our patient cohort. Our study identified GDPD5 as a GPC-PDE that probably participates in the regulation of choline phospholipid metabolism in breast cancer, which possibly occurs in cooperation with CHKA and PLD1.

Dataset Information

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

Publications

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

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