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| The structure of ENPP7 protein. The regions with green, red, gray, blue and white colors indicate the amino acids coded by different exons. The five N-glycosylation sites are shown above the bar and two metal binding sits formed by 6 amino acids are shown under the bar. Two hydrophobic domains (from T5 to A22, and P441 to V457) and the predicted catalytic site (T73-H79) are indicated. |
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Description | The wild type ENPP7 contains 458 amino acids, which shares 30-36% identity to other members of the NPP family. The protein has a signal peptide at the N-terminal, which is cleaved in the mature enzyme, and a transmembrane domain at the C-terminal, which anchors the enzyme on the plasma membrane. The rest part of the enzyme is located outside the cells. The enzyme has 5 N-glycosylation sites and glycosylation is important for both transport of the enzyme to the plasma membrane and for enzyme activity. Similar to other NPP members, ENPP7 has two metal binding sites formed by 6 amino acids. These sites are predicted to serve as substrate binding site. |
Expression | The enzyme has so far been found to express in the intestinal mucosal cells of many species and additionally human liver cells. The expression in liver may be restricted to human, because no activity or mRNA of ENPP7 could be found in the bile or liver of many other species. The expression is associated with differentiation of both intestinal and hepatic cells. ENPP7 is developed early in the fetus and high activity has been found in the meconium of human fetus at the age of 23 week gestation. |
Localisation | The enzyme is localized at the apical part but not basolateral part of intestinal epithelial cells. The enzyme can be dissociated from the membrane by bile salt and by pancreatic trypsin and released into the lumen in fully active form. Along the intestinal tract, the activity is low in the duodenum, high in the jejunum, and rapidly decreasing in the distal part of ileum and colon. The enzyme is also found in human bile, which is expressed in the liver and released to the bile. |
Function | ENPP7 is a member of the ecto-nucleotide pyrophosphatase/ phosphodiesterase (NPP) family with specific activity against lipids with positively charged phosphocholine headgroup including sphingomyelin, lysophosphatidylcholine and platelet activating factor (PAF). It hydrolyzes sphingomyelin to generate ceramide, a potent antiproliferative and proapoptotic molecule. It hydrolyzes lysophosphatidylcholine to monoglyceride and therefore competes with lysophospholipase D to reduce the formation of lysophosphatidic acid, a potent factor for inflammation and angiogenesis. It hydrolyses PAF to 1-0-alkyl-2-acetyl-sn-glycerol and inhibits PAF-induced inflammatory responses. ENPP7 has been proposed as a tumor suppressor protein. In addition, ENPP7 may influence cholesterol absorption by hydrolyzing sphingomyelin in the intestinal lumen and on the apical surface of microvilli, as the levels of sphingomyelin in the intestinal tract affect cholesterol absorption. |
Homology | ENPP7 shares 30-35% homology with other members of ENPP family. Regard to ENPP7, human ENPP7 shares 85% identity with rat form (NP_001012484), 82% with the mouse form (NP_001025462.1), and 82% with fowl form (XP 423912.1). The N-glycosylation sites, the amino acids forming the metal coordinate sites and active core are all conserved in the forms mentioned above. |
Purification, characterization, and expression of rat intestinal alkaline sphingomyelinase. |
Cheng Y, Nilsson A, Tömquist E, Duan RD |
Journal of lipid research. 2002 ; 43 (2) : 316-324. |
PMID 11861674 |
|
Psyllium and fat in diets differentially affect the activities and expressions of colonic sphingomyelinases and caspase in mice. |
Cheng Y, Ohlsson L, Duan RD |
The British journal of nutrition. 2004 ; 91 (5) : 715-723. |
PMID 15137923 |
|
Ursodeoxycholic acid increases the activities of alkaline sphingomyelinase and caspase-3 in the rat colon. |
Cheng Y, Tauschel HD, Nilsson A, Duan RD |
Scandinavian journal of gastroenterology. 1999 ; 34 (9) : 915-920. |
PMID 10522612 |
|
Detection of alkaline sphingomyelinase activity in human stool: proposed role as a new diagnostic and prognostic marker of colorectal cancer. |
Di Marzio L, Di Leo A, Cinque B, Fanini D, Agnifili A, Berloco P, Linsalata M, Lorusso D, Barone M, De Simone C, Cifone MG |
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 2005 ; 14 (4) : 856-862. |
PMID 15824156 |
|
Alkaline sphingomyelinase: an old enzyme with novel implications. |
Duan RD |
Biochimica et biophysica acta. 2006 ; 1761 (3) : 281-291. |
PMID 16631405 |
|
Identification of human intestinal alkaline sphingomyelinase as a novel ecto-enzyme related to the nucleotide phosphodiesterase family. |
Duan RD, Bergman T, Xu N, Wu J, Cheng Y, Duan J, Nelander S, Palmberg C, Nilsson A |
The Journal of biological chemistry. 2003 ; 278 (40) : 38528-38536. |
PMID 12885774 |
|
Human meconium contains significant amounts of alkaline sphingomyelinase, neutral ceramidase, and sphingolipid metabolites. |
Duan RD, Cheng Y, Jönsson BA, Ohlsson L, Herbst A, Hellström-Westas L, Nilsson A |
Pediatric research. 2007 ; 61 (1) : 61-66. |
PMID 17211142 |
|
Distribution of alkaline sphingomyelinase activity in human beings and animals. Tissue and species differences. |
Duan RD, Hertervig E, Nyberg L, Hauge T, Sternby B, Lillienau J, Farooqi A, Nilsson A |
Digestive diseases and sciences. 1996 ; 41 (9) : 1801-1806. |
PMID 8794797 |
|
Purification of a newly identified alkaline sphingomyelinase in human bile and effects of bile salts and phosphatidylcholine on enzyme activity. |
Duan RD, Nilsson A |
Hepatology (Baltimore, Md.). 1997 ; 26 (4) : 823-830. |
PMID 9328299 |
|
Alkaline sphingomyelinase activity in rat gastrointestinal tract: distribution and characteristics. |
Duan RD, Nyberg L, Nilsson A |
Biochimica et biophysica acta. 1995 ; 1259 (1) : 49-55. |
PMID 7492615 |
|
Effects of bile diversion in rats on intestinal sphingomyelinases and ceramidase. |
Duan RD, Verkade HJ, Cheng Y, Havinga R, Nilsson A |
Biochimica et biophysica acta. 2007 ; 1771 (2) : 196-201. |
PMID 17204455 |
|
Purified intestinal alkaline sphingomyelinase inhibits proliferation without inducing apoptosis in HT-29 colon carcinoma cells. |
Hertervig E, Nilsson A, Cheng Y, Duan RD |
Journal of cancer research and clinical oncology. 2003 ; 129 (10) : 577-582. |
PMID 12920578 |
|
Development of intestinal alkaline sphingomyelinase in rat fetus and newborn rat. |
Lillienau J, Cheng Y, Nilsson A, Duan RD |
Lipids. 2003 ; 38 (5) : 545-549. |
PMID 12880111 |
|
Ursodeoxycholic acid differentially affects three types of sphingomyelinase in human colon cancer Caco 2 cells. |
Liu F, Cheng Y, Wu J, Tauschel HD, Duan RD |
Cancer letters. 2006 ; 235 (1) : 141-146. |
PMID 16290921 |
|
In vitro effects of fat, FA, and cholesterol on sphingomyelin hydrolysis induced by rat intestinal alkaline sphingomyelinase. |
Liu JJ, Nilsson A, Duan RD |
Lipids. 2002 ; 37 (5) : 469-474. |
PMID 12056588 |
|
The presence of spingomyelin- and ceramide-cleaving enzymes in the small intestinal tract. |
Nilsson A |
Biochimica et biophysica acta. 1969 ; 176 (2) : 339-347. |
PMID 5775951 |
|
Absorption and lipoprotein transport of sphingomyelin. |
Nilsson A, Duan RD |
Journal of lipid research. 2006 ; 47 (1) : 154-171. |
PMID 16251722 |
|
A mutual inhibitory effect on absorption of sphingomyelin and cholesterol. |
Nyberg L, Duan RD, Nilsson A |
The Journal of nutritional biochemistry. 2000 ; 11 (5) : 244-249. |
PMID 10876096 |
|
Chronic colitis is associated with a reduction of mucosal alkaline sphingomyelinase activity. |
Sjöqvist U, Hertervig E, Nilsson A, Duan RD, Ost A, Tribukait B, Löfberg R |
Inflammatory bowel diseases. 2002 ; 8 (4) : 258-263. |
PMID 12131609 |
|
Cloning of alkaline sphingomyelinase from rat intestinal mucosa and adjusting of the hypothetical protein XP_221184 in GenBank. |
Wu J, Cheng Y, Palmberg C, Bergman T, Nilsson A, Duan RD |
Biochimica et biophysica acta. 2005 ; 1687 (1-3) : 94-102. |
PMID 15708357 |
|
Functional studies of human intestinal alkaline sphingomyelinase by deglycosylation and mutagenesis. |
Wu J, Hansen GH, Nilsson A, Duan RD |
The Biochemical journal. 2005 ; 386 (Pt 1) : 153-160. |
PMID 15458386 |
|
Pancreatic trypsin cleaves intestinal alkaline sphingomyelinase from mucosa and enhances the sphingomyelinase activity. |
Wu J, Liu F, Nilsson A, Duan RD |
American journal of physiology. Gastrointestinal and liver physiology. 2004 ; 287 (5) : G967-G973. |
PMID 15205117 |
|
Intestinal alkaline sphingomyelinase hydrolyses and inactivates platelet-activating factor by a phospholipase C activity. |
Wu J, Nilsson A, Jönsson BA, Stenstad H, Agace W, Cheng Y, Duan RD |
The Biochemical journal. 2006 ; 394 (Pt 1) : 299-308. |
PMID 16255717 |
|