ENPP7 (ectonucleotide pyrophosphatase/phosphodiesterase 7)

Identity

Other names	ALK-SMase (Alkaline sphingomyelinase)
	E-NPP7
	MGC50179
	NPP-7
Hugo	ENPP7
Location	17q25.3
Local_order	Upstream to a hypothetical protein LOC146743 and downstream to CBX2.

DNA/RNA

	Structure of ENPP7 gene: intron-exon organization.
Description	The ENPP7 gene is 11.139 bp in length and is composed of 6 exons in the size of 1841 bp. The first 20 bp in exon 1, the last 17 bp in exon 5 and the exon 6 are not translated.
Transcription	Besides the wild type transcript shown above, different transcripts have been identified. The first is the one with exon 4 deletion, which has been found in HepG2 liver cancer cells and some human colon and liver cancer tissues. The second one also deletes exon 4 but inserts 7 foreign amino acids due to the shift of the splice site. This transcript was identified in human HT29 colon cancer cells. The third one has a larger exon 1 than the wild type, which includes upstream another starting codon (219 bp upstream), and was identified in one liver tumor. Some factors such as ursodeoxycholic acid and psyllium have been found to stimulate the expression of ENPP7 whereas high fat diet decreases ENPP7 expression.
Pseudogene	LOC401847

Protein

	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.

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.

Mutations

	The figure shows the aberrant transcript forms of ENPP7 identified in colon and liver cancers. The first is the one with deleted exon 4, which was found in HepG2 liver cancer cells and human liver cancer and colon cancer tissues. The second is similar as the first one but with an insertion of 7 foreign amino acids due to the shift of the splice site. The third one has a larger exon 1 than the wild type, which includes another starting codon, and was identified in one liver tumor (not shown in the figure). Formation of these aberrant forms are not caused by genomic mutation, but alternative splicing.

Implicated in

Entity	Colon cancer, inflammatory bowel diseases, and liver cancer
Disease	ENPP7 may have implications in colon cancer, inflammatory bowel diseases such as ulcerative colitis, necrotizing enterocolitis, and liver cancer. Significant reduction of ENPP7 activity has been found in human longstanding ulcerative colitis, sporadic colon cancer and familial adenomatous polyposis The reduction may be caused by formation of the aberrant transcripts, which cause the inactivation of ENPP7, and have been found in human HT29 colon cancer cells, HepG2 liver cancer cells and also in human colon and liver cancer tissues. The frequency of such mutations is unknown. ENPP7 may also affect the pathogenesis of atherosclerosis as it influences the sphingomyelin levels in the gut and thus affect cholesterol absorption.
Prognosis	The enzyme activity is easy to be determined in the feces. Fecal activity reflects the total enzyme levels in the intestinal tract and has been shown to be decreased in colonic inflammation and cancer.

External links

	Nomenclature
Hugo	ENPP7
GDB	ENPP7
Entrez_Gene	ENPP7  339221  ectonucleotide pyrophosphatase/phosphodiesterase 7
	Cards
Atlas	ENPP7ID44055ch17q25
GeneCards	ENPP7
Ensembl	ENPP7 [Search_View]   ENSG00000182156 [Gene_View]
Genatlas	ENPP7
GeneLynx	ENPP7
eGenome	ENPP7
euGene	339221
	Genomic and cartography
GoldenPath	ENPP7  -  17q25.3   chr17:75319477-75330615 +  17q25.3   [Description]    (hg18-Mar_2006)
Ensembl	ENPP7 - 17q25.3 [CytoView]
NCBI	Mapview
HomoloGene	ENPP7
	Gene and transcription
Genbank	AK126250 [ ENTREZ ]
Genbank	AK128662 [ ENTREZ ]
Genbank	AY230663 [ ENTREZ ]
Genbank	AY358622 [ ENTREZ ]
Genbank	BC041453 [ ENTREZ ]
RefSeq	NM_178543 [ SRS ]    NM_178543 [ ENTREZ ]
RefSeq	AC_000060 [ SRS ]    AC_000060 [ ENTREZ ]
RefSeq	NC_000017 [ SRS ]    NC_000017 [ ENTREZ ]
RefSeq	NT_024871 [ SRS ]    NT_024871 [ ENTREZ ]
RefSeq	NW_926918 [ SRS ]    NW_926918 [ ENTREZ ]
AceView	ENPP7 AceView - NCBI
Unigene	Hs.114084 [ SRS ]    Hs.114084 [ NCBI ]     HS114084 [ spliceNest ]
Fast-db	15385 (alternative variants)
	Protein : pattern, domain, 3D structure
SwissProt	Q6UWV6 [ SRS]    Q6UWV6 [ EXPASY ]     Q6UWV6 [ INTERPRO ]
Interpro	IPR001952 Alk_phosphtse [ SRS ]    IPR001952 Alk_phosphtse [ EBI ]
Interpro	IPR002591 Phosphodiest/P_Trfase [ SRS ]    IPR002591 Phosphodiest/P_Trfase [ EBI ]
CluSTr	Q6UWV6
Pfam	PF01663 Phosphodiest [ SRS ]    PF01663 Phosphodiest [ Sanger ]    pfam01663 [ NCBI-CDD ]
Blocks	Q6UWV6
	Protein Interaction databases
DIP	Q6UWV6
IntAct	Q6UWV6
	Polymorphism : SNP, mutations, diseases
SNP	ENPP7 [dbSNP-NCBI]
SNP	NM_178543 [SNP-NCI]
SNP	ENPP7 [GeneSNPs - Utah]  ENPP7] [HGBASE - SRS]
HAPMAP	ENPP7 [HAPMAP]
HGMD	ENPP7
	General knowledge
Family Browser	ENPP7 [UCSC Family Browser]
SOURCE	NM_178543
SMD	Hs.114084
SAGE	Hs.114084
Enzyme	3.1.4.12 [ Enzyme-SRS ]   3.1.4.12 [ Brenda-SRS ]   3.1.4.12 [ KEGG ]   3.1.4.12 [ WIT ]
GO	sphingomyelin phosphodiesterase activity [Amigo]  sphingomyelin phosphodiesterase activity
GO	Golgi apparatus [Amigo]  Golgi apparatus
GO	microvillus [Amigo]  microvillus
GO	sphingomyelin metabolic process [Amigo]  sphingomyelin metabolic process
GO	metabolic process [Amigo]  metabolic process
GO	negative regulation of DNA replication [Amigo]  negative regulation of DNA replication
GO	negative regulation of cell proliferation [Amigo]  negative regulation of cell proliferation
GO	membrane [Amigo]  membrane
GO	integral to membrane [Amigo]  integral to membrane
GO	hydrolase activity [Amigo]  hydrolase activity
KEGG	Sphingolipid metabolism
PubGene	ENPP7
TreeFam	ENPP7
CTD	339221 [Comparative ToxicoGenomics Database]
	Other databases
	Probes
Probe	ENPP7 Related clones (RZPD - Berlin)
	PubMed
PubMed	11 Pubmed reference(s) in LocusLink

Bibliography

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

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

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

Identification of an alkaline sphingomyelinase activity in human bile.

Nyberg L, Duan RD, Axelson J, Nilsson A

Biochimica et biophysica acta. 1996 ; 1300 (1) : 42-48.

PMID 8608160

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 is decreased in human colorectal carcinoma.

Hertervig E, Nilsson A, Nyberg L, Duan RD

Cancer. 1997 ; 79 (3) : 448-453.

PMID 9028353

Sphingomyelin hydrolysis in the gut and clinical implications in colorectal tumorigenesis and other gastrointestinal diseases.

Duan RD

Scandinavian journal of gastroenterology. 1998 ; 33 (7) : 673-683.

PMID 9712229

Effects of ursodeoxycholate and other bile salts on levels of rat intestinal alkaline sphingomyelinase: a potential implication in tumorigenesis.

Duan RD, Cheng Y, Tauschel HD, Nilsson A

Digestive diseases and sciences. 1998 ; 43 (1) : 26-32.

PMID 9508530

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

Familial adenomatous polyposis is associated with a marked decrease in alkaline sphingomyelinase activity: a key factor to the unrestrained cell proliferation?

Hertervig E, Nilsson A, Bj��rk J, Hultkrantz R, Duan RD

British journal of cancer. 1999 ; 81 (2) : 232-236.

PMID 10496347

Alkaline sphingomyelinases and ceramidases of the gastrointestinal tract.

Nilsson A, Duan RD

Chemistry and physics of lipids. 1999 ; 102 (1-2) : 97-105.

PMID 11001564

Effects of phospholipids on sphingomyelin hydrolysis induced by intestinal alkaline sphingomyelinase: an in vitro study.

Liu JJ, Nilsson A, Duan RD

The Journal of nutritional biochemistry. 2000 ; 11 (4) : 192-197.

PMID 10827341

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

Purification, characterization, and expression of rat intestinal alkaline sphingomyelinase.

Cheng Y, Nilsson A, T��mquist E, Duan RD

Journal of lipid research. 2002 ; 43 (2) : 316-324.

PMID 11861674

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

Chronic colitis is associated with a reduction of mucosal alkaline sphingomyelinase activity.

Sj��qvist U, Hertervig E, Nilsson A, Duan RD, Ost A, Tribukait B, L��fberg R

Inflammatory bowel diseases. 2002 ; 8 (4) : 258-263.

PMID 12131609

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

Purification, localization, and expression of human intestinal alkaline sphingomyelinase.

Duan RD, Cheng Y, Hansen G, Hertervig E, Liu JJ, Syk I, Sjostrom H, Nilsson A

Journal of lipid research. 2003 ; 44 (6) : 1241-1250.

PMID 12671034

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

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

Identification of one exon deletion of intestinal alkaline sphingomyelinase in colon cancer HT-29 cells and a differentiation-related expression of the wild-type enzyme in Caco-2 cells.

Wu J, Cheng Y, Nilsson A, Duan RD

Carcinogenesis. 2004 ; 25 (8) : 1327-1333.

PMID 15016655

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

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

Anticancer compounds and sphingolipid metabolism in the colon.

Duan RD

In vivo (Athens, Greece). 2005 ; 19 (1) : 293-300.

PMID 15796189

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

Alkaline sphingomyelinase: an old enzyme with novel implications.

Duan RD

Biochimica et biophysica acta. 2006 ; 1761 (3) : 281-291.

PMID 16631405

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

Absorption and lipoprotein transport of sphingomyelin.

Nilsson A, Duan RD

Journal of lipid research. 2006 ; 47 (1) : 154-171.

PMID 16251722

Intestinal alkaline sphingomyelinase hydrolyses and inactivates platelet-activating factor by a phospholipase C activity.

Wu J, Nilsson A, J��nsson BA, Stenstad H, Agace W, Cheng Y, Duan RD

The Biochemical journal. 2006 ; 394 (Pt 1) : 299-308.

PMID 16255717

Human meconium contains significant amounts of alkaline sphingomyelinase, neutral ceramidase, and sphingolipid metabolites.

Duan RD, Cheng Y, J��nsson BA, Ohlsson L, Herbst A, Hellstr��m-Westas L, Nilsson A

Pediatric research. 2007 ; 61 (1) : 61-66.

PMID 17211142

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

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Contributor(s)

Written	08-2007	Rui-Dong Duan
		Biomedical B11, Institution of Clinical Sciences, Lund University, Lund, Sweden

Citation

This paper should be referenced as such :

Duan RD . ENPP7 (ectonucleotide pyrophosphatase/phosphodiesterase 7). Atlas Genet Cytogenet Oncol Haematol. August 2007 . URL : http://AtlasGeneticsOncology.org/Genes/ENPP7ID44055ch17q25.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology

indexed on : Wed Jul 2 08:23:19 2008