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ENPP7 (ectonucleotide pyrophosphatase/phosphodiesterase 7)

Written2007-08Rui-Dong Duan
Biomedical B11, Institution of Clinical Sciences, Lund University, Lund, Sweden

(Note : for Links provided by Atlas : click)

Identity

Alias_symbol (synonym)alk-SMase
NPP7
Other aliasALK-SMase (Alkaline sphingomyelinase)
E-NPP7
MGC50179
NPP-7
HGNC (Hugo) ENPP7
LocusID (NCBI) 339221
Atlas_Id 44055
Location 17q25.3  [Link to chromosome band 17q25]
Location_base_pair Starts at 79731103 and ends at 79742222 bp from pter ( according to hg19-Feb_2009)  [Mapping ENPP7.png]
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

Note
  
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.
  

Bibliography

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
 

Citation

This paper should be referenced as such :
Duan, RD
ENPP7 (ectonucleotide pyrophosphatase/phosphodiesterase 7)
Atlas Genet Cytogenet Oncol Haematol. 2008;12(2):96-99.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/ENPP7ID44055ch17q25.html


External links

Nomenclature
HGNC (Hugo)ENPP7   23764
Cards
AtlasENPP7ID44055ch17q25
Entrez_Gene (NCBI)ENPP7  339221  ectonucleotide pyrophosphatase/phosphodiesterase 7
AliasesALK-SMase; E-NPP; NPP-7; NPP7
GeneCards (Weizmann)ENPP7
Ensembl hg19 (Hinxton)ENSG00000182156 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000182156 [Gene_View]  chr17:79731103-79742222 [Contig_View]  ENPP7 [Vega]
ICGC DataPortalENSG00000182156
TCGA cBioPortalENPP7
AceView (NCBI)ENPP7
Genatlas (Paris)ENPP7
WikiGenes339221
SOURCE (Princeton)ENPP7
Genetics Home Reference (NIH)ENPP7
Genomic and cartography
GoldenPath hg38 (UCSC)ENPP7  -     chr17:79731103-79742222 +  17q25.3   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)ENPP7  -     17q25.3   [Description]    (hg19-Feb_2009)
EnsemblENPP7 - 17q25.3 [CytoView hg19]  ENPP7 - 17q25.3 [CytoView hg38]
Mapping of homologs : NCBIENPP7 [Mapview hg19]  ENPP7 [Mapview hg38]
OMIM616997   
Gene and transcription
Genbank (Entrez)AK126250 AK128662 AY230663 AY358622 BC041453
RefSeq transcript (Entrez)NM_178543
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)ENPP7
Cluster EST : UnigeneHs.114084 [ NCBI ]
CGAP (NCI)Hs.114084
Alternative Splicing GalleryENSG00000182156
Gene ExpressionENPP7 [ NCBI-GEO ]   ENPP7 [ EBI - ARRAY_EXPRESS ]   ENPP7 [ SEEK ]   ENPP7 [ MEM ]
Gene Expression Viewer (FireBrowse)ENPP7 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)339221
GTEX Portal (Tissue expression)ENPP7
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ6UWV6   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ6UWV6  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ6UWV6
Splice isoforms : SwissVarQ6UWV6
Catalytic activity : Enzyme3.1.4.12 [ Enzyme-Expasy ]   3.1.4.123.1.4.12 [ IntEnz-EBI ]   3.1.4.12 [ BRENDA ]   3.1.4.12 [ KEGG ]   
PhosPhoSitePlusQ6UWV6
Domains : Interpro (EBI)Alkaline_Pase-like_a/b/a    Alkaline_phosphatase_core    ENPP7    Phosphodiest/P_Trfase   
Domain families : Pfam (Sanger)Phosphodiest (PF01663)   
Domain families : Pfam (NCBI)pfam01663   
Conserved Domain (NCBI)ENPP7
DMDM Disease mutations339221
Blocks (Seattle)ENPP7
SuperfamilyQ6UWV6
Human Protein AtlasENSG00000182156
Peptide AtlasQ6UWV6
IPIIPI00419668   
Protein Interaction databases
DIP (DOE-UCLA)Q6UWV6
IntAct (EBI)Q6UWV6
FunCoupENSG00000182156
BioGRIDENPP7
STRING (EMBL)ENPP7
ZODIACENPP7
Ontologies - Pathways
QuickGOQ6UWV6
Ontology : AmiGOsphingomyelin phosphodiesterase activity  sphingomyelin phosphodiesterase activity  Golgi apparatus  plasma membrane  microvillus  sphingomyelin metabolic process  sphingomyelin catabolic process  glycosphingolipid metabolic process  negative regulation of DNA replication  negative regulation of cell proliferation  membrane  integral component of membrane  
Ontology : EGO-EBIsphingomyelin phosphodiesterase activity  sphingomyelin phosphodiesterase activity  Golgi apparatus  plasma membrane  microvillus  sphingomyelin metabolic process  sphingomyelin catabolic process  glycosphingolipid metabolic process  negative regulation of DNA replication  negative regulation of cell proliferation  membrane  integral component of membrane  
Pathways : KEGGSphingolipid metabolism   
REACTOMEQ6UWV6 [protein]
REACTOME PathwaysR-HSA-1660662 [pathway]   
NDEx NetworkENPP7
Atlas of Cancer Signalling NetworkENPP7
Wikipedia pathwaysENPP7
Orthology - Evolution
OrthoDB339221
GeneTree (enSembl)ENSG00000182156
Phylogenetic Trees/Animal Genes : TreeFamENPP7
HOVERGENQ6UWV6
HOGENOMQ6UWV6
Homologs : HomoloGeneENPP7
Homology/Alignments : Family Browser (UCSC)ENPP7
Gene fusions - Rearrangements
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerENPP7 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)ENPP7
dbVarENPP7
ClinVarENPP7
1000_GenomesENPP7 
Exome Variant ServerENPP7
ExAC (Exome Aggregation Consortium)ENPP7 (select the gene name)
Genetic variants : HAPMAP339221
Genomic Variants (DGV)ENPP7 [DGVbeta]
DECIPHERENPP7 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisENPP7 
Mutations
ICGC Data PortalENPP7 
TCGA Data PortalENPP7 
Broad Tumor PortalENPP7
OASIS PortalENPP7 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICENPP7  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDENPP7
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch ENPP7
DgiDB (Drug Gene Interaction Database)ENPP7
DoCM (Curated mutations)ENPP7 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)ENPP7 (select a term)
intoGenENPP7
NCG5 (London)ENPP7
Cancer3DENPP7(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM616997   
Orphanet
MedgenENPP7
Genetic Testing Registry ENPP7
NextProtQ6UWV6 [Medical]
TSGene339221
GENETestsENPP7
Target ValidationENPP7
Huge Navigator ENPP7 [HugePedia]
snp3D : Map Gene to Disease339221
BioCentury BCIQENPP7
ClinGenENPP7
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD339221
Chemical/Pharm GKB GenePA134986550
Clinical trialENPP7
Miscellaneous
canSAR (ICR)ENPP7 (select the gene name)
Probes
Litterature
PubMed15 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineENPP7
EVEXENPP7
GoPubMedENPP7
iHOPENPP7
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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