P22413 (ENPP1_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Ectonucleotide pyrophosphatase/phosphodiesterase family member 1
Short name=E-NPP 1

Alternative name(s):
Membrane component chromosome 6 surface marker 1
Phosphodiesterase I/nucleotide pyrophosphatase 1
Plasma-cell membrane glycoprotein PC-1

Including the following 2 domains:

1. Alkaline phosphodiesterase I
   EC=3.1.4.1
2. Nucleotide pyrophosphatase
   Short name=NPPase
   EC=3.6.1.9

Gene names

Name:	ENPP1
Synonyms:	M6S1, NPPS, PC1, PDNP1

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	925 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Involved primarily in ATP hydrolysis at the plasma membrane. Plays a role in regulating pyrophosphate levels, and functions in bone mineralization and soft tissue calcification. In vitro, has a broad specificity, hydrolyzing other nucleoside 5' triphosphates such as GTP, CTP, TTP and UTP to their corresponding monophosphates with release of pyrophosphate and diadenosine polyphosphates, and also 3',5'-cAMP to AMP. May also be involved in the regulation of the availability of nucleotide sugars in the endoplasmic reticulum and Golgi, and the regulation of purinergic signaling. Appears to modulate insulin sensitivity. Ref.10
Catalytic activity	Hydrolytically removes 5'-nucleotides successively from the 3'-hydroxy termini of 3'-hydroxy-terminated oligonucleotides. A dinucleotide + H2O = 2 mononucleotides.
Cofactor	Binds 2 divalent metal cations per subunit Probable.
Enzyme regulation	At low concentrations of ATP, a phosphorylated intermediate is formed which inhibits further hydrolysis.
Subunit structure	Homodimer; disulfide-linked. Interacts with INSR. Ref.10
Subcellular location	Membrane; Single-pass type II membrane protein. Basolateral cell membrane; Single-pass type II membrane protein. Note: Targeted to the basolateral membrane in polarized epithelial cells and in hepatocytes, and to matrix vesicles in osteoblasts. In bile duct cells and cancer cells, located to the apical cytoplasmic side. Ref.11 Ref.12
Tissue specificity	Expressed in plasma cells and also in a number of non-lymphoid tissues, including the distal convoluted tubule of the kidney, chondrocytes and epididymis. Ref.9
Domain	The di-leucine motif is required for basolateral targeting in epithelial cells, and for targeting to matrix vesicles derived from mineralizing cells By similarity.
Post-translational modification	Autophosphorylated as part of the catalytic cycle of phosphodiesterase/pyrophosphatase activity. N-glycosylated. It has been suggested that the active SMB domain may be permitted considerable disulfide bond heterogeneity or variability, thus two alternate disulfide patterns based on 3D structures are described with 1 disulfide bond conserved in both.
Involvement in disease	Ossification of the posterior longitudinal ligament of the spine (OPLL) [MIM:602475]: A calcification of the posterior longitudinal ligament of the spinal column, usually at the level of the cervical spine. Patients with OPLL frequently present with a severe myelopathy that can lead to tetraparesis. Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.16 Arterial calcification of infancy, generalized, 1 (GACI1) [MIM:208000]: A severe autosomal recessive disorder characterized by calcification of the internal elastic lamina of muscular arteries and stenosis due to myointimal proliferation. The disorder is often fatal within the first 6 months of life because of myocardial ischemia resulting in refractory heart failure. Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.17 Ref.18 Ref.20 Ref.24 Diabetes mellitus, non-insulin-dependent (NIDDM) [MIM:125853]: A multifactorial disorder of glucose homeostasis caused by a lack of sensitivity to the body's own insulin. Affected individuals usually have an obese body habitus and manifestations of a metabolic syndrome characterized by diabetes, insulin resistance, hypertension and hypertriglyceridemia. The disease results in long-term complications that affect the eyes, kidneys, nerves, and blood vessels. Note: Disease susceptibility is associated with variations affecting the gene represented in this entry. Ref.19 Hypophosphatemic rickets, autosomal recessive, 2 (ARHR2) [MIM:613312]: A hereditary form of hypophosphatemic rickets, a disorder of proximal renal tubule function that causes phosphate loss, hypophosphatemia and skeletal deformities, including rickets and osteomalacia unresponsive to vitamin D. Symptoms are bone pain, fractures and growth abnormalities. Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.21 Ref.22
Sequence similarities	Belongs to the nucleotide pyrophosphatase/phosphodiesterase family. Contains 2 SMB (somatomedin-B) domains.
Caution	It is uncertain whether Met-1 or Met-53 is the initiator.
Sequence caution	The sequence AAA63237.1 differs from that shown. Reason: Erroneous initiation. Translation N-terminally extended. The sequence AAH59375.2 differs from that shown. Reason: Erroneous initiation. Translation N-terminally extended. The sequence BAA02054.1 differs from that shown. Reason: Erroneous initiation. Translation N-terminally extended.

Ontologies

Keywords
Biological process	Biomineralization
Cellular component	Cell membrane Membrane
Coding sequence diversity	Polymorphism
Disease	Diabetes mellitus Disease mutation Obesity
Domain	Repeat Signal-anchor Transmembrane Transmembrane helix
Ligand	Metal-binding
Molecular function	Hydrolase
PTM	Disulfide bond Glycoprotein
Technical term	3D-structure Complete proteome Multifunctional enzyme Reference proteome
Gene Ontology (GO)
Biological_process	3'-phosphoadenosine 5'-phosphosulfate metabolic process Inferred from direct assay PubMed 7830796. Source: BHF-UCL biomineral tissue development Inferred from electronic annotation. Source: UniProtKB-KW bone remodeling Inferred from electronic annotation. Source: Compara cellular phosphate ion homeostasis Inferred from direct assay PubMed 11159191. Source: BHF-UCL cellular response to insulin stimulus Inferred from direct assay PubMed 17849011PubMed 7830796. Source: BHF-UCL generation of precursor metabolites and energy Inferred from direct assay PubMed 12746903. Source: BHF-UCL immune response Inferred from electronic annotation. Source: InterPro inorganic diphosphate transport Inferred from direct assay PubMed 10513816. Source: BHF-UCL negative regulation of cell growth Inferred from direct assay PubMed 17849011. Source: BHF-UCL negative regulation of fat cell differentiation Inferred from direct assay PubMed 17849011. Source: BHF-UCL negative regulation of glucose import Inferred from direct assay PubMed 17849011. Source: BHF-UCL negative regulation of glycogen biosynthetic process Inferred from direct assay PubMed 11289049. Source: BHF-UCL negative regulation of insulin receptor signaling pathway Inferred from direct assay PubMed 17849011PubMed 7830796. Source: BHF-UCL negative regulation of ossification Inferred from electronic annotation. Source: Compara negative regulation of protein autophosphorylation Inferred from direct assay PubMed 11289049. Source: BHF-UCL nucleoside triphosphate catabolic process Inferred from direct assay PubMed 10513816. Source: BHF-UCL regulation of bone mineralization Inferred by curator PubMed 10513816. Source: BHF-UCL riboflavin metabolic process Traceable author statement. Source: Reactome sequestering of triglyceride Inferred from direct assay PubMed 17849011. Source: BHF-UCL
Cellular_component	basolateral plasma membrane Non-traceable author statement PubMed 9553761. Source: BHF-UCL cell surface Inferred from direct assay PubMed 10513816. Source: BHF-UCL extracellular space Inferred from direct assay PubMed 11159191. Source: BHF-UCL integral to membrane Traceable author statement Ref.2. Source: ProtInc
Molecular_function	3'-phosphoadenosine 5'-phosphosulfate binding Inferred by curator PubMed 7830796. Source: BHF-UCL ATP binding Inferred from direct assay PubMed 7830796. Source: BHF-UCL NADH pyrophosphatase activity Inferred from electronic annotation. Source: EC insulin receptor binding Inferred from direct assay PubMed 7830796. Source: BHF-UCL metal ion binding Inferred from electronic annotation. Source: UniProtKB-KW nucleic acid binding Inferred from electronic annotation. Source: InterPro nucleoside-triphosphate diphosphatase activity Inferred from direct assay PubMed 10513816PubMed 11159191PubMed 7830796. Source: BHF-UCL nucleotide diphosphatase activity Inferred from direct assay PubMed 12746903. Source: BHF-UCL phosphodiesterase I activity Inferred from electronic annotation. Source: EC polysaccharide binding Inferred from electronic annotation. Source: InterPro protein homodimerization activity Inferred from direct assay PubMed 7830796. Source: BHF-UCL scavenger receptor activity Inferred from electronic annotation. Source: InterPro
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 925

925

Ectonucleotide pyrophosphatase/phosphodiesterase family member 1

PRO_0000188564

Regions

Topological domain

1 – 76

76

Cytoplasmic Potential

Transmembrane

77 – 97

21

Helical; Signal-anchor for type II membrane protein; Potential

Topological domain

98 – 925

828

Extracellular Potential

Domain

104 – 144

41

SMB 1

Domain

145 – 189

45

SMB 2

Region

191 – 591

401

Phosphodiesterase

Region

654 – 925

272

Nuclease

Motif

45 – 52

8

Di-leucine motif

Sites

Active site

256

1

AMP-threonine intermediate By similarity

Metal binding

218

1

Divalent metal cation 2 Probable

Metal binding

376

1

Divalent metal cation 1 Probable

Metal binding

380

1

Divalent metal cation 1 Probable

Metal binding

423

1

Divalent metal cation 2 Probable

Metal binding

424

1

Divalent metal cation 2 Probable

Metal binding

535

1

Divalent metal cation 1 Probable

Site

915

1

Essential for catalytic activity By similarity

Amino acid modifications

Glycosylation

179

1

N-linked (GlcNAc...) Potential

Glycosylation

285

1

N-linked (GlcNAc...) Potential

Glycosylation

341

1

N-linked (GlcNAc...) Ref.13 Ref.14

Glycosylation

477

1

N-linked (GlcNAc...) Potential

Glycosylation

585

1

N-linked (GlcNAc...) Potential

Glycosylation

643

1

N-linked (GlcNAc...) Ref.14

Glycosylation

700

1

N-linked (GlcNAc...) Potential

Glycosylation

731

1

N-linked (GlcNAc...) Potential

Glycosylation

748

1

N-linked (GlcNAc...) Ref.14

Disulfide bond

108 ↔ 122

Alternate By similarity

Disulfide bond

108 ↔ 112

Alternate By similarity

Disulfide bond

112 ↔ 140

Alternate By similarity

Disulfide bond

120 ↔ 133

Alternate By similarity

Disulfide bond

120 ↔ 122

Alternate By similarity

Disulfide bond

126 ↔ 132

By similarity

Disulfide bond

133 ↔ 140

Alternate By similarity

Disulfide bond

149 ↔ 166

Alternate By similarity

Disulfide bond

149 ↔ 154

Alternate By similarity

Disulfide bond

154 ↔ 184

Alternate By similarity

Disulfide bond

164 ↔ 177

Alternate By similarity

Disulfide bond

164 ↔ 166

Alternate By similarity

Disulfide bond

170 ↔ 176

By similarity

Disulfide bond

177 ↔ 184

Alternate By similarity

Disulfide bond

480 ↔ 868

By similarity

Natural variations

Natural variant

91

1

L → P in OPLL. Ref.16

VAR_014141

Natural variant

173

1

K → Q Associated with NIDDM. Ref.6 Ref.16 Ref.19 Ref.23
Corresponds to variant rs1044498 [ dbSNP | Ensembl ].

VAR_008873

Natural variant

179

1

N → S.
Corresponds to variant rs2273411 [ dbSNP | Ensembl ].

VAR_037432

Natural variant

250

1

P → L in GACI1. Ref.20

VAR_067910

Natural variant

252

1

Missing in GACI1. Ref.20

VAR_067911

Natural variant

266

1

G → V in ARHR2; rs121908248. Ref.21

VAR_063719

Natural variant

268

1

Y → H. Ref.16
Corresponds to variant rs1805139 [ dbSNP | Ensembl ].

VAR_014142

Natural variant

287

1

S → F in OPLL. Ref.16

VAR_014143

Natural variant

305

1

P → T in GACI1. Ref.20

VAR_067912

Natural variant

342

1

G → V in GACI1. Ref.18 Ref.20

VAR_037433

Natural variant

371

1

Y → F in GACI1; unknown pathological significance. Ref.18 Ref.20

VAR_037434

Natural variant

538

1

D → H in GACI1. Ref.24

VAR_067913

Natural variant

579

1

L → F in GACI1. Ref.17

VAR_018514

Natural variant

586

1

G → R in GACI1. Ref.24

VAR_067914

Natural variant

774

1

R → C in GACI1; unknown pathological significance. Ref.17 Ref.20
Corresponds to variant rs28933977 [ dbSNP | Ensembl ].

VAR_018515

Natural variant

779

1

T → P. Ref.16
Corresponds to variant rs1805138 [ dbSNP | Ensembl ].

VAR_014144

Natural variant

886

1

R → T.
Corresponds to variant rs8192683 [ dbSNP | Ensembl ].

VAR_037435

Natural variant

901

1

Y → S in ARHR2; loss of activity. Ref.22
Corresponds to variant rs121908249 [ dbSNP | Ensembl ].

VAR_063720

Secondary structure

1

.

.

.

.

.

.

.

.

.

925

Helix Strand Turn

Details...

Turn

151 – 155

5

Beta strand

163 – 165

3

Helix

168 – 173

6

Helix

180 – 183

4

Sequences

	Sequence		Length	Mass (Da)
	P22413 [UniParc]. Last modified September 19, 2002. Version 2. Checksum: 0ECAA063801CAFEB	FASTA	925	104,924
	10 20 30 40 50 60 MERDGCAGGG SRGGEGGRAP REGPAGNGRD RGRSHAAEAP GDPQAAASLL APMDVGEEPL 70 80 90 100 110 120 EKAARARTAK DPNTYKVLSL VLSVCVLTTI LGCIFGLKPS CAKEVKSCKG RCFERTFGNC 130 140 150 160 170 180 RCDAACVELG NCCLDYQETC IEPEHIWTCN KFRCGEKRLT RSLCACSDDC KDKGDCCINY 190 200 210 220 230 240 SSVCQGEKSW VEEPCESINE PQCPAGFETP PTLLFSLDGF RAEYLHTWGG LLPVISKLKK 250 260 270 280 290 300 CGTYTKNMRP VYPTKTFPNH YSIVTGLYPE SHGIIDNKMY DPKMNASFSL KSKEKFNPEW 310 320 330 340 350 360 YKGEPIWVTA KYQGLKSGTF FWPGSDVEIN GIFPDIYKMY NGSVPFEERI LAVLQWLQLP 370 380 390 400 410 420 KDERPHFYTL YLEEPDSSGH SYGPVSSEVI KALQRVDGMV GMLMDGLKEL NLHRCLNLIL 430 440 450 460 470 480 ISDHGMEQGS CKKYIYLNKY LGDVKNIKVI YGPAARLRPS DVPDKYYSFN YEGIARNLSC 490 500 510 520 530 540 REPNQHFKPY LKHFLPKRLH FAKSDRIEPL TFYLDPQWQL ALNPSERKYC GSGFHGSDNV 550 560 570 580 590 600 FSNMQALFVG YGPGFKHGIE ADTFENIEVY NLMCDLLNLT PAPNNGTHGS LNHLLKNPVY 610 620 630 640 650 660 TPKHPKEVHP LVQCPFTRNP RDNLGCSCNP SILPIEDFQT QFNLTVAEEK IIKHETLPYG 670 680 690 700 710 720 RPRVLQKENT ICLLSQHQFM SGYSQDILMP LWTSYTVDRN DSFSTEDFSN CLYQDFRIPL 730 740 750 760 770 780 SPVHKCSFYK NNTKVSYGFL SPPQLNKNSS GIYSEALLTT NIVPMYQSFQ VIWRYFHDTL 790 800 810 820 830 840 LRKYAEERNG VNVVSGPVFD FDYDGRCDSL ENLRQKRRVI RNQEILIPTH FFIVLTSCKD 850 860 870 880 890 900 TSQTPLHCEN LDTLAFILPH RTDNSESCVH GKHDSSWVEE LLMLHRARIT DVEHITGLSF 910 920 YQQRKEPVSD ILKLKTHLPT FSQED

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Plasma cell membrane glycoprotein PC-1. cDNA cloning of the human molecule, amino acid sequence, and chromosomal location." Buckley M.F., Loveland K.A., McKinstry W.J., Garson O.M., Goding J.W. J. Biol. Chem. 265:17506-17511(1990) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Skin fibroblast.
[2]	"Molecular cloning of cDNAs for human fibroblast nucleotide pyrophosphatase." Funakoshi I., Kato H., Horie K., Yano T., Hori Y., Kobayashi H., Inoue T., Suzuki H., Fukui S., Tsukahara M., Kajii T., Yamashina I. Arch. Biochem. Biophys. 295:180-187(1992) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Skin fibroblast.
[3]	"Genomic structure of the human PC1 gene." Bozzali M., Pizzuti A., Trischitta E. Submitted (APR-1999) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[4]	"The DNA sequence and analysis of human chromosome 6." Mungall A.J., Palmer S.A., Sims S.K., Edwards C.A., Ashurst J.L., Wilming L., Jones M.C., Horton R., Hunt S.E., Scott C.E., Gilbert J.G.R., Clamp M.E., Bethel G., Milne S., Ainscough R., Almeida J.P., Ambrose K.D., Andrews T.D. , Ashwell R.I.S., Babbage A.K., Bagguley C.L., Bailey J., Banerjee R., Barker D.J., Barlow K.F., Bates K., Beare D.M., Beasley H., Beasley O., Bird C.P., Blakey S.E., Bray-Allen S., Brook J., Brown A.J., Brown J.Y., Burford D.C., Burrill W., Burton J., Carder C., Carter N.P., Chapman J.C., Clark S.Y., Clark G., Clee C.M., Clegg S., Cobley V., Collier R.E., Collins J.E., Colman L.K., Corby N.R., Coville G.J., Culley K.M., Dhami P., Davies J., Dunn M., Earthrowl M.E., Ellington A.E., Evans K.A., Faulkner L., Francis M.D., Frankish A., Frankland J., French L., Garner P., Garnett J., Ghori M.J., Gilby L.M., Gillson C.J., Glithero R.J., Grafham D.V., Grant M., Gribble S., Griffiths C., Griffiths M.N.D., Hall R., Halls K.S., Hammond S., Harley J.L., Hart E.A., Heath P.D., Heathcott R., Holmes S.J., Howden P.J., Howe K.L., Howell G.R., Huckle E., Humphray S.J., Humphries M.D., Hunt A.R., Johnson C.M., Joy A.A., Kay M., Keenan S.J., Kimberley A.M., King A., Laird G.K., Langford C., Lawlor S., Leongamornlert D.A., Leversha M., Lloyd C.R., Lloyd D.M., Loveland J.E., Lovell J., Martin S., Mashreghi-Mohammadi M., Maslen G.L., Matthews L., McCann O.T., McLaren S.J., McLay K., McMurray A., Moore M.J.F., Mullikin J.C., Niblett D., Nickerson T., Novik K.L., Oliver K., Overton-Larty E.K., Parker A., Patel R., Pearce A.V., Peck A.I., Phillimore B.J.C.T., Phillips S., Plumb R.W., Porter K.M., Ramsey Y., Ranby S.A., Rice C.M., Ross M.T., Searle S.M., Sehra H.K., Sheridan E., Skuce C.D., Smith S., Smith M., Spraggon L., Squares S.L., Steward C.A., Sycamore N., Tamlyn-Hall G., Tester J., Theaker A.J., Thomas D.W., Thorpe A., Tracey A., Tromans A., Tubby B., Wall M., Wallis J.M., West A.P., White S.S., Whitehead S.L., Whittaker H., Wild A., Willey D.J., Wilmer T.E., Wood J.M., Wray P.W., Wyatt J.C., Young L., Younger R.M., Bentley D.R., Coulson A., Durbin R.M., Hubbard T., Sulston J.E., Dunham I., Rogers J., Beck S. Nature 425:805-811(2003) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[5]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Placenta.
[6]	"A polymorphism (K121Q) of the human glycoprotein PC-1 gene coding region is strongly associated with insulin resistance." Pizzuti A., Frittitta L., Argiolas A., Baratta R., Goldfine I.D., Bozzali M., Ercolino T., Scarlato G., Iacoviello L., Vigneri R., Tassi V., Trischitta V. Diabetes 48:1881-1884(1999) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 145-185, VARIANT GLN-173.
[7]	"Biochemical characterization of human PC-1, an enzyme possessing alkaline phosphodiesterase I and nucleotide pyrophosphatase activities." Belli S.I., Goding J.W. Eur. J. Biochem. 226:433-443(1994) [PubMed] [Europe PMC] [Abstract] Cited for: CHARACTERIZATION.
[8]	"Autophosphorylation of PC-1 (alkaline phosphodiesterase I/nucleotide pyrophosphatase) and analysis of the active site." Belli S.I., Mercuri F.A., Sali A., Goding J.W. Eur. J. Biochem. 228:669-676(1995) [PubMed] [Europe PMC] [Abstract] Cited for: ACTIVE SITE.
[9]	"Molecular cloning and chromosomal localization of PD-Ibeta (PDNP3), a new member of the human phosphodiesterase I genes." Piao J.-H., Goding J.W., Nakamura H., Sano K. Genomics 45:412-415(1997) [PubMed] [Europe PMC] [Abstract] Cited for: TISSUE SPECIFICITY.
[10]	"Membrane glycoprotein PC-1 inhibition of insulin receptor function occurs via direct interaction with the receptor alpha-subunit." Maddux B.A., Goldfine I.D. Diabetes 49:13-19(2000) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH INSR, FUNCTION IN INHIBITION OF INSR KINASE ACTIVITY.
[11]	"Characterization of a di-leucine-based signal in the cytoplasmic tail of the nucleotide-pyrophosphatase NPP1 that mediates basolateral targeting but not endocytosis." Bello V., Goding J.W., Greengrass V., Sali A., Dubljevic V., Lenoir C., Trugnan G., Maurice M. Mol. Biol. Cell 12:3004-3015(2001) [PubMed] [Europe PMC] [Abstract] Cited for: CHARACTERIZATION, SUBCELLULAR LOCATION.
[12]	"Expression and localization of ecto-nucleotide pyrophosphatase/phosphodiesterase I-1 (E-NPP1/PC-1) and -3 (E-NPP3/CD203c/PD-Ibeta/B10/gp130(RB13-6)) in inflammatory and neoplastic bile duct diseases." Yano Y., Hayashi Y., Sano K., Nagano H., Nakaji M., Seo Y., Ninomiya T., Yoon S., Yokozaki H., Kasuga M. Cancer Lett. 207:139-147(2004) [PubMed] [Europe PMC] [Abstract] Cited for: SUBCELLULAR LOCATION.
[13]	"Glycoproteomics analysis of human liver tissue by combination of multiple enzyme digestion and hydrazide chemistry." Chen R., Jiang X., Sun D., Han G., Wang F., Ye M., Wang L., Zou H. J. Proteome Res. 8:651-661(2009) [PubMed] [Europe PMC] [Abstract] Cited for: GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-341, MASS SPECTROMETRY. Tissue: Liver.
[14]	"Mass-spectrometric identification and relative quantification of N-linked cell surface glycoproteins." Wollscheid B., Bausch-Fluck D., Henderson C., O'Brien R., Bibel M., Schiess R., Aebersold R., Watts J.D. Nat. Biotechnol. 27:378-386(2009) [PubMed] [Europe PMC] [Abstract] Cited for: GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-341; ASN-643 AND ASN-748, MASS SPECTROMETRY. Tissue: Leukemic T-cell.
[15]	"Solution structure of the somatomedin B domain of human ectonucleotide pyrophosphatase/phosphodiesterase family member." RIKEN structural genomics initiative (RSGI) Submitted (OCT-2007) to the PDB data bank Cited for: STRUCTURE BY NMR OF 147-189.
[16]	"Association of the human NPPS gene with ossification of the posterior longitudinal ligament of the spine (OPLL)." Nakamura I., Ikegawa S., Okawa A., Okuda S., Koshizuka Y., Kawaguchi H., Nakamura K., Koyama T., Goto S., Toguchida J., Matsushita M., Ochi T., Takaoka K., Nakamura Y. Hum. Genet. 104:492-497(1999) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS OPLL PRO-91 AND PHE-287, VARIANTS GLN-173; HIS-268 AND PRO-779.
[17]	"Mutations in ENPP1 are associated with 'idiopathic' infantile arterial calcification." Rutsch F., Ruf N., Vaingankar S., Toliat M.R., Suk A., Hohne W., Schauer G., Lehmann M., Roscioli T., Schnabel D., Epplen J.T., Knisely A., Superti-Furga A., McGill J., Filippone M., Sinaiko A.R., Vallance H., Hinrichs B. , Smith W., Ferre M., Terkeltaub R., Nuernberg P. Nat. Genet. 34:379-381(2003) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS GACI1 PHE-579 AND CYS-774.
[18]	"Generalized arterial calcification of infancy: different clinical courses in two affected siblings." Cheng K.-S., Chen M.-R., Ruf N., Lin S.-P., Rutsch F. Am. J. Med. Genet. A 136:210-213(2005) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS GACI1 VAL-342 AND PHE-371.
[19]	"The K121Q polymorphism of the ENPP1/PC-1 gene is associated with insulin resistance/atherogenic phenotypes, including earlier onset of type 2 diabetes and myocardial infarction." Bacci S., Ludovico O., Prudente S., Zhang Y.Y., Di Paola R., Mangiacotti D., Rauseo A., Nolan D., Duffy J., Fini G., Salvemini L., Amico C., Vigna C., Pellegrini F., Menzaghi C., Doria A., Trischitta V. Diabetes 54:3021-3025(2005) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT GLN-173, ASSOCIATION WITH NIDDM.
[20]	"The mutational spectrum oENPP1 as arising after the analysis of 23 unrelated patients with generalized arterial calcification of infancy (GACI)." Ruf N., Uhlenberg B., Terkeltaub R., Nurnberg P., Rutsch F. Hum. Mutat. 25:98-98(2005) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS GACI1 LEU-250; TYR-252 DEL; THR-305; VAL-342; PHE-371 AND CYS-774.
[21]	"Loss-of-function ENPP1 mutations cause both generalized arterial calcification of infancy and autosomal-recessive hypophosphatemic rickets." Lorenz-Depiereux B., Schnabel D., Tiosano D., Hausler G., Strom T.M. Am. J. Hum. Genet. 86:267-272(2010) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT ARHR2 VAL-266.
[22]	"Autosomal-recessive hypophosphatemic rickets is associated with an inactivation mutation in the ENPP1 gene." Levy-Litan V., Hershkovitz E., Avizov L., Leventhal N., Bercovich D., Chalifa-Caspi V., Manor E., Buriakovsky S., Hadad Y., Goding J., Parvari R. Am. J. Hum. Genet. 86:273-278(2010) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT ARHR2 SER-901, CHARACTERIZATION OF VARIANT ARHR2 SER-901.
[23]	"An unusual severe vascular case of pseudoxanthoma elasticum presenting as generalized arterial calcification of infancy." Le Boulanger G., Labreze C., Croue A., Schurgers L.J., Chassaing N., Wittkampf T., Rutsch F., Martin L. Am. J. Med. Genet. A 152:118-123(2010) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT GLN-173.
[24]	"Generalized arterial calcification of infancy and pseudoxanthoma elasticum can be caused by mutations in either ENPP1 or ABCC6." Nitschke Y., Baujat G., Botschen U., Wittkampf T., du Moulin M., Stella J., Le Merrer M., Guest G., Lambot K., Tazarourte-Pinturier M.F., Chassaing N., Roche O., Feenstra I., Loechner K., Deshpande C., Garber S.J., Chikarmane R., Steinmann B. , Shahinyan T., Martorell L., Davies J., Smith W.E., Kahler S.G., McCulloch M., Wraige E., Loidi L., Hohne W., Martin L., Hadj-Rabia S., Terkeltaub R., Rutsch F. Am. J. Hum. Genet. 90:25-39(2012) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS GACI1 HIS-538 AND ARG-586.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

M57736 mRNA. Translation: AAA63237.1. Different initiation.
D12485 mRNA. Translation: BAA02054.1. Different initiation.
AF110304 , AF110280, AF110281, AF110283, AF110284, AF110285, AF110286, AF110287, AF110288, AF110289, AF110290, AF110291, AF110292, AF110293, AF110294, AF110295, AF110296, AF110297, AF110298, AF110299, AF110300, AF110301, AF110302, AF110303 Genomic DNA. Translation: AAF36094.1.
AJ242020 , AJ242021, AJ242022, AJ242023, AJ242024, AJ242025, AJ242026, AJ242027, AJ242028, AJ242029, AJ242030, AJ242031, AJ242032, AJ242033, AJ242034, AJ242035, AJ242036, AJ242037, AJ242038, AJ242039, AJ242040, AJ242041, AJ242042, AJ242043, AJ242044 Genomic DNA. Translation: CAC39442.1.
AL117378, AL139805 Genomic DNA. Translation: CAI19514.1.
AL139805, AL117378 Genomic DNA. Translation: CAI20161.1.
BC059375 mRNA. Translation: AAH59375.2. Different initiation.
AF067177 Genomic DNA. Translation: AAD38420.1.
AF067178 Genomic DNA. Translation: AAD38421.1.

IPI

IPI00184311.

PIR

A39216.

RefSeq

NP_006199.2. NM_006208.2.

UniGene

Hs.527295.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2YS0	NMR	-	A	147-189	[»]

ProteinModelPortal

P22413.

ModBase

Search...

Protein-protein interaction databases

IntAct

P22413. 1 interaction.

STRING

9606.ENSP00000354238.

PTM databases

PhosphoSite

P22413.

Polymorphism databases

DMDM

23503088.

Proteomic databases

PaxDb

P22413.

PRIDE

P22413.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000360971; ENSP00000354238; ENSG00000197594.

GeneID

5167.

KEGG

hsa:5167.

UCSC

uc011ecf.2. human.

Organism-specific databases

CTD

5167.

GeneCards

GC06P132170.

HGNC

HGNC:3356. ENPP1.

HPA

CAB032904.

MIM

125853. phenotype.
173335. gene.
208000. phenotype.
602475. phenotype.
613312. phenotype.

neXtProt

NX_P22413.

Orphanet

289176. Autosomal recessive hypophosphatemic rickets.
51608. Generalized arterial calcification of infancy.

PharmGKB

PA27791.

GenAtlas

Search...

Phylogenomic databases

eggNOG

COG1524.

HOGENOM

HOG000037439.

HOVERGEN

HBG051484.

InParanoid

P22413.

KO

K01513.

OMA

ERPHFYT.

OrthoDB

EOG4S7JPJ.

Enzyme and pathway databases

Reactome

REACT_111217. Metabolism.

SABIO-RK

P22413.

Gene expression databases

ArrayExpress

P22413.

Bgee

P22413.

CleanEx

HS_ENPP1.

Genevestigator

P22413.

GermOnline

ENSG00000197594. Homo sapiens.

Family and domain databases

Gene3D

3.40.570.10. 1 hit.
3.40.720.10. 1 hit.

InterPro

IPR017849. Alkaline_Pase-like_a/b/a.
IPR017850. Alkaline_phosphatase_core.
IPR001604. DNA/RNA_non-sp_Endonuclease.
IPR024873. E-NPP.
IPR020821. Extracellular_endonuc_su_A.
IPR002591. Phosphodiest/P_Trfase.
IPR020436. Somatomedin_B_chordata.
IPR001212. Somatomedin_B_dom.
[Graphical view]

PANTHER

PTHR10151. PTHR10151. 1 hit.

Pfam

PF01223. Endonuclease_NS. 1 hit.
PF01663. Phosphodiest. 1 hit.
PF01033. Somatomedin_B. 2 hits.
[Graphical view]

PRINTS

PR00022. SOMATOMEDINB.

SMART

SM00892. Endonuclease_NS. 1 hit.
SM00477. NUC. 1 hit.
SM00201. SO. 2 hits.
[Graphical view]

SUPFAM

SSF53649. Alkaline_phosphatase_core. 1 hit.

PROSITE

PS00524. SMB_1. 2 hits.
PS50958. SMB_2. 2 hits.
[Graphical view]

ProtoNet

Search...

Other

BindingDB

P22413.

ChEMBL

CHEMBL5925.

DrugBank

DB01143. Amifostine.
DB00811. Ribavirin.

EvolutionaryTrace

P22413.

GenomeRNAi

5167.

NextBio

19990.

SOURCE

Search...

Entry information

Entry name

ENPP1_HUMAN

Accession

Primary (citable) accession number: P22413
Secondary accession number(s): Q5T9R6 , Q9NPZ3, Q9P1P6, Q9UP61, Q9Y6K3

Entry history

Integrated into UniProtKB/Swiss-Prot:	August 1, 1991
Last sequence update:	September 19, 2002
Last modified:	May 1, 2013
This is version 148 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.