MGP Database

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MGP002234

UniProt Annotations

Entry Information
Gene Nameectonucleotide pyrophosphatase/phosphodiesterase 1
Protein EntryENPP1_HUMAN
UniProt IDP22413
SpeciesHuman
Comments
Comment typeDescription
Catalytic ActivityA dinucleotide + H(2)O = 2 mononucleotides. {ECO:0000269|PubMed:8001561}.
Catalytic ActivityHydrolytically removes 5'-nucleotides successively from the 3'-hydroxy termini of 3'-hydroxy-terminated oligonucleotides. {ECO:0000269|PubMed:8001561}.
CautionIt is uncertain whether Met-1 or Met-53 is the initiator. {ECO:0000305}.
CofactorName=Zn(2+); Xref=ChEBI:CHEBI:29105; Evidence={ECO:0000250}; Note=Binds 2 Zn(2+) ions per subunit. {ECO:0000250};
DiseaseArterial 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. {ECO:0000269|PubMed:12881724, ECO:0000269|PubMed:15605415, ECO:0000269|PubMed:15940697, ECO:0000269|PubMed:22209248}. Note=The disease is caused by mutations affecting the gene represented in this entry.
DiseaseCole disease (COLED) [MIM:615522]: A rare autosomal dominant genodermatosis characterized by punctate keratoderma associated with irregularly shaped hypopigmented macules, which are typically found over the arms and legs but not the trunk or acral regions. Skin biopsies of palmoplantar lesions show hyperorthokeratosis, hypergranulosis, and acanthosis. Hypopigmented areas of skin, however, reveal a reduction in melanin content in keratinocytes but not in melanocytes, as well as hyperkeratosis and a normal number of melanocytes. Ultrastructurally, melanocytes show a disproportionately large number of melanosomes in the cytoplasm and dendrites, whereas keratinocytes show a paucity of these organelles, suggestive of impaired melanosome transfer. Some patients also exhibit calcinosis cutis or calcific tendinopathy. {ECO:0000269|PubMed:24075184}. Note=The disease is caused by mutations affecting the gene represented in this entry.
DiseaseDiabetes 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.
DiseaseHypophosphatemic 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. {ECO:0000269|PubMed:20137772, ECO:0000269|PubMed:20137773}. Note=The disease is caused by mutations affecting the gene represented in this entry.
DiseaseOssification 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. {ECO:0000269|PubMed:10453738}. Note=The disease is caused by mutations affecting the gene represented in this entry.
DomainThe di-leucine motif is required for basolateral targeting in epithelial cells, and for targeting to matrix vesicles derived from mineralizing cells. {ECO:0000250}.
Enzyme RegulationAt low concentrations of ATP, a phosphorylated intermediate is formed which inhibits further hydrolysis.
FunctionBy generating PPi, plays a role in regulating pyrophosphate levels, and functions in bone mineralization and soft tissue calcification. PPi inhibits mineralization by binding to nascent hydroxyapatite (HA) crystals, thereby preventing further growth of these crystals. Preferentially hydrolyzes ATP, but can also hydrolyze 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 and function. {ECO:0000269|PubMed:10615944, ECO:0000269|PubMed:8001561}.
InteractionP06213:INSR; NbExp=2; IntAct=EBI-3197846, EBI-475899;
PtmA secreted form is produced through cleavage at Lys-103 by intracellular processing. {ECO:0000250}.
PtmAutophosphorylated as part of the catalytic cycle of phosphodiesterase/pyrophosphatase activity.
PtmN-glycosylated. {ECO:0000269|PubMed:19159218, ECO:0000269|PubMed:19349973, ECO:0000269|PubMed:8001561}.
Sequence CautionSequence=AAA63237.1; Type=Erroneous initiation; Note=Translation N-terminally extended.; Evidence={ECO:0000305}; Sequence=AAH59375.2; Type=Erroneous initiation; Note=Translation N-terminally extended.; Evidence={ECO:0000305}; Sequence=BAA02054.1; Type=Erroneous initiation; Note=Translation N-terminally extended.; Evidence={ECO:0000305};
SimilarityBelongs to the nucleotide pyrophosphatase/phosphodiesterase family. {ECO:0000305}.
SimilarityContains 2 SMB (somatomedin-B) domains. {ECO:0000305}.
Subcellular LocationCell membrane; Single-pass type II membrane protein. Basolateral cell membrane; Single-pass type II membrane protein. Secreted {ECO:0000250}. Note=The proteolytically processed form is secreted (By similarity). 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. {ECO:0000250}.
SubunitThe secreted form is monomeric (By similarity). Homodimer. Interacts with INSR. {ECO:0000250, ECO:0000269|PubMed:10615944}.
Tissue SpecificityExpressed in plasma cells and also in a number of non-lymphoid tissues, including the distal convoluted tubule of the kidney, chondrocytes and epididymis. {ECO:0000269|PubMed:9344668}.
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