ENPP1

This gene is a member of the ecto-nucleotide pyrophosphatase/phosphodiesterase (ENPP) family. The encoded protein is a type II transmembrane glycoprotein comprising two identical disulfide-bonded subunits. This protein has broad specificity and cleaves a variety of substrates, including phosphodiester bonds of nucleotides and nucleotide sugars and pyrophosphate bonds of nucleotides and nucleotide sugars. This protein may function to hydrolyze nucleoside 5' triphosphates to their corresponding monophosphates and may also hydrolyze diadenosine polyphosphates. Mutations in this gene have been associated with 'idiopathic' infantile arterial calcification, ossification of the posterior longitudinal ligament of the spine (OPLL), and insulin resistance. [provided by RefSeq, Jul 2008]

Ectonucleotide Pyrophosphatase/Phosphodiesterase 1

Nucleotide pyrophosphatase that generates diphosphate (PPi) and functions in bone mineralization and soft tissue calcification by regulating pyrophosphate levels (By similarity).

PPi inhibits bone mineralization and soft tissue calcification by binding to nascent hydroxyapatite crystals, thereby preventing further growth of these crystals (PubMed:11004006).

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 (PubMed:27467858, PubMed:8001561, PubMed:25344812).

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 (PubMed:27467858, PubMed:8001561).

Inhibits ectopic joint calcification and maintains articular chondrocytes by repressing hedgehog signaling; it is however unclear whether hedgehog inhibition is direct or indirect (By similarity).

Appears to modulate insulin sensitivity and function (PubMed:10615944).

Also involved in melanogenesis (PubMed:28964717).

Also able to hydrolyze 2'-3'-cGAMP (cyclic GMP-AMP), a second messenger that activates TMEM173/STING and triggers type-I interferon production (PubMed:25344812).

2'-3'-cGAMP degradation takes place in the lumen or extracellular space, and not in the cytosol where it is produced; the role of 2'-3'-cGAMP hydrolysis is therefore unclear (PubMed:25344812).

Not able to hydrolyze the 2'-3'-cGAMP linkage isomer 3'-3'-cGAMP (PubMed:25344812).

3'-phosphoadenosine 5'-phosphosulfate metabolic process Source: BHF-UCL
ATP metabolic process Source: UniProtKB
Biomineral tissue development Source: UniProtKB-KW
Cellular phosphate ion homeostasis Source: BHF-UCL
Cellular response to insulin stimulus Source: BHF-UCL
Generation of precursor metabolites and energy Source: BHF-UCL
Immune response Source: InterPro
Inorganic diphosphate transport Source: BHF-UCL
Melanocyte differentiation Source: UniProtKB
Negative regulation of bone mineralization Source: UniProtKB
Negative regulation of cell growth Source: BHF-UCL
Negative regulation of fat cell differentiation Source: BHF-UCL
Negative regulation of glucose import Source: BHF-UCL
Negative regulation of glycogen biosynthetic process Source: BHF-UCL
Negative regulation of hh target transcription factor activity Source: UniProtKB
Negative regulation of insulin receptor signaling pathway Source: BHF-UCL
Negative regulation of protein autophosphorylation Source: BHF-UCL
Nucleic acid phosphodiester bond hydrolysis Source: UniProtKB
Nucleoside triphosphate catabolic process Source: BHF-UCL
Phosphate-containing compound metabolic process Source: BHF-UCL
Regulation of bone mineralization Source: GO_Central
Sequestering of triglyceride Source: BHF-UCL

Ectonucleotide pyrophosphatase/phosphodiesterase family member 1: Cell membrane; Basolateral cell membrane. Targeted to the basolateral membrane in polarized epithelial cells and in hepatocytes, and to matrix vesicles in osteoblasts (PubMed:11598187). In bile duct cells and cancer cells, located to the apical cytoplasmic side (PubMed:11598187).
Ectonucleotide pyrophosphatase/phosphodiesterase family member 1, secreted form: Secreted. Secreted following proteolytic cleavage.

Ossification of the posterior longitudinal ligament of the spine (OPLL):
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.
Arterial calcification of infancy, generalized, 1 (GACI1):
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.
Diabetes mellitus, non-insulin-dependent (NIDDM):
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.
Hypophosphatemic rickets, autosomal recessive, 2 (ARHR2):
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.
Cole disease (COLED):
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.

Cytoplasmic: 1-76
Helical: 77-97
Extracellular: 98-925

Autophosphorylated as part of the catalytic cycle of phosphodiesterase/pyrophosphatase activity.
N-glycosylated.
The secreted form is produced through cleavage at Lys-103 by intracellular processing.