Nucleotide pyrophosphatase that generates diphosphate (PPi) and functions in bone mineralization and soft tissue calcification by regulating pyrophosphate levels (PubMed:9662402, PubMed:10352096, PubMed:11004006, PubMed:12082181, PubMed:22510396, PubMed:25260930). PPi inhibits bone mineralization and soft tissue calcification by binding to nascent hydroxyapatite crystals, thereby preventing further growth of these crystals (PubMed:9662402, PubMed:10352096, PubMed:11004006, PubMed:12082181, PubMed:19419305, PubMed:22510396, PubMed:25260930, PubMed:25479107, PubMed:26910915, PubMed:30111653). Preferentially hydrolyzes ATP, but can also hydrolyze other nucleoside 5' triphosphates such as GTP, CTP and UTP to their corresponding monophosphates with release of pyrophosphate, as well as diadenosine polyphosphates, and also 3',5'-cAMP to AMP (PubMed:11027689, PubMed:1647027, PubMed:23027977, PubMed:8223581). 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:1647027). Inhibits ectopic joint calcification and maintains articular chondrocytes by repressing hedgehog signaling; it is however unclear whether hedgehog inhibition is direct or indirect (PubMed:30111653). Appears to modulate insulin sensitivity (By similarity). Also involved in melanogenesis (By similarity). 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 (By similarity). Not able to hydrolyze the 2',3'-cGAMP linkage isomer 3',3'-cGAMP (By similarity). Hydrolytically removes 5'-nucleotides successively from the 3'-hydroxy termini of 3'-hydroxy-terminated oligonucleotides. a ribonucleoside 5'-triphosphate + H2O = a ribonucleoside 5'-phosphate + diphosphate + H(+) ATP + H2O = AMP + diphosphate + H(+) H2O + UTP = diphosphate + H(+) + UMP GTP + H2O = diphosphate + GMP + H(+) CTP + H2O = CMP + diphosphate + H(+) 2',3'-cGAMP + 2 H2O = AMP + GMP + 2 H(+) H2O + P(1),P(4)-bis(5'-adenosyl) tetraphosphate = AMP + ATP + 2 H(+) 3',5'-cyclic AMP + H2O = AMP + H(+) Binds 2 Zn(2+) ions per subunit. At low concentrations of ATP, a phosphorylated intermediate is formed which inhibits further hydrolysis. kcat is 16 sec(-1) with ATP as substrate. kcat is 200 sec(-1) with UTP as substrate. kcat is 820 sec(-1) with GTP as substrate. kcat is 8.7 sec(-1) with CTP as substrate. Ectonucleotide pyrophosphatase/phosphodiesterase family member 1: Homodimer (PubMed:23027977, PubMed:23041369). Ectonucleotide pyrophosphatase/phosphodiesterase family member 1: Interacts with INSR; leading to inhibit INSR autophosphorylation and subsequent activation of INSR kinase activity (By similarity). Ectonucleotide pyrophosphatase/phosphodiesterase family member 1, secreted form: Monomeric (PubMed:23041369). Targeted to the basolateral membrane in polarized epithelial cells and in hepatocytes, and to matrix vesicles in osteoblasts. Secreted following proteolytic cleavage. Selectively expressed on the surface of antibody-secreting cells (PubMed:3104326). Expressed in osteocytes and osteoclasts (PubMed:25260930). The di-leucine motif is required for basolateral targeting in polarized epithelial cells, and for targeting to matrix vesicles derived from mineralizing cells. N-glycosylated. The secreted form is produced through cleavage at Lys-85 by intracellular processing. Defects in Enpp1 are the cause of the tiptoe walking (ttw) phenotype. Ttw mice exhibit ossification of the spinal ligaments (PubMed:9662402). Mice display increased bone formation process in joints and develop spontaneous osteoarthritis-like changes (PubMed:22510396). Defects in Enpp1 are the cause of spontaneous asj-2J mutant characterized by gait due to stiffening of the joints (PubMed:25479107). Defects are caused by a significant reduction in the plasma diphosphate (PPi) concentration, leading to extensive aberrant mineralization affecting the arterial vasculature, a number of internal organs and the dermal sheath of vibrissae (PubMed:25479107). Asj-2J mice are used as a model for arterial calcification of infancy disorder (GACI1) (PubMed:25479107). Mice also show ectopic mineralization of cartilage and collagen-rich tendons and ligaments (PubMed:26910915). Mice show ectopic calcification of articular cartilage, the joint capsule and certain tendons (PubMed:25260930). Mice also display calcification of the joints and vertebrae as well as soft tissues including the whisker follicles, ear pinna and trachea (PubMed:25260930). This calcification worsened as the animals aged (PubMed:25260930). Bone mineralization in mice lacking both Enpp1 and Alpl is essentially normal, demonstrating that Enpp1 and Alpl are antagonist key regulators of bone mineralization by determining the normal steady-state levels of diphosphate (PPi) (PubMed:12082181). Belongs to the nucleotide pyrophosphatase/phosphodiesterase family. It is uncertain whether Met-1 or Met-35 is the initiator.