The nuclease-like domain is most probably catalytically inactive as residues that are essential for catalysis in the DNA/RNA non-specific endonucleases are not conserved. However, it is required for the stability of the protein and the catalytic activity born by the phosphodiesterase domain.
The di-leucine motif is required for basolateral targeting in polarized epithelial cells, and for targeting to matrix vesicles derived from mineralizing cells.
Nucleotide pyrophosphatase that generates diphosphate (PPi) and functions in bone mineralization and soft tissue calcification by regulating pyrophosphate levels (PubMed:10352096, PubMed:11004006, PubMed:12082181, PubMed:22510396, PubMed:25260930, PubMed:9662402). PPi inhibits bone mineralization and soft tissue calcification by binding to nascent hydroxyapatite crystals, thereby preventing further growth of these crystals (PubMed:10352096, PubMed:11004006, PubMed:12082181, PubMed:19419305, PubMed:22510396, PubMed:25260930, PubMed:25479107, PubMed:26910915, PubMed:30111653, PubMed:35147247, PubMed:9662402). 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).
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).
N-glycosylated.
The secreted form is produced through cleavage at Lys-85 by intracellular processing.
Belongs to the nucleotide pyrophosphatase/phosphodiesterase family.
Selectively expressed on the surface of antibody-secreting cells (PubMed:3104326). Expressed in osteocytes and osteoclasts (PubMed:25260930).
Npps, Pc1, Pdnp1, Enpp1, Ectonucleotide pyrophosphatase/phosphodiesterase family member 1, E-NPP 1, Alkaline phosphodiesterase I, Lymphocyte antigen 41, Nucleotide diphosphatase, Nucleotide pyrophosphatase, Phosphodiesterase I/nucleotide pyrophosphatase 1, Plasma-cell membrane glycoprotein PC-1, Ly-41, NPPase
Proteins
Metabolism
103176Da
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