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ectonucleotide pyrophosphatase/phosphodiesterase family member 1; E-NPP 1; membrane component chromosome 6 surface marker 1; phosphodiesterase I/nucleotide pyrophosphatase 1; plasma-cell membrane glycoprotein PC-1; includes: alkaline phosphodiesterase I; nucleotide pyrophosphatase; NPPase (ENPP1, M6S1, NPPS, PC1, PDNP1)
Function:
- role primarily in ATP hydrolysis at the plasma membrane
- role in regulating pyrophosphate levels
- functions in bone mineralization
- in vitro, has a broad specificity, hydrolyzing other nucleoside 5' triphosphates including as GTP, CTP, TTP & UTP to their corresponding monophosphates with release of pyrophosphate & diadenosine polyphosphates
- hydrolyzes 3',5'-cAMP to AMP
- may also be involved in regulation of availability of nucleotide sugars in the endoplasmic reticulum & Golgi, & the regulation of purinergic signaling
- appears to modulate insulin sensitivity
- hydrolytically removes 5'-nucleotides successively from the 3'-hydroxy termini of 3'-hydroxy-terminated oligonucleotides
- at low concentrations of ATP, a phosphorylated intermediate is formed which inhibits further hydrolysis
- autophosphorylated as part of the catalytic cycle of phosphodiesterase/pyrophosphatase activity
Cofactor:
- binds 2 divalent metal cations per subunit (probable) homodimer; disulfide-linked
Structure:
- N-glycosylated
- the di-leucine motif is required for basolateral targeting in epithelial cells, & for targeting to matrix vesicles derived from mineralizing cells (putative)
- contains 2 SMB (somatomedin-B) domains
- 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
- belongs to the nucleotide pyrophosphatase/phosphodiesterase family
Compartment:
- membrane; single-pass type 2 membrane protein
- basolateral cell membrane
- targeted to the basolateral membrane in polarized epithelial cells & in hepatocytes, & to matrix vesicles in osteoblasts
- in bile duct cells & cancer cells, located to the apical cytoplasmic side
Expression:
- expressed in plasma cells & also in a number of non-lymphoid tissues, including the distal convoluted tubule of the kidney, chondrocytes & epididymis
Pathology:
- role in soft tissue calcification
- defects in ENPP1 are a cause of
a) increased susceptibility for ossification of the posterior longitudinal ligament of the spine
b) idiopathic infantile arterial calcification
- defects in ENPP1 are associated with metabolic syndrome X
- defects in ENPP1 are the cause of hypophosphatemic rickets, autosomal recessive type 2
Note:
- uncertain whether Met-1 or Met-53 is the initiator
General
glycoprotein
membrane protein
nucleotidase
phosphodiesterase I/nucleotide pyrophosphatase or ectonucleotide pyrophosphatase/phosphodiesterase
Properties
SIZE: entity length = 925 aa
MW = 105 kD
COMPARTMENT: cytoplasm
cellular membrane
MOTIF: Di-leucine {45-52}
transmembrane domain {77-97}
SMB 1 {104-144}
MOTIF: cysteine residue {C108}
MODIFICATION: cysteine residue {C122}
cysteine residue {C108}
MODIFICATION: cysteine residue {C112}
cysteine residue {C112}
MODIFICATION: cysteine residue {C108}
cysteine residue {C112}
MODIFICATION: cysteine residue {C140}
cysteine residue {C120}
MODIFICATION: cysteine residue {C133}
cysteine residue {C120}
MODIFICATION: cysteine residue {C122}
cysteine residue {C122}
MODIFICATION: cysteine residue {C108}
cysteine residue {C122}
MODIFICATION: cysteine residue {C120}
cysteine residue {C126}
MODIFICATION: cysteine residue {C132}
cysteine residue {C132}
MODIFICATION: cysteine residue {C126}
cysteine residue {C133}
MODIFICATION: cysteine residue {C120}
cysteine residue {C133}
MODIFICATION: cysteine residue {C140}
cysteine residue {C140}
MODIFICATION: cysteine residue {C112}
cysteine residue {C140}
MODIFICATION: cysteine residue {C133}
SMB 2 {145-189}
MOTIF: cysteine residue {C149}
MODIFICATION: cysteine residue {C166}
cysteine residue {C149}
MODIFICATION: cysteine residue {C154}
cysteine residue {C154}
MODIFICATION: cysteine residue {C149}
cysteine residue {C154}
MODIFICATION: cysteine residue {C184}
cysteine residue {C164}
MODIFICATION: cysteine residue {C177}
cysteine residue {C164}
MODIFICATION: cysteine residue {C166}
cysteine residue {C166}
MODIFICATION: cysteine residue {C149}
cysteine residue {C166}
MODIFICATION: cysteine residue {C164}
cysteine residue {C170}
MODIFICATION: cysteine residue {C176}
cysteine residue {C176}
MODIFICATION: cysteine residue {C170}
cysteine residue {C177}
MODIFICATION: cysteine residue {C164}
cysteine residue {C177}
MODIFICATION: cysteine residue {C184}
N-glycosylation site {N179}
cysteine residue {C184}
MODIFICATION: cysteine residue {C154}
cysteine residue {C184}
MODIFICATION: cysteine residue {C177}
Phosphodiesterase {191-591}
MOTIF: threonine residue {T256}
N-glycosylation site {N285}
N-glycosylation site {N341}
N-glycosylation site {N477}
cysteine residue {C480}
MODIFICATION: cysteine residue {C868}
N-glycosylation site {N585}
N-glycosylation site {N643}
Nuclease {654-925}
MOTIF: N-glycosylation site {N700}
N-glycosylation site {N731}
N-glycosylation site {N748}
cysteine residue {C868}
MODIFICATION: cysteine residue {C480}
lysine residue {915}
Database Correlations
OMIM correlations
MORBIDMAP 173335
UniProt P22413
PFAM correlations
Entrez Gene 5167
KEGG correlations
ENZYME correlations
References
UniProt :accession P22413