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EC Tree
IUBMB Comments The enzyme preferentially hydrolyses ATP, but can also hydrolyse other nucleoside 5' triphosphates such as GTP, CTP, TTP and UTP to their corresponding monophosphates. In vitro the enzyme also acts as a nucleotidohydrolase on ADP, NAD+, NADP+, FAD, and CoA.
The taxonomic range for the selected organisms is: Mus musculus The enzyme appears in selected viruses and cellular organisms
Synonyms
npp, cd203c, itpase, inosine triphosphatase, inosine triphosphate pyrophosphatase, maf protein, enpp3, nppase, e-npp, nucleoside triphosphate pyrophosphohydrolase,
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nucleotide pyrophosphatase
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nucleoside triphosphate diphosphatase
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nucleoside-triphosphate pyrophosphatase
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nucleotide pyrophosphatase
nucleotide pyrophosphatase/phosphodiesterase 1
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nucleotide pyrophosphatase/phosphodiesterase NPP1
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nucleotide pyrophosphatase/phosphodiesterase-1
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nucleotide pyrophosphatase/phosphodiesterase-I
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nucleotide pyrophosphohydrolase
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nucleotide-sugar pyrophosphatase
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plasma cell membrane glycoprotein-1
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pyrophosphatase, nucleoside triphosphate
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additional information
see also EC 3.1.4.1
NPP1
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nucleotide pyrophosphatase
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nucleotide pyrophosphatase
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hydrolysis of phosphoric ester
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dinucleotide nucleotidohydrolase
The enzyme preferentially hydrolyses ATP, but can also hydrolyse other nucleoside 5' triphosphates such as GTP, CTP, TTP and UTP to their corresponding monophosphates. In vitro the enzyme also acts as a nucleotidohydrolase on ADP, NAD+, NADP+, FAD, and CoA.
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4-nitrophenyl phosphate + H2O
4-nitrophenol + phosphate
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-
-
-
?
4-nitrophenyl phosphate dianion + H2O
4-nitrophenol + phosphate
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-
-
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?
4-nitrophenyl phosphate monoanion + H2O
4-nitrophenol + phosphate
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72fold higher activity than with 4-nitrophenyl phosphate dianion
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-
?
4-nitrophenyl-5'-thymidine monophosphate + H2O
4-nitrophenol + 5'-thymidine monophosphate
artificial substrate
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-
?
4-nitrophenyl-TMP + H2O
4-nitrophenol + TMP
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?
ADP + H2O
AMP + phosphate
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-
?
ATP + H2O
AMP + diphosphate
bis-4-nitrophenyl phosphate + H2O
4-nitrophenol + phosphate
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2000fold higher activity than with 4-nitrophenyl phosphate dianion
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?
CTP + H2O
CMP + diphosphate
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?
diphosphate + H2O
phosphate
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?
GTP + H2O
GMP + diphosphate
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?
methyl 4-nitrophenyl phosphate + H2O
4-nitrophenol + methyl phosphate
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200fold higher activity than with 4-nitrophenyl phosphate dianion
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?
NAD+ + H2O
NMN + AMP
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?
NADH + H2O
NMNH + AMP
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?
p-nitrophenyl 5'-thymidine monophosphate + H2O
4-nitrophenol + TMP
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1500000fold higher activity than with 4-nitrophenyl phosphate dianion
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?
p-nitrophenyl phenylphosphonate + H2O
p-nitrophenol + phenylphosphonate
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phosphodiesterase-1 activity
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?
p-nitrophenyl thymidine 5'-monophosphate + H2O
?
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?
p-nitrophenyl-dTMP + H2O
p-nitrophenol + dTMP
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Ca2+-dependent
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?
UDP-alpha-D-galactose + H2O
UMP + alpha-D-galactose-1-phosphate
UDP-N-acetyl-alpha-D-glucosamine + H2O
UMP + N-acetyl-alpha-D-glucosaminyl-1-phosphate
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?
UTP + H2O
UMP + diphosphate
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?
additional information
?
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ATP + H2O
AMP + diphosphate
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?
ATP + H2O
AMP + diphosphate
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?
ATP + H2O
AMP + diphosphate
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?
ATP + H2O
AMP + diphosphate
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?
UDP-alpha-D-galactose + H2O
UMP + alpha-D-galactose-1-phosphate
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?
UDP-alpha-D-galactose + H2O
UMP + alpha-D-galactose-1-phosphate
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?
additional information
?
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functional enzyme is required in carminerin-deficiency to suppress the resulting pathological endochondral ossifications
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?
additional information
?
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the enzyme does not hydrolyze pyridoxal 5'-phosphate
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?
additional information
?
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NPP1 hydrolyzes a wide range of phosphodiester bonds, e.g. in nucleoside triphosphates, (cyclic) dinucleotides, and nucleotide sugars yielding nucleoside 5'-monophosphates as products. Its main substrate is ATP which is cleaved to AMP and diphosphate. Purine nucleotides (ATP and GTP) are better substrates than pyrimidine nucleotides (CTP and UTP)
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ATP + H2O
AMP + diphosphate
CTP + H2O
CMP + diphosphate
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?
GTP + H2O
GMP + diphosphate
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?
NAD+ + H2O
NMN + AMP
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?
NADH + H2O
NMNH + AMP
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?
UDP-alpha-D-galactose + H2O
UMP + alpha-D-galactose-1-phosphate
UDP-N-acetyl-alpha-D-glucosamine + H2O
UMP + N-acetyl-alpha-D-glucosaminyl-1-phosphate
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?
UTP + H2O
UMP + diphosphate
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additional information
?
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functional enzyme is required in carminerin-deficiency to suppress the resulting pathological endochondral ossifications
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ATP + H2O
AMP + diphosphate
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ATP + H2O
AMP + diphosphate
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ATP + H2O
AMP + diphosphate
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?
UDP-alpha-D-galactose + H2O
UMP + alpha-D-galactose-1-phosphate
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?
UDP-alpha-D-galactose + H2O
UMP + alpha-D-galactose-1-phosphate
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?
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CaCl2
2-5 mM restores activity of EDTA-inhibited enzyme
MgCl2
2-5 mM partially restores activity of EDTA-inhibited enzyme
ZnCl2
2-5 mM restores activity of EDTA-inhibited enzyme
Ca2+
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2fold activation at 10 mM
Mg2+
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2fold activation at 10 mM
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EDTA
activity can be restored by addition of 2-5 mM ZnCl2 or CaCl2, but only partially by 2-5 mM MgCl2
EDTA
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strong inhibition at 1 mM, partially reversed by Mg2+, complete reactivation at 10 mM Ca2+
EGTA
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strong inhibition at 1 mM, partially reversed by Mg2+, complete reactivation at 10 mM Ca2+
UDP-galactose
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competitive inhibition, Ki: 29 mM
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0.21
4-nitrophenyl-5'-thymidine monophosphate
pH and temperature not specified in the publication, liver enzyme
0.046
ATP
pH and temperature not specified in the publication
1.2
CTP
pH and temperature not specified in the publication
4.2
GTP
pH and temperature not specified in the publication
0.11
p-nitrophenyl 5'-thymidine monophosphate
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25°C, pH 8.0
21
p-nitrophenyl deoxyTMP
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4.3
UTP
pH and temperature not specified in the publication
additional information
additional information
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additional information
additional information
kinetic analysis
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additional information
additional information
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substrate methyl 4-nitrophenyl phosphate, KM-value greater than 2 mM, substrate bis-4-nitrophenyl phosphate, KM-value greater than 1 mM
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16
ATP
pH and temperature not specified in the publication
8.7
CTP
pH and temperature not specified in the publication
820
GTP
pH and temperature not specified in the publication
200
UTP
pH and temperature not specified in the publication
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347.8
ATP
pH and temperature not specified in the publication
7.25
CTP
pH and temperature not specified in the publication
195.2
GTP
pH and temperature not specified in the publication
46.5
UTP
pH and temperature not specified in the publication
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29
UDP-galactose
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competitive inhibition
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SwissProt
brenda
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brenda
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deficient in carminerin, encoded by Cst10. Functional enzyme is required in carminerin-deficiency to suppress the resulting pathological endochondral ossifications
brenda
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brenda
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enzyme knockout osteoblast cell
brenda
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brenda
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brenda
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brenda
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isoform NPP1, enriched in matrix vesicles
brenda
NPP1 is a homodimeric type II transmembrane glycoprotein with an N-terminal transmembrane domain
brenda
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brenda
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brenda
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surface membrane
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evolution
ecto-nucleotide pyrophosphatase/phosphodiesterase 1 (NPP1) is a metalloenzyme that belongs to the NPP family, which comprises seven subtypes (NPP1-7)
physiological function
the enzyme is involved in various biological processes including bone mineralization, soft tissue calcification, insulin receptor signalling, cancer cell proliferation and immune modulation
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ENPP5_MOUSE
477
0
54387
Swiss-Prot
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120000
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2 * 120000, reducing SDS-PAGE
130000
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gel filtration, SDS-PAGE
240000
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non-reducing SDS-PAGE
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dimer
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2 * 120000, reducing SDS-PAGE
homodimer
NPP1 is a homodimeric type II transmembrane glycoprotein characterized by an N-terminal transmembrane domain, two somatomedin-B-like domains, a catalytic domain and a C-terminal nuclease-like domain
monomer
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1 * 130000, SDS-PAGE
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phosphoprotein
mutations D358N and H362Q still allow a weak labeling, whereas mutation His517, Asp200, Asp405 and His406 completely abolish autophosphorylation in presence of ATP
phosphoprotein
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autophosphorylation
glycoprotein
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5% neutral sugar content, glucosamine, sialic acid, glucose, galactose, mannose, fucose
glycoprotein
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N-linked oligosaccharides, human 120 kDa-precursor form possesses high-mannose oligosaccharides, which disappear in the mature 130 kDa form
glycoprotein
NPP1 is a homodimeric type II transmembrane glycoprotein
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in absence of ligands and in complex with vanadate or AMP. Comparison of bimetallo active site with Escherichia coli alkaline phosphatase
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D200N
mutation abolishes formation of the nucleotidylated intermediate
D358N
mutant enzyme can still form nucleotidylated catalytic intermediates but is hampered in the second step of catalysis
F239A
mutation halves activity, decreased ability to trap the catalytic intermediate
F239Q
decreased activity and level of covalent intermediate of the mutant may be accounted for by a decreased binding of the substrate
H362Q
mutant enzyme can still form nucleotidylated catalytic intermediates but is hampered in the second step of catalysis
H406Q
mutation abolishes formation of the nucleotidylated intermediate
K237A
mutation halves activity
T238S
mutant enzyme can still form nucleotidylated catalytic intermediates but is hampered in the second step of catalysis
DELTA804-905
mutation results in complete loss of activity, protein remains entirely intracellular
H242L
60% decrease in enzymic acitivity
H242L/V246A
60% decrease in enzymic acitivity
K173Q
polymorphisms of NPP1 is associated with the aetiology of insulin resistance, does not affect the dimerization or catalytic activity of NPP1 and does not endow NPP1 with an affinity for the insulin receptor
V246A
40% decrease in enzymic acitivity
additional information
chimera of enzyme catalytic domain fused to the N- and C-terminal domains of rat NPP2, a lysophospholipase D enzyme. Chimera is hyperactive in enzymic activity, but shows no lysophospholipase D activity. Second chimera of enzyme N- and/or C-terminal domains fused to the catalytic domain of NPP2 is completely inactive
additional information
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enzyme knockout osteoblast cells, about 80% depletion of enzyme activity in matrix vesicles. Transfection of SaOS-2 cells with chimeras of enzyme membrane isoform NPP1 and isoform NPP3, which is not transferred to matrix vesicles. The AASLLAP motif in the cytosolic tail of NPP1 is required for its localization to matrix vesicles and also directs chimeric NPP3 to matrix vesicles
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slight loss of activity if repeated freezed and thawed
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to homogeneity, chromatography techniques
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mutants expressed in COS-1 cells
expressed in COS-1 cells
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expression in Cos-7 and mouse Ltk- cells
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wild-type enzyme NPP1 and NPP1-DELTA804-905 is expressed in COS cells as fusions with enhanced green fluorescent protein
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Belli, S.I.; Goding, J.W.
Biochemical characterization of human PC-1, an enzyme possessing alkaline phosphodiesterase I and nucleotide pyrophosphatase activities
Eur. J. Biochem.
226
433-443
1994
Homo sapiens, Mus musculus
brenda
Abney, E.R.; Evans, W.H.; Parkhouse, R.M.E.
Location of nucleotide pyrophosphatase and alkaline phosphodiesterase activities on the lymphocyte surface membrane
Biochem. J.
159
293-299
1976
Mus musculus
brenda
Evans, W.H.; Hood, D.; Gurd, J.W.
Purification and properties of a mouse liver plasma-membrane glycoprotein hydrolysing nucleotide pyrophosphate and phosphodiester bonds
Biochem. J.
135
819-826
1973
Mus musculus
brenda
Gijsbers, R.; Ceulemans, H.; Bollen, M.
Functional characterization of the non-catalytic ectodomains of the nucleotide pyrophosphatase/phosphodiesterase NPP1
Biochem. J.
371
321-330
2003
Mus musculus (P06802)
brenda
Gijsbers, R.; Ceulemans, H.; Stalmans, W.; Bollen, M.
Structural and catalytic similarities between nucleotide pyrophosphatases/phosphodiesterases and alkaline phosphatases
J. Biol. Chem.
276
1361-1368
2001
Mus musculus (Q9EQG7)
brenda
Vaingankar, S.M.; Fitzpatrick, T.A.; Johnson, K.; Goding, J.W.; Maurice, M.; Terkeltaub, R.
Subcellular targeting and function of osteoblast nucleotide pyrophosphatase phosphodiesterase 1
Am. J. Physiol.
286
C1177-C1187
2004
Homo sapiens, Mus musculus
brenda
Cimpean, A.; Stefan, C.; Gijsbers, R.; Stalmans, W.; Bollen, M.
Substrate-specifying determinants of the nucleotide pyrophosphatases/phosphodiesterases NPP1 and NPP2
Biochem. J.
381
71-77
2004
Mus musculus (P06802)
brenda
Zalatan, J.G.; Fenn, T.D.; Brunger, A.T.; Herschlag, D.
Structural and functional comparisons of nucleotide pyrophosphatase/phosphodiesterase and alkaline phosphatase: implications for mechanism and evolution
Biochemistry
45
9788-9803
2006
Mus musculus
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Yamada, T.; Kawano, H.; Koshizuka, Y.; Fukuda, T.; Yoshimura, K.; Kamekura, S.; Saito, T.; Ikeda, T.; Kawasaki, Y.; Azuma, Y.; Ikegawa, S.; Hoshi, K.; Chung, U.I.; Nakamura, K.; Kato, S.; Kawaguchi, H.
Carminerin contributes to chondrocyte calcification during endochondral ossification
Nat. Med.
12
665-670
2006
Mus musculus
brenda
Simao, A.M.; Yadav, M.C.; Narisawa, S.; Bolean, M.; Pizauro, J.M.; Hoylaerts, M.F.; Ciancaglini, P.; Millan, J.L.
Proteoliposomes harboring alkaline phosphatase and nucleotide pyrophosphatase as matrix vesicle biomimetics
J. Biol. Chem.
285
7598-7609
2010
Mus musculus
brenda
Lee, S.Y.; Mueller, C.E.
Nucleotide pyrophosphatase/phosphodiesterase 1 (NPP1) and its inhibitors
MedChemComm
8
823-840
2017
Mus musculus (P06802), Homo sapiens (P22413), Homo sapiens, Rattus norvegicus (Q924C3)
brenda