Information on EC 3.4.21.B1 - hyaluronan-binding serine protease

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The enzyme appears in viruses and cellular organisms

EC NUMBER
COMMENTARY hide
3.4.21.B1
preliminary BRENDA-supplied EC number
RECOMMENDED NAME
GeneOntology No.
hyaluronan-binding serine protease
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REACTION
REACTION DIAGRAM
COMMENTARY hide
ORGANISM
UNIPROT
LITERATURE
endopeptidase activity. Cleaves C-terminal site of Lys and Arg
show the reaction diagram
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REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
cleavage of C-N-linkage
hydrolysis of peptide bond
CAS REGISTRY NUMBER
COMMENTARY hide
246521-08-4
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ORGANISM
COMMENTARY hide
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
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Manually annotated by BRENDA team
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Manually annotated by BRENDA team
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Manually annotated by BRENDA team
gene HABP2; gene HABP2
UniProt
Manually annotated by BRENDA team
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
evolution
the active site residues of a serine proteinase are conserved in the serine protease domain of the enzyme. The enzyme has a similar domain structure and tissue distribution to those of human hyaluronan binding protein 2 (HABP2), putative phylogenetic tree
malfunction
-
the variant Marburg I polymorphism results in low enzymatic activity and is associated with an enhanced risk of carotid stenosis and stroke
physiological function
SUBSTRATE
PRODUCT                       
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
basic fibroblast growth factor + H2O
?
show the reaction diagram
benzoyl-Ile-Glu(gamma-OR)-Gly-Arg-4-nitroanilide + H2O
benzoyl-Ile-Glu(gamma-OR)-Gly-Arg + 4-nitroaniline
show the reaction diagram
i.e. A-2222, weak chromogenic substrate
-
?
CH2SO2-D-cyclohexylalanine-butanoyl-Arg-4-nitroanilide + H2O
CH2SO2-D-cyclohexylalanine-butanoyl-Arg + 4-nitroaniline
show the reaction diagram
i.e. Pefa-5979, chromogenic substrate
-
?
CH2SO2-D-cyclohexylglycine-Gly-Arg-4-nitroanilide
CH2SO2-D-cyclohexylglycine-Gly-Arg + 4-nitroaniline
show the reaction diagram
i.e. Pefa-3107, chromogenic substrate
-
?
CH3-OCO-D-cyclohexylalanine-Gly-Arg-4-nitroanilide + H2O
CH3-OCO-D-cyclohexylalanine-Gly-Arg + 4-nitroaniline
show the reaction diagram
i.e. Pefa-5523, chromogenic substrate
-
?
coagulation factor FVII + H2O
?
show the reaction diagram
-
-
-
?
CTCF + H2O
?
show the reaction diagram
D-Ala-cyclohexyltyrosine-Lys-4-nitroanilide + H2O
D-Ala-cyclohexyltyrosine-Lys + 4-nitroaniline
show the reaction diagram
i.e. Pefa-5329, weak chromogenic substrate
-
?
D-cyclohexylglycine-Ala-Arg-4-nitroanilide + H2O
D-cyclohexylglycine-Ala-Arg + 4-nitroaniline
show the reaction diagram
i.e. Pefa-5114, good chromogenic substrate
-
?
D-isoleucyl-L-prolyl-L-arginine-p-nitroanilide + H2O
?
show the reaction diagram
-
-
-
-
?
D-Lys(benzyloxycarbonyl)-Pro-Arg-4-nitroanilide + H2O
D-Lys(benzyloxycarbonyl)-Pro-Arg + 4-nitroaniline
show the reaction diagram
i.e. Pefa-5773, chromogenic substrate
-
?
D-Phe-Pip-Arg-4-nitroanilide + H2O
D-Phe-Pip-Arg + 4-nitroaniline
show the reaction diagram
i.e. S-2238, chromogenic substrate
-
?
DL-pyroglutamic acid-cyclohexylglycine-Arg-4-nitroanilide + H2O
DL-pyroglutamic acid-cyclohexylglycine-Arg + 4-nitroaniline
show the reaction diagram
i.e. Pefa-3297, good chromogenic substrate
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?
factor V + H2O
?
show the reaction diagram
factor VII + H2O
?
show the reaction diagram
factor VII + H2O
activated factor VII + ?
show the reaction diagram
factor VIII + H2O
?
show the reaction diagram
fibrinogen + ?
?
show the reaction diagram
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cleaves the alpha-chain at multiple sites and the beta-chain between lysine53 and lysine54 but not the gamma-chain
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?
Fibrinogen + H2O
?
show the reaction diagram
fibroblast growth factor receptor 1 + H2O
?
show the reaction diagram
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HABP activates the p44/42-dependent MAPK (ERK1/2) signalling cascade independent of the B2-receptor, involving the fibroblast growth factor receptor-1 and basic fibroblast growth factor. This signalling pathway leads to phosphorylation of the kinases Raf, MEK1/2 and ERK1/2
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?
fibronectin + ?
?
show the reaction diagram
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?
Fibronectin + H2O
?
show the reaction diagram
high molecular weight kininogen + H2O
activated cofactor kininogen + bradykinin
show the reaction diagram
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activates kininogen
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?
high molecular weight kininogen + H2O
low molecular weight kininogen + bradykinin
show the reaction diagram
high molecular weight kininogen profactor + H2O
activated kininogen + bradykinin
show the reaction diagram
kininogen + H2O
bradykinin + ?
show the reaction diagram
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-
-
?
L-pyroglutamic acid-cyclo-hexylglycine-Arg-para-nitroanilide mono-acetate + H2O
?
show the reaction diagram
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P-3342, fluorogenic substrate
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?
L-pyroglutamic acid-Pro-Arg-4-nitroanilide + H2O
L-pyroglutamic acid-Pro-Arg + 4-nitroaniline
show the reaction diagram
i.e. S-2366, chromogenic substrate
-
?
L-pyroglutamylglycyl-L-arginine-p-nitroanilide + H2O
L-pyroglutamylglycyl-L-arginine + p-nitroaniline
show the reaction diagram
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-
?
low molecular weight kininogen + H2O
bradykinin + ?
show the reaction diagram
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-
?
N-tert-butoxycarbonyl-Phe-Ser-Arg-7-amido-4-methylcoumarin + H2O
N-tert-butoxycarbonyl-Phe-Ser-Arg + 7-amino-4-methylcoumarin
show the reaction diagram
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synthetic substrate
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?
plasminogen activator precursor + H2O
?
show the reaction diagram
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?
platelet derived growth factor-AA + H2O
?
show the reaction diagram
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?
platelet derived growth factor-BB + H2O
?
show the reaction diagram
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?
platelet-derived growth factor-BB + H2O
?
show the reaction diagram
pro-uPA + H2O
?
show the reaction diagram
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-
-
-
?
pro-uPa + H2O
uPa
show the reaction diagram
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-
?
Protein + H2O
?
show the reaction diagram
prourokinase + H2O
?
show the reaction diagram
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-
-
?
prourokinase + H2O
urokinase + ?
show the reaction diagram
S-2288 + H2O
?
show the reaction diagram
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-
-
-
?
single chain urokinase type plasminogen activator + H2O
two chain urokinase type plasminogen activator
show the reaction diagram
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?
Spectrozyme TH + H2O
? + 4-nitroaniline
show the reaction diagram
tissue factor pathway inhibitor + H2O
?
show the reaction diagram
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the enzyme inhibits tissue factor pathway inhibitor, cleavage occurs between kringle domains K1 and K2 (Lys86-Thr87), as well as in the active site of K2 (Arg107-Gly108) and K3 (Arg199-Ala200) domains
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?
tissue type plasminogen activator + H2O
?
show the reaction diagram
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?
transcription factor of amyloid beta protein precursor + H2O
?
show the reaction diagram
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?
urinary plasminogen activator + ?
?
show the reaction diagram
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converts the inactive single chain urinary plasminogen activator to the active two chain form
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?
vacular endothelial cell growth factor + H2O
?
show the reaction diagram
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?
Vitronectin + H2O
?
show the reaction diagram
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?
Z-D-Arg-Gly-Arg-4-nitroanilide + H2O
Z-D-Arg-Gly-Arg + 4-nitroaniline
show the reaction diagram
i.e. S-2765, good chromogenic substrate
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?
additional information
?
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NATURAL SUBSTRATES
NATURAL PRODUCTS
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
factor VII + H2O
activated factor VII + ?
show the reaction diagram
fibrinogen + ?
?
show the reaction diagram
-
cleaves the alpha-chain at multiple sites and the beta-chain between lysine53 and lysine54 but not the gamma-chain
-
?
Fibrinogen + H2O
?
show the reaction diagram
fibronectin + ?
?
show the reaction diagram
-
-
-
?
Fibronectin + H2O
?
show the reaction diagram
-
-
-
-
?
high molecular weight kininogen profactor + H2O
activated kininogen + bradykinin
show the reaction diagram
platelet-derived growth factor-BB + H2O
?
show the reaction diagram
-
the enzyme inhibits platelet-derived growth factor-BB
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?
Protein + H2O
?
show the reaction diagram
prourokinase + H2O
urokinase + ?
show the reaction diagram
tissue factor pathway inhibitor + H2O
?
show the reaction diagram
-
the enzyme inhibits tissue factor pathway inhibitor, cleavage occurs between kringle domains K1 and K2 (Lys86-Thr87), as well as in the active site of K2 (Arg107-Gly108) and K3 (Arg199-Ala200) domains
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?
additional information
?
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METALS and IONS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
Ca2+
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strong dependence, 3.5-4fold increase of activity at 1 mM
Mg2+
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activates at 2 mM
Mn2+
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activates at 2 mM
INHIBITORS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
alpha1-proteinase
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less efficient inhibition
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Alpha1-proteinase inhibitor
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alpha2 antiplasmin
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inhibits autoactivation at physiological concentrations
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alpha2-antiplasmin
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alpha2-Plasmin inhibitor
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antithrombin
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Aprotinin
C1 esterase inhibitor
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inhibits autoactivation at physiological concentrations
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C1 inhibitor
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C1-esterase inhibitor
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less efficient inhibition
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C1-inhibitor
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potent inhibitor
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Co2+
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inhibits at 2 mM
Cu2+
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inhibits at 2 mM
inhibitor C1
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C1 inhibitor of the serpin family, forms a complex with the enzyme, 50% inhibition at 0.001 mg/ml
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inter-alpha-trypsin inhibitor
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KPI domain of amyloid-beta precursor protein
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leupeptin
phenylmethylsulfonyl fluoride
plasminogen activator inhibitor-1
PPACK
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potent serine protease inhibitor, inhibits autoactivation at physiological concentrations
Protease nexin-1
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additional information
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ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
chondroitin sulfate
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increases kininogen cleavage at above 1 mg/ml
Dextran sulfate
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heparan sulfate
heparin
histone
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histones H1, H2A, H2B, H3, and H4 promote pro-plasma hyaluronan-binding protein autoactivation in vivo. Histones do not affect enzymatic activity of the active form of plasma hyaluronan-binding protein
hyaluronic acid
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activates single-chain inactivate zymogen to the two-chain active enzyme
IL-6
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stimulates FSAP mRNA expression 5.5fold at 24 h
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IL-8
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can stimulate the expression of HABP mRNA in lung microvascular endothelial cells and in bronchial epithelial cells
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IL-alpha
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stimulates FSAP mRNA expression 4fold at 24 h
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LPS
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stimulates FSAP mRNA expression 6fold after 1 h, reaching a plateau at 2 h (7fold stimulation) and gradually decreases until returning to the base level at 24 h
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phosphatidylethanolamine
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enhances autofragmentation and serine protease activity at 0.001 mg/ml and 0.00001 mg/ml
poly-L-lysine
urokinase
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potential physiological activator
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additional information
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KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.58
D-Phe-Pip-Arg-4-nitroanilide
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pH 8.2, 37C
0.56
DL-pyroglutamic acid-cyclohexylglycine-Arg 4-nitroanilide
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pH 8.2, 37C
Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.00000088
Aprotinin
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pH 8.2, 37C
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
additional information
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improved FSAP activity test is developed
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
pI VALUE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
SOURCE
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circulation of HABP as a zymogen
Manually annotated by BRENDA team
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IL-8 can stimulate the expression of HABP mRNA in lung microvascular endothelial cells and in bronchial epithelial cells
Manually annotated by BRENDA team
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weak expression
Manually annotated by BRENDA team
additional information
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY hide
GeneOntology No.
LITERATURE
SOURCE
additional information
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
58000 - 60000
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nonreducing PAGE, proenzyme
60000
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gel-filtration, proenzyme
65000
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77000
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proenzyme
SUBUNITS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
heterodimer
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1 * 50000 + 1 * 27000, active form after cleavage at Arg290 by autocatalytic action, subunits are linked by a disulfide bond
additional information
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
glycoprotein
proteolytic modification
TEMPERATURE STABILITY
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
50
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inactivation above
Purification/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
95% purity
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by affinity chromatography
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homogeneity
purification with 6M urea yields the single-chain zymogen, whereas native conditions yield the activated two-chain form
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Cloned/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
expressed in HEK-293 cells
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expressed in HUVEC cells. Subcutaneous systemic administration of SCID mice
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expression of recombinant FSAP-isoforms in HEK-293 cells
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FSAP expressed in mouse models of atherosclerosis
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gene HABP2, from hepatopancreas, DNA and amino acid sequence determination and analysis, phylogenetic analysis
EXPRESSION
ORGANISM
UNIPROT
LITERATURE
in late pregnancy the plasma FSAP antigen and activity is significantly higher compared with levels in non-pregnant women and remains elevated after delivery, plasma FSAP levels in women using oral contraceptives are also significantly elevated compared to the control group. FSAP mRNA levels are strongly induced by estradiol in monocytes but not in hepatocytes
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oral contraceptive use with preparartions containing ethinylestradiol, levonorgestrel, desogestrel, gestodene, and norgestimate increases the plasma measures of factor VII-activating protease
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ENGINEERING
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
E393Q
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Marburg II single nucleotide polymorphism. Is not associated with altered enzymatic activity or any other changes in FSAP function
G511E
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Marburg I mutant, underlies a polymorphism in the HABP2 gene, is found in 5-10% of the population. Is associated with an impaired pro-urikinase activation, and increased neointima formation correlated with reduced proteolysis of platlet derived growth factor-BB. The polymorphism is correlated with carotid stenosis and may contribute to the risk of venous thrombosis
additional information
Renatured/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
complete recovery of enzyme activity within 2 min of incubation at 1 M urea after denaturation in 6M urea
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APPLICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
medicine
additional information
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nucleic acids are cofactors for FSAP-mediated inhibition of platelet-derived growth factor-BB-induced cell proliferation and mitogen-activated protein kinase 44/42 phosphorylation in vascular smooth muscle cells. FSAP protects RNA from the actions of RNase