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active factor Va + H2O
inactive factor V + ?
active factor Va + H2O
inactive factor V + domain B
active factor Va + H2O
inactive factor V heavy chain + peptide fragment 307-709
active factor Va mutant R306Q + H2O
?
-
proteolytic inactivation, cleavage at Arg506
-
-
?
active factor Va mutant R306Q + H2O
inactive factor V mutant R306Q + ?
-
proteolytic inactivation, cleavage of the heavy chain at Arg506 and Arg679
-
-
?
active factor Va mutant R306Q/R679Q + H2O
inactive factor V mutant R306Q/R679Q + ?
-
recombinant substrate expressed in COS-1 cells, proteolytic inactivation, cleavage of the heavy chain at Arg506, protected by factor Xa
-
-
?
active factor Va mutant R506Q + H2O
?
-
proteolytic inactivation, cleavage at Arg306
-
-
?
active factor Va mutant R506Q + H2O
inactive factor V mutant R506Q + ?
-
proteolytic inactivation, cleavage of the heavy chain at Arg306 and Arg679
-
-
?
active factor Va mutant R506Q/R679Q + H2O
inactive factor V mutant R506Q/R679Q + ?
-
recombinant substrate expressed in COS-1 cells, proteolytic inactivation, cleavage of the heavy chain at Arg306, stimulated by factor Xa
-
-
?
active factor Va mutant R679Q + H2O
inactive factor V mutant R679Q + ?
-
proteolytic inactivation, cleavage of the heavy chain at Arg306 and Arg506
-
-
?
active factor VIII + H2O
inactive factor VIII + domain B
-
activated protein C and activated factor X play a role in proteolytic inactivation of activated coagulation factor VIII involving the B domain, the inactivated substrate factor VIII is less efficient on blood clotting, overview
-
-
?
active factor VIIIa + H2O
inactive factor VIII + domain B
Benzyloxycarbonyl-Val-Gly-Arg + H2O
?
-
-
-
-
?
Boc-Leu-Ser-Thr-Arg-4-nitroanilide + H2O
Boc-Leu-Ser-Thr-Arg + 4-nitroaniline
bradykinin + H2O
?
-
proteolytic inactivation
-
-
?
D-Ile-Pro-Arg + H2O
?
-
-
-
-
?
D-Phe-Pip-Arg-4-nitroanilide + H2O
D-Phe-Pip-Arg + 4-nitroaniline
-
S-2238
-
-
?
D-Phe-pipecolyl-Arg + H2O
?
-
-
-
-
?
D-Pro-Phe-Arg + H2O
?
-
-
-
-
?
D-Val-Arg-p-nitroanilide + H2O
?
-
i.e. S-S2266
-
?
D-Val-cyclohexyl-Ala-Arg + H2O
?
-
-
-
-
?
D-Val-Leu-Arg + H2O
?
-
-
-
-
?
L-pGln-L-Pro-L-Arg-4-nitroanilide + H2O
L-pGln-L-Pro-L-Arg + 4-nitroaniline
-
-
-
-
?
membrane-bound factor Va + H2O
?
-
cleavage of Arg506 in membrane-bound factor Va
-
-
?
Nalpha-benzoyl-L-Arg 4-nitroanilide + H2O
Nalpha-benzoyl-L-Arg + 4-nitroaniline
-
amidase activity
-
-
?
octanoyl-ghrelin + H2O
octanoyl ghrelin(1-15) + ?
octanoyl-truncated ghrelin + H2O
?
octanoyl-truncated ghrelin + H2O
ghrelin(1-15) + ?
pro-factor V + H2O
factor V + ?
cleavage at R506
-
-
?
pro-factor VIIa + H2O
factor VIIa + ?
recombinant substrate
-
-
?
protease activated receptor 1 + H2O
?
protease activated receptor 3 N-terminal peptide + H2O
?
-
the enzyme cleaves a synthetic PAR3 N-terminal peptide at Arg41
-
-
?
protease activated receptor 3 zymogen H2O
active protease activated receptor 3 + ?
protease-activated receptor 1 + H2O
?
protease-activated receptor-1 + H2O
?
-
-
-
-
?
pyroGlu-Pro-Arg-4-nitroanilide + H2O
pyroGlu-Pro-Arg + 4-nitroaniline
S-2238 + H2O
?
-
a chromogenic substrate
-
-
?
S-2288 + H2O
?
-
i.e. D-Ile-L-Pro-L-Arg-p-nitroanilide
-
?
S2238 + H2O
?
-
a commercial chromogenic substrate
-
-
?
spectrozyme PCa + H2O
?
-
-
?
SpPCa + H2O
?
-
a commercial tripeptidyl chromogenic substrate
-
-
?
Toluene-p-sulfonyl-Gly-Pro-Arg + H2O
?
-
-
-
-
?
Toluene-p-sulfonyl-Gly-Pro-Lys + H2O
?
-
-
-
-
?
Z-Gly-Gly-Arg-7-amido-4-methylcoumarin + H2O
?
Z-Gly-Gly-Arg-aminomethylcoumarin + H2O
?
-
a fluorogenic substrate, S-2366
-
-
?
additional information
?
-
active factor Va + H2O
inactive factor V + ?
-
proteolytic inactivation
-
-
?
active factor Va + H2O
inactive factor V + ?
-
proteolytic inactivation of the cofactor in the prothrombinase complex
-
-
?
active factor Va + H2O
inactive factor V + ?
-
proteolytic inactivation, cleavage of the heavy chain at Arg506, Arg306, and Arg679, factor Xa protects factor Va from inactivation by APC, interaction of factor Va and APC at residues 311-325 of the substrate
-
-
?
active factor Va + H2O
inactive factor V + ?
-
proteolytic inactivation, the autolysis loop of APC represents the active site, active site topology, the loop plays a critical role in restricting both the specificity and spatial environment of the active-site groove of APC, overview
-
-
?
active factor Va + H2O
inactive factor V + domain B
-
proteolytic inactivation
-
-
?
active factor Va + H2O
inactive factor V + domain B
-
activated protein C inhibits the procoagulant function of activated factor V through proteolytic cleavage
-
-
?
active factor Va + H2O
inactive factor V + domain B
-
proteolytic inactivation requires interactions with both EPCR and PAR-1
-
-
?
active factor Va + H2O
inactive factor V + domain B
-
proteolytic inactivation, cleavage at Arg306 and Arg506
-
-
?
active factor Va + H2O
inactive factor V + domain B
-
proteolytic inactivation, cleavages at Arg306, Arg506, and Arg679, the cleavage at Arg506 is kinetically favored but protected by factor Xa
-
-
?
active factor Va + H2O
inactive factor V + domain B
-
proteolytic inactivation, the basic residues of two surface loops including those on 39 and the Ca2+-binding 70-80 loops constitute interactive sites for both factors Va and VIIIa, thereby mediating the interaction of APC specifically with these procoagulant cofactors
-
-
?
active factor Va + H2O
inactive factor V heavy chain + peptide fragment 307-709
-
proteolytic inactivation
-
-
?
active factor Va + H2O
inactive factor V heavy chain + peptide fragment 307-709
-
proteolytic inactivation, cleavage at Arg306 and Arg506
-
-
?
active factor VIIIa + H2O
inactive factor VIII + domain B
-
proteolytic inactivation
-
-
?
active factor VIIIa + H2O
inactive factor VIII + domain B
-
the inactivation of factor VIIIa by the enzyme is responsible for its high anticoagulation effect, high factor VIII contents lead to increased resistance to activated protein C, while factor II and factor X are not correleted to active protein C resistance, mechanism, overview
-
-
?
active factor VIIIa + H2O
inactive factor VIII + domain B
-
proteolytic inactivation with cleavage at Arg336 within the factor VIIIa A1 subunit and Arg562 within the A2 subunit, reduced activity with three 336(P4-P3')562 fator VIII variants, possessing mutations surrounding Arg336, compared to wild-type fVIIIa, the rate of cleavage for the A1 subunit of the fully substituted P4-P3' mutant is reduced by 100fold relative to wild-type, cleavage of the A2 subunit for the 336(P4-P3')562 appear a few fold slower than that for wild-type, overview
-
-
?
active factor VIIIa + H2O
inactive factor VIII + domain B
-
proteolytic inactivation, cleavage at Arg336 and Arg572 in domains A1 and A2, respectively
-
-
?
active factor VIIIa + H2O
inactive factor VIII + domain B
-
proteolytic inactivation, the basic residues of two surface loops including those on 39 and the Ca2+-binding 70-80 loops constitute interactive sites for both factors Va and VIIIa, thereby mediating the interaction of APC specifically with these procoagulant cofactors
-
-
?
Boc-Leu-Ser-Thr-Arg-4-nitroanilide + H2O
Boc-Leu-Ser-Thr-Arg + 4-nitroaniline
-
amidolytic activity
-
-
?
Boc-Leu-Ser-Thr-Arg-4-nitroanilide + H2O
Boc-Leu-Ser-Thr-Arg + 4-nitroaniline
-
-
-
-
?
Boc-Leu-Ser-Thr-Arg-4-nitroanilide + H2O
Boc-Leu-Ser-Thr-Arg + 4-nitroaniline
-
-
-
-
?
factor V + H2O
?
-
-
-
?
factor V + H2O
?
-
proteolytic inactivation
-
?
Factor Va + H2O
?
-
-
-
-
?
Factor Va + H2O
?
-
-
-
?
Factor Va + H2O
?
-
-
-
?
Factor Va + H2O
?
-
-
-
?
Factor Va + H2O
?
-
time- and temperature-dependent inactivation of factor V
-
-
?
Factor Va + H2O
?
-
APC cleavage at Arg 505 and Arg 662
-
?
Factor Va + H2O
?
-
-
-
-
?
Factor Va + H2O
?
-
-
-
?
Factor Va + H2O
?
-
-
-
-
?
Factor Va + H2O
?
-
-
-
?
Factor Va + H2O
?
-
in the membrane-bound factor Va cleavage occurs rapidly at Arg506 and is followed by a slower proteolysis at Arg306 and a final, very slow cleavage at Arg679
-
-
?
Factor Va + H2O
?
-
cleaves rapidly at Arg506 and slowly at Arg 306
-
?
Factor Va + H2O
?
-
natural anticoagulant, inhibits thrombin generation by degrading factors Va and VIIIa
-
?
Factor Va + H2O
?
-
natural anticoagulant, inhibits thrombin generation by degrading factors Va and VIIIa
-
?
Factor Va + H2O
?
-
protein C anticoagulanat pathway, multi-domain vitamin K-dependent plasma serine protease zymogen, down-regulates the blood coagulation cascade upon activation by the thrombin-TM complex by selectively inactivating factors Va and VIII a
-
?
Factor Va + H2O
?
-
protein C anticoagulanat pathway, multi-domain vitamin K-dependent plasma serine protease zymogen, down-regulates the blood coagulation cascade upon activation by the thrombin-TM complex by selectively inactivating factors Va and VIII a
-
?
Factor Va + H2O
?
-
hydrolysis at Arg506
-
-
?
Factor Va + H2O
?
-
hydrolysis at Arg506 and Arg 306
-
-
?
Factor Va + H2O
?
-
inactivation
-
-
?
Factor Va + H2O
?
-
activated protein C downregulates thrombin formation through proteolytic inactivation of factor Va by cleavage at Arg506 and Arg306. Docking of APC to FVa and FVIIIa constitutes the first step in the inactivation of the cofactor
-
-
?
Factor Va + H2O
?
-
activated protein C inactivates membrane-bound factor Va following cleavages of the heavy chain at Arg306, Arg506, and Arg679. In the absence of the APC-cleavage sites at Arg306 and Arg506, the active cofactor is unable to be significantly inactivated by APC in the presence of a membrane surface
-
-
?
Factor Va + H2O
?
-
APC can inactivate FVa by proteolysis of three different peptide bonds at positions R306, R506 and R679. The cleavage at R506 is kinetically favoured, protein S-independent and yields a FVa intermediate with decreased factor Xa-cofactor activity. The slower cleavage at R306 is stimulated by protein S and completely inactivates FVa
-
-
?
Factor Va + H2O
?
-
cleavage at Arg306, Arg506, and Arg679 of the heavy chain
-
-
?
Factor Va + H2O
?
-
inactivation through cleavage at Arg306, Arg506, and Arg679
-
-
?
Factor Va + H2O
?
-
activated protein C inactivates membrane-bound factor Va following cleavages of the heavy chain at Arg306, Arg506, and Arg679. It is the first cleavage at Arg306 that is the inactivating cleavage. Cleavage at Arg306 leads to full loss of cofactor function and the dissociation of the A2 domain from the rest of the molecule. Complete inactivation of factor Va by APC requires the presence of a membrane surface, however, factor Va can be cleaved by APC in the absence of a membrane surface at Arg506 and Arg679, retaining approximately 80% of its cofactor activity
-
-
?
Factor Va + H2O
?
-
cleavage at Arg306, Arg506, and Arg679 of the heavy chain. FVa is protected by prothrombin about 7.6fold in the absence of FXa
-
-
?
Factor Va + H2O
?
-
-
-
?
factor Va Leiden + H2O
?
-
-
-
?
factor Va Leiden + H2O
?
-
inactivation is much less sensitive to prothrombin inhibition
-
?
Factor VaR506Q + H2O
?
-
The substrate is derived from factor Va by replacing Arg506 by Gln. In the presence of phospholipids the substrate is hydrolyzed at Arg306, but in the absence of phospholipids hydrolysis occurs at Arg679, followed by cleavage at Arg306, suggesting that the binding of phospholipids alters the accessibility of Arg679
-
-
?
Factor VaR506Q + H2O
?
-
cleavage of Arg306 in factor VaR506Q
-
-
?
factor VIII + H2O
?
-
-
-
?
factor VIII + H2O
?
-
-
-
-
?
factor VIII + H2O
?
-
proteolytic inactivation
-
?
Factor VIIIa + H2O
?
-
-
-
-
?
Factor VIIIa + H2O
?
-
-
-
?
Factor VIIIa + H2O
?
-
-
-
-
?
Factor VIIIa + H2O
?
-
-
-
?
Factor VIIIa + H2O
?
-
-
-
-
?
Factor VIIIa + H2O
?
-
-
-
?
Factor VIIIa + H2O
?
-
cleavage at two sites: at Arg336 near the C-terminus of the A1 subunit, and at Arg562, bisecting the A2 subunit, the proteolysis abolishes the cofactor activity in the intrinsic factor Xase
-
-
?
Factor VIIIa + H2O
?
-
natural anticoagulant, inhibits thrombin generation by degrading factors Va and VIIIa
-
?
Factor VIIIa + H2O
?
-
natural anticoagulant, inhibits thrombin generation by degrading factors Va and VIIIa
-
?
Factor VIIIa + H2O
?
-
protein C anticoagulanat pathway, multi-domain vitamin K-dependent plasma serine protease zymogen, down-regulates the blood coagulation cascade upon activation by the thrombin-TM complex by selectively inactivating factors Va and VIII a
-
?
Factor VIIIa + H2O
?
-
protein C anticoagulanat pathway, multi-domain vitamin K-dependent plasma serine protease zymogen, down-regulates the blood coagulation cascade upon activation by the thrombin-TM complex by selectively inactivating factors Va and VIII a
-
?
Factor VIIIa + H2O
?
-
proteolytic inactivation
-
?
Factor VIIIa + H2O
?
-
#>
-
?
Factor VIIIa + H2O
?
-
proteolytic inactivation by cleavage at Arg336 in A1 subunit and Arg562 in A2 subunit. Cleavage at A1 site is the dominant mechanism for factor VIIIa inactivation
-
-
?
Factor VIIIa + H2O
?
-
inactivation
-
-
?
Factor VIIIa + H2O
?
-
activated protein C downregulates thrombin formation through proteolytic inactivation of factor VIIIa by cleavage at Arg336 and Arg56. Docking of APC to FVa and FVIIIa constitutes the first step in the inactivation of the cofactor
-
-
?
Factor VIIIa + H2O
?
-
APC cleaves factor VIIIa at two peptide bonds, Arg336 and Arg562
-
-
?
Factor VIIIa + H2O
?
-
inactivation through cleavages at Arg336 in the A1 subunit and Arg562 in the A2 subunit
-
-
?
Factor VIIIa + H2O
?
-
inactivation through cleavages at Arg336 in the A1 subunit and Arg562 in the A2 subunit. Proteolysis at Arg336 occurs 25fold faster than at Arg562. Activities with substrate mutants, overview. The inactivation rates observed for point mutations at the P3 and P2 positions, Gln334Asp, Leu335Gln, and Leu335Arg, are reduced by about 2fold compared with wild-type factor VIIIa
-
-
?
Factor VIIIa + H2O
?
-
-
-
?
ghrelin + H2O
?
-
ghrelin is converted into smaller fragments in blood plasma in circulation under thrombotic and inflammatory conditions
-
-
?
ghrelin + H2O
?
-
ghrelin is converted into smaller fragments in blood plasma in circulation under thrombotic and inflammatory conditions
-
-
?
ghrelin + H2O
?
-
ghrelin is converted into smaller fragments in blood plasma in circulation under thrombotic and inflammatory conditions
-
-
?
ghrelin + H2O
?
-
ghrelin is converted into smaller fragments in blood plasma in circulation under thrombotic and inflammatory conditions
-
-
?
octanoyl-ghrelin + H2O
?
-
-
-
-
?
octanoyl-ghrelin + H2O
?
-
-
-
-
?
octanoyl-ghrelin + H2O
octanoyl ghrelin(1-15) + ?
-
preferred substrate
-
-
?
octanoyl-ghrelin + H2O
octanoyl ghrelin(1-15) + ?
-
preferred substrate
-
-
?
octanoyl-truncated ghrelin + H2O
?
-
preferred substrate, synthetic human substrate, octanoyl-truncated ghrelin(1-15) activates GHSR1a-dependent signaling similar to the full-length peptide
-
-
?
octanoyl-truncated ghrelin + H2O
?
-
preferred substrate, synthetic human substrate, octanoyl-truncated ghrelin(1-15) activates GHSR1a-dependent signaling similar to the full-length peptide
-
-
?
octanoyl-truncated ghrelin + H2O
ghrelin(1-15) + ?
-
octanoyl-truncated ghrelin(1-15) activates GHSR1a-dependent signaling similar to the full-length peptide
-
-
?
octanoyl-truncated ghrelin + H2O
ghrelin(1-15) + ?
-
octanoyl-truncated ghrelin(1-15) activates GHSR1a-dependent signaling similar to the full-length peptide
-
-
?
protease activated receptor 1 + H2O
?
-
activation
-
-
?
protease activated receptor 1 + H2O
?
-
APC can also bind to endothelial protein C receptor to activate protease activated receptor 1, PAR-1, thereby eliciting antiinflammatory and cytoprotective signaling responses in endothelial cells
-
-
?
protease activated receptor 1 + H2O
?
-
APC exhibits cytoprotective and antiinflammatory activity through the endothelial protein C receptor-dependent cleavage of protease activated receptor 1, PAR-1, on endothelial cells
-
-
?
protease activated receptor 1 + H2O
?
-
activation, cleavage at Arg41
-
-
?
protease activated receptor 1 + H2O
?
-
activation, the basic residues of surface loops are indispensable for interaction with APC, also two acidic residues on helix-162, Glu167 and Glu170, on the protease domain of APC which are required for the protease interaction with PAR-1
-
-
?
protease activated receptor 1 + H2O
?
-
APC can also bind to endothelial protein C receptor to activate protease activated receptor 1, PAR-1, APC cleaves the PAR-1 exodomain with about 750fold lower catalytic efficiency than thrombin
-
-
?
protease activated receptor 3 zymogen H2O
active protease activated receptor 3 + ?
-
the enzyme cleaves the substrate PAR3 in transfected and endothelial cells in the presence of endothelial protein C receptor, as well as substrate mutant K38Q-PAR3, but fails to cleave the substrate mutant R41Q-PAR3
-
-
?
protease activated receptor 3 zymogen H2O
active protease activated receptor 3 + ?
-
enzyme-mediated cleavage of PAR3 is analyzed by the proteolytic release of SEAP from a SEAP-PAR3 fusion protein expressed in HEK-293 cells in the absence or presence of stable endothelial protein C receptor coexpression
-
-
?
protease-activated receptor 1 + H2O
?
PAR1
-
-
?
protease-activated receptor 1 + H2O
?
-
PAR1
-
-
?
protease-activated receptor 1 + H2O
?
PAR1, cleavage at Arg46
-
-
?
protease-activated receptor 1 + H2O
?
PAR1
-
-
?
protease-activated receptor 1 + H2O
?
-
PAR1
-
-
?
protease-activated receptor 1 + H2O
?
PAR1, generation of unique tethered ligands by APC by cleavage at Arg46 on PAR1
-
-
?
pyroGlu-Pro-Arg-4-nitroanilide + H2O
pyroGlu-Pro-Arg + 4-nitroaniline
-
S-2366
-
-
?
pyroGlu-Pro-Arg-4-nitroanilide + H2O
pyroGlu-Pro-Arg + 4-nitroaniline
-
S-2366, APC is labeled with AF546
-
-
?
S-2366 + H2O
?
-
i.e. 5-oxo-L-Pro-L-Pro-L-Arg-p-anitroanilide
-
?
S-2366 + H2O
?
-
synthetic substrate for amidolytic activity
-
-
?
S2366 + H2O
?
-
a chromogenic substrate
-
-
?
S2366 + H2O
?
-
a commercial chromogenic substrate
-
-
?
Tie2 + H2O
?
activation
-
-
?
Tie2 + H2O
?
activated protein C binds directly to and activates Tie2. Tie2 is a transmembrane endothelial tyrosine kinase receptor that not only regulates vessel maturation and remodeling angiogenesis, but also controls endothelial inflammation and permeability
-
-
?
Z-Gly-Gly-Arg-7-amido-4-methylcoumarin + H2O
?
-
-
-
-
?
Z-Gly-Gly-Arg-7-amido-4-methylcoumarin + H2O
?
-
a fluorogenic substrate, S-2366
-
-
?
additional information
?
-
-
no effect on the coagulation activity of factor XII, factor XI, factor X, factor IX, factor VII or prothrombin
-
-
?
additional information
?
-
-
identification of the binding site for activated protein C on the light chains of factors V and VIII
-
-
?
additional information
?
-
-
role of protein C in the regulation of blood coagulation
-
-
?
additional information
?
-
-
activated protein C complexes with protein S on the surface of either platelets or the endothelium, these complexes catalyze the proteolytic inactivation of factors Va and VIIIa
-
-
?
additional information
?
-
-
potential role of the enzyme in blood coagulation and hemostasis
-
-
?
additional information
?
-
-
the enzyme is one of the gamma-carboxyglutamic acid-containing coagulation factors. It is formed by protein C, the proenzyme that circulates in plasma, by the action of a complex of thrombin with thrombomodulin or by serine endopeptidases present in several snake venoms
-
-
?
additional information
?
-
-
the enzyme is one of the gamma-carboxyglutamic acid-containing coagulation factors. It is formed by protein C, the proenzyme that circulates in plasma, by the action of a complex of thrombin with thrombomodulin or by serine endopeptidases present in several snake venoms
-
-
?
additional information
?
-
-
the enzyme is one of the gamma-carboxyglutamic acid-containing coagulation factors. It is formed by protein C, the proenzyme that circulates in plasma, by the action of a complex of thrombin with thrombomodulin or by serine endopeptidases present in several snake venoms
-
-
?
additional information
?
-
-
does not seem to be necessary for blood coagulation
-
-
?
additional information
?
-
-
bovine enzyme preferentially hydrolyzes the major form of octanoylated ghrelin(28), i.e. about twice as much hydrolysis as is observed for a longer acyl chain of decanoylated ghrelin(28). But both acyl and desacyl ghrelin are hydrolyzed at the peptidebond between Arg15 and Lys16, generating an N-terminal peptide consisting of the first 15 residues
-
-
?
additional information
?
-
-
the enzyme is able to accomodate large hydrophobic residues such as phenylalanine and leucine in the P2 position. In the P3 position, the enzyme prefers an apolar D-amino acid residue
-
-
?
additional information
?
-
-
conversion of glutamic acid 192 to glutamine in activated protein C changes the substrate specificity
-
-
?
additional information
?
-
-
specificity: substrates with arginine in the P1 position have the highest activity
-
-
?
additional information
?
-
-
role of protein C in the regulation of blood coagulation
-
-
?
additional information
?
-
-
activated protein C complexes with protein S on the surface of either platelets or the endothelium, these complexes catalyze the proteolytic inactivation of factors Va and VIIIa
-
-
?
additional information
?
-
-
physiological relevance of the protein C anticoagulant pathway
-
-
?
additional information
?
-
-
the enzyme is one of the gamma-carboxyglutamic acid-containing coagulation factors. It is formed by protein C, the proenzyme that circulates in plasma, by the action of a complex of thrombin with thrombomodulin or by serine endopeptidases present in several snake venoms
-
-
?
additional information
?
-
-
the enzyme is one of the gamma-carboxyglutamic acid-containing coagulation factors. It is formed by protein C, the proenzyme that circulates in plasma, by the action of a complex of thrombin with thrombomodulin or by serine endopeptidases present in several snake venoms
-
-
?
additional information
?
-
-
human umbilical vein endothelial cells respond to stimulation by enzyme with induction of COX-2-expression, enzyme promotes upregulation of prostanoid production in human endothelium
-
-
?
additional information
?
-
-
activated protein C acts as feedback inhibitor of thrombin production
-
-
?
additional information
?
-
-
activated protein C downregulates p38 mitogen-activated protein kinase p53 and improves clinical parameters in an in-vivo model of septic shock, overview, the activated enzyme prevents acidosis and tends to improve heart rate responses to endotoxia
-
-
?
additional information
?
-
-
activated protein C has endothelial barrier protective effects that require binding to endothelial protein C receptor, EPCR, and cleavage of protease activated receptor-1, PAR1, and that may play a role in the anti-inflammatory action of APC, thrombin does not exert directly barrier protective effects, overview
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-
?
additional information
?
-
-
activated protein C has potent anticoagulant and antiinflammatory properties that are mediated in part by its interactions with its cofactor protein S and the endothelial cell protein C receptor, EPCR, the protein C/APC Gla domain is implicated in both interactions
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?
additional information
?
-
-
activated protein C is a physiological anticoagulant, it also exerts anti-inflammatory and antiapoptotic effects, activated protein C inhibits the production of TNF, IL-1beta, IL-6, and IL-8 and inhibits camptothecin-induced apoptosis in a dose-dependent manner in the LPS-stimulated immortalized human monocytic cell line THP-1, activated protein C inhibited spontaneous apoptosis in primary blood monocytes from healthy individuals, activated protein C does not influence the phagocytic internalization of Gram-negative and Gram-positive bioparticles by THP-1 cells or by primary blood monocytes, it does not affect the expression of adhesion molecules by LPS-stimulated blood monocytes nor the ability of monocytes to adhere to LPS-stimulated endothelial cells
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-
?
additional information
?
-
-
activated protein C is a plasma serine protease with systemic anticoagulant, anti-inflammatory and antiapoptotic activities, and direct vasculoprotective and neuroprotective activities, it blocks tissue plasminogen activator-mediated brain hemorrhage after transient brain ischemia and embolic stroke in mice, overview, APC inhibits a pro-hemorrhagic tissue plasminogen activator-induced, NF-kappaB-dependent matrix metalloproteinase-9 pathway in ischemic brain endothelium in vivo and in vitro by acting through protease-activated receptor 1, overview
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-
?
additional information
?
-
-
activated protein C reduces mortality in severe sepsis patients and exhibits beneficial effects in multiple animal injury models. APC anticoagulant activity involves inactivation of factors Va and VIIIa, whereas APC cytoprotective activities involve the endothelial protein C receptor and protease-activated receptor-1, PAR-1, anticoagulantly active APC inhibits secondary extended thrombin generation and concomitant thrombin dependent activation of thrombin activable fibrinolysis inhibitor in plasma, both recombinant wild-type and mutant APCs inhibit staurosporine-induced endothelial cell apoptosis
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?
additional information
?
-
-
in addition to an anticoagulant activity, activated protein C also exhibits anti-inflammatory and cytoprotective properties, but can cause bleeding because of its anticoagulant function, the cytoprotective activity of APC is mediated through inhibition of caspase-3 activity
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?
additional information
?
-
-
protein C has antiinflammatory, anticoagulant and pro-fibrinolytic activities in humans, counteracting some of the main pro-inflammatory pathophysiological mechanisms in sepsis, overview, the antithrombotic effect is caused by irreversible inactivation of factors Va and VIIIa, the anti-inflammatory activity reduces formation of TNF, IL-8, IL-6 and thrombin and limits the rolling of monocytes and neutrophils on injured endothelium by binding selectins, it may reduce apoptosis, the pro-fibrinolytic activity occurs due to inhibition of PAI-1 and indirectly via reduced thrombin and thrombin-activatable fibrinolysis inhibitor
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-
?
additional information
?
-
-
recombinant activated protein C enhances intracellular antibacterial activity, against Escherichia coli strain ATCC 25922, in presence of antibiotics, e.g. levofloxacin or ampicillin, but has no antibacterial effects without antibiotics, while it decreases the production of cytokines, such as TNF-alpha, IL-1beta and interleukin-6, but not interleukin-8, by monocytes
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?
additional information
?
-
-
the activated enzyme induces signal transduction in an endothelial protein C receptor- or PAR1-dependent manner involved in apoptosis, microcirculation, and vascular permeability, the activated enzyme plays an important role in sepsis, but does not protect against sepsis, effects of long time treatment, overview, the activated enzyme induces expression of monocyte chemoattractant protein-1, MCP-1, in endothelial cells, overview
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-
?
additional information
?
-
-
the activated protein C constitutes an important natural coagulation inhibitor and key regulator of both coagulation and inflammation
-
-
?
additional information
?
-
-
the enzyme has anticoagulant, antiapoptotic, and cytoprotective activities, mechanisms, overview, severe homozygous enzyme-deficiency causes massive, usually lethal thrombotic complications that arise in infants, heterozygous adults show a risk for venous thrombosis
-
-
?
additional information
?
-
-
the enzyme is a serine protease that regulates thrombin production through inactivation of blood coagulation factors Va and VIIIa, overview, treatment of breast cancer cells with exogenous active enzyme leads to increased invasion and chemotaxis, thereby not acting as a chemoattractant, but via endothelial protein C receptor and protease-activated receptor-1, PAR-1, receptor blocking b antibodies blocks the enzyme effects, overview, the enzyme does not increase cell division and proliferation
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-
?
additional information
?
-
-
the enzyme shows anticoagulation activity and can prolonge life of sepsis patients, but can also cause hemorrhage, mechanism of action and biological effects, detailed overview
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-
?
additional information
?
-
-
the protein C pathway plays a key role in the regulation of blood coagulation, APC inhibits thrombin generation, and functions as a physiological anticoagulant with cytoprotective, anti-inflammatory and anti-apoptotic properties, mechanisms, overview, APC exerts its protective effects via an intriguing mechanism requiring endothelial protein C receptor and the thrombin receptor, protease-activated receptor-1, but even though APC cleaves this receptor in an identical fashion to thrombin, it exerts opposing effects, overview, administration of APC leads to reduced mortality in a subset of patients with severe sepsis, APC improves cerebral blood flow in the ischemic hemisphere and markedly reduces the volume of brain injury caused by middle cerebral vein occlusion effects, APC dramatically inhibits NFkappa B activity and TNF-alpha in monocytes from rheumatoid arthritis patients, APC protects against diabetic nephropathy by inhibiting endothelial and podocyte apoptosis, APC may have beneficial effects in patients with inflammatory lung diseases, APC stimulates new blood vessel formation and ectodermal epithelial cells to grow across the top of the gelatin sponge in the chorio-allantoic membrane assay
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?
additional information
?
-
-
the recombinant enzyme shows antithrombotic and anticoagulant effects in a rat model of arterial thrombosis, overview
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?
additional information
?
-
-
the recombinant human activated protein C affects apoptosis-related proteins, e.g. Bcl-2, p21, and p53, in mice, and reduces mortality in patients with severe sepsis, mechanism, overview
-
-
?
additional information
?
-
-
the serine protease has antithrombotic and antiinflammatory activities, that play an important role in vascular function, APC inhibits TNF-related apoptosis-inducing ligand expression and secretion and its induction by cell activation, mechanism, overview, APC affects signal transduction by increasing ERK phosphorylation, overview
-
-
?
additional information
?
-
-
APC inhibits a pro-hemorrhagic tissue plasminogen activator-induced, NF-kappaB-dependent matrix metalloproteinase-9 pathway in ischemic brain endothelium in vivo and in vitro by acting through protease-activated receptor 1
-
-
?
additional information
?
-
-
recombinant activated protein C upregulates the release of soluble fractalkine, a unique endothelial cell-derived chemokine that functions both as a chemoattractant and as an adhesion molecule, from human umbilical vein endothelial cells about 2.5fold, PAR-1- and PAR-2-agonist peptides stimulate the fractalkine release, the protein C zymogen is inactive, overview
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-
?
additional information
?
-
-
the enzyme is a vitamin K-dependent serine protease
-
-
?
additional information
?
-
-
the recombinant enzyme shows in vitro anticoagulant activity alone and in combination with melagatran, a thrombin inhibitor, and with unfractionated or low molecular weight heparins, overview
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-
?
additional information
?
-
-
activated protein C treatment of human neutrophils results in a decreased interleukin-6 expression in a concentration-dependent manner and a decreased chemotaxis, without affecting other cytokines, apoptosis, or respiratory burst activity
-
-
?
additional information
?
-
-
directly binds to beta1 and beta3 integrins and inhibits neutrophil migration, both in vitro and in vivo. Activated protein C possesses an Arg-Gly-Asp sequence, which is critical for the inhibition. The enzyme does not functionally alter the signaling pathway associated with chemotaxis receptors on neutrophil
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?
additional information
?
-
-
patients with frequent arteriovenous fistula/graft failures have a significantly lower level of APC-protein C inhibitor complex in plasma than those with less frequent arteriovenous fistula/graft failures
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?
additional information
?
-
-
pretreatment of endothelial monolayers with recombinant activated protein C concentrations (10-25 nmol) leads to significantly decreased adhesion of B16-F10 melanoma cells. A 44% reduction in lung metastases in recombinant activated protein C-treated compared with control mice. Recombinant activated protein C markedly decreases tumor cell entrapment within the liver of mice
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?
additional information
?
-
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treatment of lipopolysaccharide-stimulated blood monocytes with recombinant activated protein C results in an upregulation of interleukin-10 protein production and mRNA synthesis and a downregulation of tissue factor Ag and activity levels. Serine protease activity is required for the upregulation of interleukin-10 by recombinant activated protein C
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?
additional information
?
-
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APC activates Tie2, a tyrosine kinase receptor, not through its major ligand, angiopoietin-1, but instead by binding to endothelial protein C receptor, cleaving protease-activated receptor-1 and transactivating EGF receptor
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?
additional information
?
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APC upregulates TNF receptor-associated factor 2, TRAF2, and phosphorylates NF-kappaB p65 at Ser276 and Ser536 independently of IkappaB degradation, real-time quantitative PCR analysis, overview
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?
additional information
?
-
-
function relationships of APC, overview
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?
additional information
?
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lower concentrations of APC, 300-30000 ng/ml, show a cell-protective effect against hypoxia in vitro, whereas higher concentrations of about 0.120 mg/ml demonstrate cytotoxicity in both RPE and photoreceptor cells
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?
additional information
?
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-
APC activity is measured using the commercial chromogenic substrate Spectrozyme PCa
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-
?
additional information
?
-
-
CRVO-induced retinal cell apoptosis is reduced dramatically by intravitreal injection of APC
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?
additional information
?
-
-
P4-P3' residues flanking cleavage sites in factors VIIIa and Va, overview
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-
?
additional information
?
-
-
cleavage of protease activated receptor 3 zymogen by thrombin at Lys38 fails to induce PAR3-dependent intracellular signaling pathways but rather activates PAR1 and PAR2
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?
additional information
?
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-
both acyl and desacyl ghrelin are hydrolyzed at the peptide bond between Arg15 and Lys16, generating an N-terminal peptide consisting of the first 15 residues
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?
additional information
?
-
-
the enzyme has anticoagulant, antiapoptotic, and cytoprotective activities, murine injury models, mechanisms, overview
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-
?
additional information
?
-
-
both acyl and desacyl ghrelin are hydrolyzed at the peptide bond between Arg15 and Lys16, generating an N-terminal peptide consisting of the first 15 residues
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-
?
additional information
?
-
-
both acyl and desacyl ghrelin are hydrolyzed at the peptide bond between Arg15 and Lys16, generating an N-terminal peptide consisting of the first 15 residues
-
-
?
additional information
?
-
-
the protein C pathway plays an important role in vascular function, and acquired deficiency during sepsis is associated with increased organ damage and dysfunction, and mortality, cecal ligation and puncture model, overview, activated protein C acts as feedback inhibitor of thrombin production and has receptor-mediated anti-inflammatory and cytoprotective effects, treatment with activated protein C results in suppression of cytokine response and improved organ function
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?
additional information
?
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-
the activated protein C reduces endotoxin-induced white matter injury in the developing rat brain, the activated enzyme attenuates the lipopolysaccharide-induced protein expression of inflammatory cytokines, tumor necrosis factor-alpha, nd interleukin-6 in treated brains, overview
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?
additional information
?
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activated protein C downregulates p38 mitogen-activated protein kinase p53 and improves clinical parameters in an in-vivo model of septic shock, overview
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?
Please wait a moment until the data is sorted. This message will disappear when the data is sorted.
active factor Va + H2O
inactive factor V + ?
active factor Va + H2O
inactive factor V + domain B
active factor Va + H2O
inactive factor V heavy chain + peptide fragment 307-709
-
proteolytic inactivation
-
-
?
active factor VIII + H2O
inactive factor VIII + domain B
-
activated protein C and activated factor X play a role in proteolytic inactivation of activated coagulation factor VIII involving the B domain, the inactivated substrate factor VIII is less efficient on blood clotting, overview
-
-
?
active factor VIIIa + H2O
inactive factor VIII + domain B
factor V + H2O
?
-
proteolytic inactivation
-
?
pro-factor V + H2O
factor V + ?
cleavage at R506
-
-
?
protease activated receptor 1 + H2O
?
protease activated receptor 3 zymogen H2O
active protease activated receptor 3 + ?
-
the enzyme cleaves the substrate PAR3 in transfected and endothelial cells in the presence of endothelial protein C receptor, as well as substrate mutant K38Q-PAR3, but fails to cleave the substrate mutant R41Q-PAR3
-
-
?
protease-activated receptor 1 + H2O
?
protease-activated receptor-1 + H2O
?
-
-
-
-
?
Tie2 + H2O
?
activated protein C binds directly to and activates Tie2. Tie2 is a transmembrane endothelial tyrosine kinase receptor that not only regulates vessel maturation and remodeling angiogenesis, but also controls endothelial inflammation and permeability
-
-
?
additional information
?
-
active factor Va + H2O
inactive factor V + ?
-
proteolytic inactivation
-
-
?
active factor Va + H2O
inactive factor V + ?
-
proteolytic inactivation of the cofactor in the prothrombinase complex
-
-
?
active factor Va + H2O
inactive factor V + domain B
-
proteolytic inactivation
-
-
?
active factor Va + H2O
inactive factor V + domain B
-
activated protein C inhibits the procoagulant function of activated factor V through proteolytic cleavage
-
-
?
active factor Va + H2O
inactive factor V + domain B
-
proteolytic inactivation requires interactions with both EPCR and PAR-1
-
-
?
active factor VIIIa + H2O
inactive factor VIII + domain B
-
proteolytic inactivation
-
-
?
active factor VIIIa + H2O
inactive factor VIII + domain B
-
the inactivation of factor VIIIa by the enzyme is responsible for its high anticoagulation effect, high factor VIII contents lead to increased resistance to activated protein C, while factor II and factor X are not correleted to active protein C resistance, mechanism, overview
-
-
?
Factor Va + H2O
?
-
-
-
?
Factor Va + H2O
?
-
-
-
?
Factor Va + H2O
?
-
-
-
?
Factor Va + H2O
?
-
-
-
?
Factor Va + H2O
?
-
-
-
-
?
Factor Va + H2O
?
-
-
-
?
Factor Va + H2O
?
-
natural anticoagulant, inhibits thrombin generation by degrading factors Va and VIIIa
-
?
Factor Va + H2O
?
-
protein C anticoagulanat pathway, multi-domain vitamin K-dependent plasma serine protease zymogen, down-regulates the blood coagulation cascade upon activation by the thrombin-TM complex by selectively inactivating factors Va and VIII a
-
?
Factor Va + H2O
?
-
inactivation
-
-
?
Factor Va + H2O
?
-
activated protein C downregulates thrombin formation through proteolytic inactivation of factor Va by cleavage at Arg506 and Arg306. Docking of APC to FVa and FVIIIa constitutes the first step in the inactivation of the cofactor
-
-
?
Factor Va + H2O
?
-
activated protein C inactivates membrane-bound factor Va following cleavages of the heavy chain at Arg306, Arg506, and Arg679. In the absence of the APC-cleavage sites at Arg306 and Arg506, the active cofactor is unable to be significantly inactivated by APC in the presence of a membrane surface
-
-
?
Factor Va + H2O
?
-
APC can inactivate FVa by proteolysis of three different peptide bonds at positions R306, R506 and R679. The cleavage at R506 is kinetically favoured, protein S-independent and yields a FVa intermediate with decreased factor Xa-cofactor activity. The slower cleavage at R306 is stimulated by protein S and completely inactivates FVa
-
-
?
Factor Va + H2O
?
-
cleavage at Arg306, Arg506, and Arg679 of the heavy chain
-
-
?
Factor Va + H2O
?
-
inactivation through cleavage at Arg306, Arg506, and Arg679
-
-
?
Factor Va + H2O
?
-
-
-
?
factor VIII + H2O
?
-
-
-
-
?
factor VIII + H2O
?
-
proteolytic inactivation
-
?
Factor VIIIa + H2O
?
-
-
-
?
Factor VIIIa + H2O
?
-
-
-
?
Factor VIIIa + H2O
?
-
natural anticoagulant, inhibits thrombin generation by degrading factors Va and VIIIa
-
?
Factor VIIIa + H2O
?
-
natural anticoagulant, inhibits thrombin generation by degrading factors Va and VIIIa
-
?
Factor VIIIa + H2O
?
-
protein C anticoagulanat pathway, multi-domain vitamin K-dependent plasma serine protease zymogen, down-regulates the blood coagulation cascade upon activation by the thrombin-TM complex by selectively inactivating factors Va and VIII a
-
?
Factor VIIIa + H2O
?
-
protein C anticoagulanat pathway, multi-domain vitamin K-dependent plasma serine protease zymogen, down-regulates the blood coagulation cascade upon activation by the thrombin-TM complex by selectively inactivating factors Va and VIII a
-
?
Factor VIIIa + H2O
?
-
#>
-
?
Factor VIIIa + H2O
?
-
inactivation
-
-
?
Factor VIIIa + H2O
?
-
activated protein C downregulates thrombin formation through proteolytic inactivation of factor VIIIa by cleavage at Arg336 and Arg56. Docking of APC to FVa and FVIIIa constitutes the first step in the inactivation of the cofactor
-
-
?
Factor VIIIa + H2O
?
-
APC cleaves factor VIIIa at two peptide bonds, Arg336 and Arg562
-
-
?
Factor VIIIa + H2O
?
-
inactivation through cleavages at Arg336 in the A1 subunit and Arg562 in the A2 subunit
-
-
?
Factor VIIIa + H2O
?
-
-
-
?
ghrelin + H2O
?
-
ghrelin is converted into smaller fragments in blood plasma in circulation under thrombotic and inflammatory conditions
-
-
?
ghrelin + H2O
?
-
ghrelin is converted into smaller fragments in blood plasma in circulation under thrombotic and inflammatory conditions
-
-
?
ghrelin + H2O
?
-
ghrelin is converted into smaller fragments in blood plasma in circulation under thrombotic and inflammatory conditions
-
-
?
ghrelin + H2O
?
-
ghrelin is converted into smaller fragments in blood plasma in circulation under thrombotic and inflammatory conditions
-
-
?
protease activated receptor 1 + H2O
?
-
activation
-
-
?
protease activated receptor 1 + H2O
?
-
APC can also bind to endothelial protein C receptor to activate protease activated receptor 1, PAR-1, thereby eliciting antiinflammatory and cytoprotective signaling responses in endothelial cells
-
-
?
protease activated receptor 1 + H2O
?
-
APC exhibits cytoprotective and antiinflammatory activity through the endothelial protein C receptor-dependent cleavage of protease activated receptor 1, PAR-1, on endothelial cells
-
-
?
protease-activated receptor 1 + H2O
?
PAR1
-
-
?
protease-activated receptor 1 + H2O
?
-
PAR1
-
-
?
protease-activated receptor 1 + H2O
?
PAR1, cleavage at Arg46
-
-
?
protease-activated receptor 1 + H2O
?
PAR1
-
-
?
protease-activated receptor 1 + H2O
?
-
PAR1
-
-
?
additional information
?
-
-
role of protein C in the regulation of blood coagulation
-
-
?
additional information
?
-
-
activated protein C complexes with protein S on the surface of either platelets or the endothelium, these complexes catalyze the proteolytic inactivation of factors Va and VIIIa
-
-
?
additional information
?
-
-
potential role of the enzyme in blood coagulation and hemostasis
-
-
?
additional information
?
-
-
the enzyme is one of the gamma-carboxyglutamic acid-containing coagulation factors. It is formed by protein C, the proenzyme that circulates in plasma, by the action of a complex of thrombin with thrombomodulin or by serine endopeptidases present in several snake venoms
-
-
?
additional information
?
-
-
the enzyme is one of the gamma-carboxyglutamic acid-containing coagulation factors. It is formed by protein C, the proenzyme that circulates in plasma, by the action of a complex of thrombin with thrombomodulin or by serine endopeptidases present in several snake venoms
-
-
?
additional information
?
-
-
the enzyme is one of the gamma-carboxyglutamic acid-containing coagulation factors. It is formed by protein C, the proenzyme that circulates in plasma, by the action of a complex of thrombin with thrombomodulin or by serine endopeptidases present in several snake venoms
-
-
?
additional information
?
-
-
does not seem to be necessary for blood coagulation
-
-
?
additional information
?
-
-
role of protein C in the regulation of blood coagulation
-
-
?
additional information
?
-
-
activated protein C complexes with protein S on the surface of either platelets or the endothelium, these complexes catalyze the proteolytic inactivation of factors Va and VIIIa
-
-
?
additional information
?
-
-
physiological relevance of the protein C anticoagulant pathway
-
-
?
additional information
?
-
-
the enzyme is one of the gamma-carboxyglutamic acid-containing coagulation factors. It is formed by protein C, the proenzyme that circulates in plasma, by the action of a complex of thrombin with thrombomodulin or by serine endopeptidases present in several snake venoms
-
-
?
additional information
?
-
-
the enzyme is one of the gamma-carboxyglutamic acid-containing coagulation factors. It is formed by protein C, the proenzyme that circulates in plasma, by the action of a complex of thrombin with thrombomodulin or by serine endopeptidases present in several snake venoms
-
-
?
additional information
?
-
-
human umbilical vein endothelial cells respond to stimulation by enzyme with induction of COX-2-expression, enzyme promotes upregulation of prostanoid production in human endothelium
-
-
?
additional information
?
-
-
activated protein C acts as feedback inhibitor of thrombin production
-
-
?
additional information
?
-
-
activated protein C downregulates p38 mitogen-activated protein kinase p53 and improves clinical parameters in an in-vivo model of septic shock, overview, the activated enzyme prevents acidosis and tends to improve heart rate responses to endotoxia
-
-
?
additional information
?
-
-
activated protein C has endothelial barrier protective effects that require binding to endothelial protein C receptor, EPCR, and cleavage of protease activated receptor-1, PAR1, and that may play a role in the anti-inflammatory action of APC, thrombin does not exert directly barrier protective effects, overview
-
-
?
additional information
?
-
-
activated protein C has potent anticoagulant and antiinflammatory properties that are mediated in part by its interactions with its cofactor protein S and the endothelial cell protein C receptor, EPCR, the protein C/APC Gla domain is implicated in both interactions
-
-
?
additional information
?
-
-
activated protein C is a physiological anticoagulant, it also exerts anti-inflammatory and antiapoptotic effects, activated protein C inhibits the production of TNF, IL-1beta, IL-6, and IL-8 and inhibits camptothecin-induced apoptosis in a dose-dependent manner in the LPS-stimulated immortalized human monocytic cell line THP-1, activated protein C inhibited spontaneous apoptosis in primary blood monocytes from healthy individuals, activated protein C does not influence the phagocytic internalization of Gram-negative and Gram-positive bioparticles by THP-1 cells or by primary blood monocytes, it does not affect the expression of adhesion molecules by LPS-stimulated blood monocytes nor the ability of monocytes to adhere to LPS-stimulated endothelial cells
-
-
?
additional information
?
-
-
activated protein C is a plasma serine protease with systemic anticoagulant, anti-inflammatory and antiapoptotic activities, and direct vasculoprotective and neuroprotective activities, it blocks tissue plasminogen activator-mediated brain hemorrhage after transient brain ischemia and embolic stroke in mice, overview, APC inhibits a pro-hemorrhagic tissue plasminogen activator-induced, NF-kappaB-dependent matrix metalloproteinase-9 pathway in ischemic brain endothelium in vivo and in vitro by acting through protease-activated receptor 1, overview
-
-
?
additional information
?
-
-
activated protein C reduces mortality in severe sepsis patients and exhibits beneficial effects in multiple animal injury models. APC anticoagulant activity involves inactivation of factors Va and VIIIa, whereas APC cytoprotective activities involve the endothelial protein C receptor and protease-activated receptor-1, PAR-1, anticoagulantly active APC inhibits secondary extended thrombin generation and concomitant thrombin dependent activation of thrombin activable fibrinolysis inhibitor in plasma, both recombinant wild-type and mutant APCs inhibit staurosporine-induced endothelial cell apoptosis
-
-
?
additional information
?
-
-
in addition to an anticoagulant activity, activated protein C also exhibits anti-inflammatory and cytoprotective properties, but can cause bleeding because of its anticoagulant function, the cytoprotective activity of APC is mediated through inhibition of caspase-3 activity
-
-
?
additional information
?
-
-
protein C has antiinflammatory, anticoagulant and pro-fibrinolytic activities in humans, counteracting some of the main pro-inflammatory pathophysiological mechanisms in sepsis, overview, the antithrombotic effect is caused by irreversible inactivation of factors Va and VIIIa, the anti-inflammatory activity reduces formation of TNF, IL-8, IL-6 and thrombin and limits the rolling of monocytes and neutrophils on injured endothelium by binding selectins, it may reduce apoptosis, the pro-fibrinolytic activity occurs due to inhibition of PAI-1 and indirectly via reduced thrombin and thrombin-activatable fibrinolysis inhibitor
-
-
?
additional information
?
-
-
recombinant activated protein C enhances intracellular antibacterial activity, against Escherichia coli strain ATCC 25922, in presence of antibiotics, e.g. levofloxacin or ampicillin, but has no antibacterial effects without antibiotics, while it decreases the production of cytokines, such as TNF-alpha, IL-1beta and interleukin-6, but not interleukin-8, by monocytes
-
-
?
additional information
?
-
-
the activated enzyme induces signal transduction in an endothelial protein C receptor- or PAR1-dependent manner involved in apoptosis, microcirculation, and vascular permeability, the activated enzyme plays an important role in sepsis, but does not protect against sepsis, effects of long time treatment, overview, the activated enzyme induces expression of monocyte chemoattractant protein-1, MCP-1, in endothelial cells, overview
-
-
?
additional information
?
-
-
the activated protein C constitutes an important natural coagulation inhibitor and key regulator of both coagulation and inflammation
-
-
?
additional information
?
-
-
the enzyme has anticoagulant, antiapoptotic, and cytoprotective activities, mechanisms, overview, severe homozygous enzyme-deficiency causes massive, usually lethal thrombotic complications that arise in infants, heterozygous adults show a risk for venous thrombosis
-
-
?
additional information
?
-
-
the enzyme is a serine protease that regulates thrombin production through inactivation of blood coagulation factors Va and VIIIa, overview, treatment of breast cancer cells with exogenous active enzyme leads to increased invasion and chemotaxis, thereby not acting as a chemoattractant, but via endothelial protein C receptor and protease-activated receptor-1, PAR-1, receptor blocking b antibodies blocks the enzyme effects, overview, the enzyme does not increase cell division and proliferation
-
-
?
additional information
?
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the enzyme shows anticoagulation activity and can prolonge life of sepsis patients, but can also cause hemorrhage, mechanism of action and biological effects, detailed overview
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additional information
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the protein C pathway plays a key role in the regulation of blood coagulation, APC inhibits thrombin generation, and functions as a physiological anticoagulant with cytoprotective, anti-inflammatory and anti-apoptotic properties, mechanisms, overview, APC exerts its protective effects via an intriguing mechanism requiring endothelial protein C receptor and the thrombin receptor, protease-activated receptor-1, but even though APC cleaves this receptor in an identical fashion to thrombin, it exerts opposing effects, overview, administration of APC leads to reduced mortality in a subset of patients with severe sepsis, APC improves cerebral blood flow in the ischemic hemisphere and markedly reduces the volume of brain injury caused by middle cerebral vein occlusion effects, APC dramatically inhibits NFkappa B activity and TNF-alpha in monocytes from rheumatoid arthritis patients, APC protects against diabetic nephropathy by inhibiting endothelial and podocyte apoptosis, APC may have beneficial effects in patients with inflammatory lung diseases, APC stimulates new blood vessel formation and ectodermal epithelial cells to grow across the top of the gelatin sponge in the chorio-allantoic membrane assay
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additional information
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the recombinant enzyme shows antithrombotic and anticoagulant effects in a rat model of arterial thrombosis, overview
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additional information
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the recombinant human activated protein C affects apoptosis-related proteins, e.g. Bcl-2, p21, and p53, in mice, and reduces mortality in patients with severe sepsis, mechanism, overview
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additional information
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the serine protease has antithrombotic and antiinflammatory activities, that play an important role in vascular function, APC inhibits TNF-related apoptosis-inducing ligand expression and secretion and its induction by cell activation, mechanism, overview, APC affects signal transduction by increasing ERK phosphorylation, overview
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additional information
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APC activates Tie2, a tyrosine kinase receptor, not through its major ligand, angiopoietin-1, but instead by binding to endothelial protein C receptor, cleaving protease-activated receptor-1 and transactivating EGF receptor
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additional information
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APC upregulates TNF receptor-associated factor 2, TRAF2, and phosphorylates NF-kappaB p65 at Ser276 and Ser536 independently of IkappaB degradation, real-time quantitative PCR analysis, overview
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additional information
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function relationships of APC, overview
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additional information
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lower concentrations of APC, 300-30000 ng/ml, show a cell-protective effect against hypoxia in vitro, whereas higher concentrations of about 0.120 mg/ml demonstrate cytotoxicity in both RPE and photoreceptor cells
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additional information
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cleavage of protease activated receptor 3 zymogen by thrombin at Lys38 fails to induce PAR3-dependent intracellular signaling pathways but rather activates PAR1 and PAR2
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additional information
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the enzyme has anticoagulant, antiapoptotic, and cytoprotective activities, murine injury models, mechanisms, overview
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additional information
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the protein C pathway plays an important role in vascular function, and acquired deficiency during sepsis is associated with increased organ damage and dysfunction, and mortality, cecal ligation and puncture model, overview, activated protein C acts as feedback inhibitor of thrombin production and has receptor-mediated anti-inflammatory and cytoprotective effects, treatment with activated protein C results in suppression of cytokine response and improved organ function
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additional information
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activated protein C downregulates p38 mitogen-activated protein kinase p53 and improves clinical parameters in an in-vivo model of septic shock, overview
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4-Amino-D-Phe-Pro-Arg-CH2Cl
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alpha-2-Macroglobulin
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alpha1-anti-trypsin
APC inhibition by its principal plasma inhibitor alpha1-anti-trypsin
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Benzamidine hydrochloride
coagulation factor V
fV, mediates inhibition of inflammatory tissue factor signaling by enzyme aPC
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DAN-Glu-Gly-Arg-CMK
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dansyl-glutamyl-glycyl-arginyl-chloromethylketone, blocks the enzyme
diisopropyl fluorophosphate
factor Xa
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stimulates factor Va cleavage at Arg306, but inhibits the cleavage at Arg506 20fold, which is counteracted by protein S, overview, factor Xa and protein S interact with distinct sites on factor Va
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heparin
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heparin forms a complex with enzyme and inhibits optimal docking at Arg506 of substrate factor Va, instead promoting association between factor Va and enzyme at position Arg306
I2-D-Phe-Pro-Arg-CH2Cl
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Leupeptin-like inhibitor
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Macromolecular inhibitor
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conversion of glutamic acid 192 to glutamine in activated protein C increases the reactivity towards macromolecular inhibitors
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Monoclonal antibodies to human protein C
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positions of some monoclonal antibody-binding sites in the protein C molecule
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Mutants of alpha1-antichymotrypsin with P1 arginine residue
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N-(2-carboxyethyl)-3-cyclohexyl-L-alanyl-N-(4-carbamimidoylbenzyl)argininamide
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N-(4-carbamimidoylbenzyl)-2-[(3-cyclohexyl-L-alanyl)amino]-4-(piperidin-4-yl)butanamide
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N-(4-[2-[(4-carbamimidoylbenzyl)carbamoyl]-2,3-dihydro-1H-inden-2-yl]-2,2-dimethyl-4-oxobutyl)glycine
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N-(4-[2-[(4-carbamimidoylbenzyl)carbamoyl]-2,3-dihydro-1H-inden-2-yl]-2-cyclohexyl-4-oxobutyl)glycine
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N-(4-[2-[(4-carbamimidoylbenzyl)carbamoyl]-2,3-dihydro-1H-inden-2-yl]-4-oxobutyl)glycine
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N-(carboxymethyl)-3-cyclohexyl-D-alanyl-4-(aminomethyl)-N-(4-carbamimidoylbenzyl)phenylalaninamide
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N-(carboxymethyl)-3-cyclohexyl-D-alanyl-4-amino-N-(4-carbamimidoylbenzyl)-D-phenylalaninamide
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N-(carboxymethyl)-3-cyclohexyl-D-alanyl-N-(4-carbamimidoylbenzyl)-4-cyanophenylalaninamide
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N-(carboxymethyl)-3-cyclohexyl-D-alanyl-N-(4-carbamimidoylbenzyl)-D-phenylalaninamide
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N-(carboxymethyl)-3-cyclohexyl-D-alanyl-N-(4-carbamimidoylbenzyl)-D-tyrosinamide
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N-(carboxymethyl)-3-cyclohexyl-L-alanyl-N-(4-carbamimidoylbenzyl)-3-piperidin-4-ylalaninamide
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N-(carboxymethyl)-3-cyclohexyl-L-alanyl-N-(4-carbamimidoylbenzyl)-3-pyrrolidin-2-yl-D-alaninamide
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N-(carboxymethyl)-3-cyclohexyl-L-alanyl-N-(4-carbamimidoylbenzyl)-3-pyrrolidin-2-yl-L-alaninamide
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N-(carboxymethyl)-3-cyclohexyl-L-alanyl-N-(4-carbamimidoylbenzyl)argininamide
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N-[(1S)-2-([1-[(4-carbamimidoylbenzyl)amino]-1-oxo-4-(piperidin-4-yl)butan-2-yl]amino)-1-cyclohexyl-2-oxoethyl]glycine
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N-[(1S)-2-([2-[(4-carbamimidoylbenzyl)carbamoyl]-2,3-dihydro-1H-inden-2-yl]amino)-1-cyclohexyl-2-oxoethyl]glycine
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the compound shows a 21fold selectivity for activated protein C over thrombin
N-[(2R)-2-(2-[2-[(4-carbamimidoylbenzyl)carbamoyl]-2,3-dihydro-1H-inden-2-yl]-2-oxoethyl)-3-methylpentyl]glycine
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N-[(2R)-2-(2-[2-[(4-carbamimidoylbenzyl)carbamoyl]-2,3-dihydro-1H-inden-2-yl]-2-oxoethyl)-4-methylpentyl]glycine
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N-[(2R)-2-benzyl-4-[2-[(4-carbamimidoylbenzyl)carbamoyl]-2,3-dihydro-1H-inden-2-yl]-4-oxobutyl]glycine
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N-[(2R)-4-[2-[(4-carbamimidoylbenzyl)carbamoyl]-2,3-dihydro-1H-inden-2-yl]-2-(cyclohexylmethyl)-4-oxobutyl]glycine
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N-[(2R)-4-[2-[(4-carbamimidoylbenzyl)carbamoyl]-2,3-dihydro-1H-inden-2-yl]-2-ethyl-4-oxobutyl]glycine
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N-[(2R)-4-[2-[(4-carbamimidoylbenzyl)carbamoyl]-2,3-dihydro-1H-inden-2-yl]-2-methyl-4-oxobutyl]glycine
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N-[(2S)-1-([1-[(4-carbamimidoylbenzyl)amino]-1-oxo-4-(piperidin-4-yl)butan-2-yl]amino)-3-cyclohexyl-1-oxopropan-2-yl]glycine
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the compound shows a 23fold selectivity for activated protein C over thrombin
N-[(2S)-1-[[(1S)-2-[(4-carbamimidoylbenzyl)amino]-2-oxo-1-(piperidin-4-yl)ethyl]amino]-3-cyclohexyl-1-oxopropan-2-yl]glycine
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N-[(2S)-2-(2-[2-[(4-carbamimidoylbenzyl)carbamoyl]-2,3-dihydro-1H-inden-2-yl]-2-oxoethyl)-3,3-dimethylbutyl]glycine
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N-[(2S)-2-([1-benzyl-2-[(4-carbamimidoylbenzyl)amino]-2-oxoethyl]carbamoyl)-3-methylbutyl]glycine
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N-[(2S)-2-([2-[(4-carbamimidoylbenzyl)amino]-1-(2,3-dihydro-1H-inden-2-yl)-2-oxoethyl]carbamoyl)-3-methylbutyl]glycine
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N-[(2S)-2-([2-[(4-carbamimidoylbenzyl)amino]-1-(diphenylmethyl)-2-oxoethyl]carbamoyl)-3-methylbutyl]glycine
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N-[(2S)-2-([2-[(4-carbamimidoylbenzyl)carbamoyl]-2,3-dihydro-1H-cyclopenta[a]naphthalen-2-yl]carbamoyl)-3-methylbutyl]glycine
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N-[(2S)-2-([2-[(4-carbamimidoylbenzyl)carbamoyl]-2,3-dihydro-1H-cyclopenta[b]naphthalen-2-yl]carbamoyl)-3-methylbutyl]glycine
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N-[(2S)-2-([2-[(4-carbamimidoylbenzyl)carbamoyl]-2,3-dihydro-1H-phenalen-2-yl]carbamoyl)-3-methylbutyl]glycine
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N-[(2S)-2-([2-[(4-carbamimidoylbenzyl)carbamoyl]-5,6-dimethoxy-2,3-dihydro-1H-inden-2-yl]carbamoyl)-3-methylbutyl]glycine
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N-[(2S)-2-([6-[(4-carbamimidoylbenzyl)carbamoyl]-6,7-dihydro-5H-cyclopenta[b]pyridin-6-yl]carbamoyl)-3-methylbutyl]glycine
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N-[(2S)-2-([6-[(4-carbamimidoylbenzyl)carbamoyl]-6,7-dihydro-5H-cyclopenta[c]pyridin-6-yl]carbamoyl)-3-methylbutyl]glycine
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N-[(2S)-2-([6-[(4-carbamimidoylbenzyl)carbamoyl]-6,7-dihydro-5H-dibenzo[a,c][7]annulen-6-yl]carbamoyl)-3-methylbutyl]glycine
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N-[(2S)-4-[2-[(4-carbamimidoylbenzyl)carbamoyl]-2,3-dihydro-1H-inden-2-yl]-2-(1-methylethyl)-4-oxobutyl]glycine
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N-[(2S)-4-[2-[(4-carbamimidoylbenzyl)carbamoyl]-2,3-dihydro-1H-inden-2-yl]-2-cyclohexyl-4-oxobutyl]glycine
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N-[[1-(2-[2-[(4-carbamimidoylbenzyl)carbamoyl]-2,3-dihydro-1H-inden-2-yl]-2-oxoethyl)cyclopentyl]methyl]glycine
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N2-[(2S)-2-amino-2-cyclohexylacetyl]-N-(4-carbamimidoylbenzyl)argininamide
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peptide VP311-325
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a peptide comprising residues 311-325 in factor Va, potent inhibition of factor Va-dependent prothrombin activation by factor Xa in the absence of APC, the peptide also inhibits the inactivation of factor Va by APC by APC-dependent cleavage of both Arg506 and Arg306, thus inhibits cleavage of wild-type factor Va and of the mutant R306Q and R506Q, overview
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Phe-Pro-Arg-chloromethylketone
phenylmethylsulfonyl fluoride
Platelet plasminogen activator inhibitor
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reacts with the enzyme to yield both, an SDS-stable complex and a modified inhibitor
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ProTac
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a protein C activator isolated from snake venom
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protein C inhibitor PCI
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inhibition stimulated by heparin
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protein S
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the cofactor is active as free protein and in complex with C4b binding protein, the latter shows a less potent effect, activation up to 10fold, but the complex inhibits proteolysis at Arg506 by 3-4fold, overview
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Zn2+
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Zn2+ enhances the binding of protein C/activated protein C to endothelial cell protein C receptor on endothelial cells by increasing the binding affinities. Zn2+ binding induces conformational changes in protein C/APC. Zn2+ binding to APC inhibits the amidolytic activity of APC, but the inhibition is reversed by Ca2+. Zn2+ increases the rate of APC generation on endothelial cells in the presence of physiological concentrations of Ca2+, but does not further enhance increased APC generation obtained in the presence of physiological concentrations of Mg2+ with Ca2+. Zn2+ has no effect on the anticoagulant activity of APC. Zn2+-mediated inhibition of APC amidolytic activity rather than the direct inhibition of protein C activation
[[(2R)-1-[[(2R)-1-[(4-carbamimidoylbenzyl)amino]-3-(naphthalen-1-yl)-1-oxopropan-2-yl]amino]-3-cyclohexyl-1-oxopropan-2-yl]amino]acetic acid
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non-preferred name
[[(2R)-1-[[(2R)-1-[(4-carbamimidoylbenzyl)amino]-3-(naphthalen-2-yl)-1-oxopropan-2-yl]amino]-3-cyclohexyl-1-oxopropan-2-yl]amino]acetic acid
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non-preferred name
alpha1-antitrypsin
APC anti-coagulant activity is eventually inhibited by the action of the serpins alpha1-antitrypsin and protein C inhibitor, which irreversibly bind and inactivate APC prior to clearance
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alpha1-antitrypsin
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major physiological inhibitor
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alpha1-antitrypsin
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P1-Arg-alpha1-antitrypsin
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alpha1-antitrypsin
APC anti-coagulant activity is eventually inhibited by the action of the serpins alpha1-antitrypsin and protein C inhibitor, which irreversibly bind and inactivate APC prior to clearance
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Benzamidine hydrochloride
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Benzamidine hydrochloride
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diisopropyl fluorophosphate
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diisopropyl fluorophosphate
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Phe-Pro-Arg-chloromethylketone
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Phe-Pro-Arg-chloromethylketone
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inhibits the active site of recombinant activated protein C
phenylmethylsulfonyl fluoride
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phenylmethylsulfonyl fluoride
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Protein C inhibitor
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bovine plasma protein C inhibitor is structural and functional homologous to human plasma protein C inhibitor
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Protein C inhibitor
APC anti-coagulant activity is eventually inhibited by the action of the serpins alpha1-antitrypsin and protein C inhibitor, which irreversibly bind and inactivate APC prior to clearance
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Protein C inhibitor
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is a potent inhibitor of the protein C anticoagulant pathway at the levels of both zymogen activation and enzyme inhibition
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Protein C inhibitor
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inhibits activated protein C by forming an enzyme-inhibitor complex accompanied with the proteolytic modification of the inhibitor by the enzyme
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Protein C inhibitor
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is the only inhibitor in plasma against activated protein C
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Protein C inhibitor
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bovine plasma protein C inhibitor is structural and functional homologous to human plasma protein C inhibitor
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Protein C inhibitor
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Protein C inhibitor
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purification
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Protein C inhibitor
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inhibits wild-type enzyme and mutants E167A and E170A
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Protein C inhibitor
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inactivates
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Protein C inhibitor
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Protein C inhibitor
APC anti-coagulant activity is eventually inhibited by the action of the serpins alpha1-antitrypsin and protein C inhibitor, which irreversibly bind and inactivate APC prior to clearance
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prothrombin
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prothrombin
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addition results in a 10fold decreased inactivation rate in absence and 4fold in presence of protein S, overview
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prothrombin
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inhibits the binding of APC(S360A) to FVa
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additional information
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factor IX does not inhibit the anticoagulant activity of APC in plasma
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additional information
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wild-type inactive protein C and inactive protein C mutant S360A inhibit the binding of activated protein C to the endothelial protein C receptor
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additional information
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inhibitor structure-activity relationship, overview
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additional information
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addition of blocking mAbs against beta1 or beta3 integrins partially displaces recombinant activated protein C from the cell surface. Cyclic RGD peptide Ac-c[(Pen)-Tyr(Me)-Ala-Arg-Gly-Asp-Asn-Tic-Cys]NH2 also significantly inhibits recombinant activated protein C binding, whereas blocking anti-beta2 integrin (non-RGD binding integrin) mAb has no effect
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additional information
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binding of APC(S360A) to FVa is not affected by protein S
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additional information
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design, synthesis, and structure-activity relationship of a series of activated protein C inhibitors with selectivity against thrombin by a basic and/or aromatic functionality for binding to the S2 pocket, for the treatment of haemophilia
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malfunction
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severe thrombophilia occurs with deficiencies in phosphatidylcholine or phosphatidylserine and with a mutation in factor Va that prevents its inactivation by APC, known as Factor V Leiden
malfunction
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naturally occuring mutation G216D in the specificity pocket of the enzyme causes protein C deficiency. Superposition of the integrin binding motifs in wild-type and mutant forms suggests that the interaction with integrin can still occur and thus the mutant is likely to retain its antiseptic function related to the neutrophyl integrin binding
malfunction
a recombinant APC variant (APCN329Q) mimicking the naturally occurring APC-beta plasma glycoform exhibits superior PAR1 proteolysis at a cleavage site that selectively mediates cytoprotective signaling.Mutant APCN329Q also enhances integrin aMb2-dependent PAR1 proteolysis to exert significantly improved anti-inflammatory activity on macrophages compared with wild-type APC
malfunction
a recombinant APC variant (APCN329Q) mimicking the naturally occurring APC-beta plasma glycoform exhibits superior PAR1 proteolysis at a cleavage site that selectively mediates cytoprotective signaling.Mutant APCN329Q also enhances integrin aMb2-dependent PAR1 proteolysis to exert significantly improved anti-inflammatory activity on macrophages compared with wild-type APC. Enhanced cytoprotective PAR1 signaling by APC-beta is a consequence of accelerated EPCR-dependent PAR1 proteolysis
malfunction
APC's cleavage in protease activated receptor 1 at a noncanonical Arg46 site through the APC mutant 3K3A-APC causes biased signaling that provides a major explanation for APC's in vivo mechanism of action for neuroprotective activities. Structure-activity relationships of protein C is used to analyse protein C dysfunction in venous thrombosis patients who have protein C mutations
malfunction
blocking Tie2 restricts endothelial barrier integrity. On blocking the Tie2 receptor, binding between APC and Tie2 is inhibited significantly irrespective of APC concentration
malfunction
coagulation factor V mediates inhibition of tissue factor signaling by activated protein C in mice. aPC resistance of factor (f)V due to the R506Q Leiden mutation protects against detrimental anticoagulant effects of aPC therapy but also abrogates the anti-inflammatory and mortality reducing effects of the signaling-selective 5A-aPC variant that has minimal anticoagulant function. aPC resistance of fV Leiden suppresses in vitro regulation of inflammatory gene expression by aPC, overview
malfunction
Mac-1 inhibition prevents APC attenuation of pro-inflammatory cytokine release from lipopolysaccharide (LPS)-stimulated murine macrophages. Furthermore, APC administration does not significantly reduce mortality in Mac-1 deficient endotoxemic mice, suggestive of an important role for Mac-1-dependent PAR1 activation on myeloid cells for the ability of APC to limit mortality in murine endotoxemia
malfunction
potent neuroprotection in murine ischemic stroke models is linked to enzyme mutant 3K3A-APC-induced signaling that arises due to APC's cleavage in protease activated receptor 1 at a noncanonical Arg46 site. This cleavage causes biased signaling that provides a major explanation for APC's in vivo mechanism of action for neuroprotective activities. Mice carrying the 46QQ-PAR1 point mutation strongly support the concept that APC-induced, PAR1-dependent biased signaling following Arg46 cleavage is central to APC's in vivo neuroprotective benefits in this model of ischemic stroke
metabolism
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the procoagulant role of the protein C pathway may have important implications for the regulation of TF- and TFPI-dependent biologic responses and for fine tuning of the hemostatic balance in the vascular system
metabolism
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the protein C pathway plays a key role in blood coagulation and inflammation
metabolism
activated protein C is the key effector molecule of the natural protein C pathway. Biological function and mechanism of the protein C pathway in which protein S and the aPC-cleaved form of factor V are cofactors for anti-inflammatory cell signaling by aPC in the context of endotoxemia and infection, overview
metabolism
other cell receptors, especially endothelial cell protein C (EPCR) and PAR3 inter alia, may also significantly contribute to APC-initiated cell signaling. APC anticoagulant and cell signaling pathways and the structure of signaling-selective 3K3A-APC, overview
metabolism
other cell receptors, especially endothelial cell protein C (EPCR) and PAR3 inter alia, may also significantly contribute to APC-initiated cell signaling. PAR1 internalization after activation by either thrombin or APC. APC anticoagulant and cell signaling pathways and the structure of signaling-selective 3K3A-APC, overview
physiological function
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activated protein C and its cofactor, protein S in the presence of a membrane surface cleaves and inactivates the cofactors of the intrinsic and prothrombinase complexes, factor VIIIa and factor Va, respectively
physiological function
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activated protein C downregulates thrombin formation through proteolytic inactivation of factor Va and factor VIIIa, the anticoagulant activity may be important for in vivo regulation of thrombin formation
physiological function
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activated protein C has anti-apoptotic effects and improves survival in sepsis, activated protein C prevents endothelial cell apoptosis, induced by serum from patients with malaria or sepsis. Activated protein C alone lowers the endothelial cell apoptosis rate from 48% to 38% in the presence of patient serum, In combination with ascorbic acid, activated protein C lowers the apoptosis rate to 25% and in combination with ulinastatin to 23%
physiological function
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activated protein C inhibits bisphosphonate-induced endothelial cell death via the endothelial protein C receptor and nuclear factor-kappaB pathways, protective effects and mechanism, overview. APC inhibits induction of cell death by alendronate, zoledronate, and pamidronate, and diminishes activation of caspase-3 by the bisphosphonates
physiological function
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activated protein C inhibits high mobility group box 1 signaling in endothelial cells, protective effects of APC are mediated through endothelial cell protein C receptor and protease-activated receptor 1, PAR-1. APC potently inhibits the release of HMGB1, downregulates the expression of HMGB1 receptors, and downregulates the adhesion of the monocytic cell line, THP-1, to HMGB1-activated endothelial cells, and it also down-regulates the cell surface expression of all 3 HMGB1 receptors in endothelial cells
physiological function
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activated protein C is a natural anticoagulant protease that displays cytoprotective and antiinflammatory activities and has been demonstrated to reduce mortality of patients with severe sepsis. Protective cross talk between activated protein C and TNF signaling in vascular endothelial cells, overview. APC signaling causes a moderate but significant induction of cell adhesion molecules including VCAM-1 at mRNA and protein levels. Activation of the noncanonical NF-kappaB and ERK1/2 are both pivotal to APC signaling leading to VCAM-1 expression, PAR1 and EPCR equally mediate APC signaling that triggers VCAM-1 expression. APC upregulates TNF receptor-associated factor 2, TRAF2, and phosphorylates NF-kappaB p65 at Ser276 and Ser536 independently of IkappaB degradation, and it shows a regulatory effect on VCAM-1 expression, detailed overview. Ability of APC to activate ERK1/2 in resting cells and to enhance ERK activation in TNF-treated cells, activated ERK1/2 MAPK serves as an antiinflammatory signal in endothelial cells
physiological function
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activated protein C is a natural anticoagulant with anti-inflammatory and endothelial barrier protective properties, which significantly increases the barrier impedance of keratinocyte monolayers, overview. APC also increases junction proteins zona occludens, claudin-1 and VE-cadherin. APC activates Tie2, via a mechanism requiring, in sequential order, the receptors, endothelial protein C receptor, protease activated receptor-1, and EGF receptor, which selectively enhances the PI3K/Akt signaling to enhance junctional complexes and reduce keratinocyte permeability. Inhibition of Tie2 by its peptide inhibitor or small interfering RNA abolishes the barrier protective effect of APC on keratinocytes, as well as inhibition of the activation of Akt, but not ERK
physiological function
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activated protein C is a serine protease that downregulates coagulation by proteolytically inactivating cofactors FVa and factor VIIIa, activated protein C proteolytically inactivates factor Va and thereby down regulates prothrombinase. Prothrombinase is inactivated by aPC during prothrombin activation much more slowly than Factor Va is inactivated in the absence of Factor Xa and prothrombin
physiological function
-
activated protein C is an anticoagulant serine protease with non-hemostatic functions related to inflammation, cell survival, and cell migration. Activated protein C enhances cell motility of endothelial cells and MDA-MB-231 breast cancer cells by intracellular signal transduction, mechanism by which APC promotes angiogenesis and breast cancer invasion, overview. APC activation of matrix metalloproteases 2 and/or 9 is necessary but not sufficient to increase invasion, and APC does not utilize the endogenous plasminogen activation system to increase invasion. APC activates the ERK, Akt, and NFkappaB, but not the JNK pathway to promote MDA-MB-231 cell motility. APC proteolytically inactivates factors Va and VIIIa in the presence of protein S. APC forms a stable complex with PAI-1, thereby removing a potent inhibitor of urokinase plasminogen activator, EC 3.4.21.73, from the system. APC promotes MDA-MB-231 breast cancer cell invasion through EPCR and PAR-1, and MDA-MB-231 cell chemotaxis through MAPK and PI3K/Akt activation
physiological function
-
activated protein C modulates inflammation, apoptosis and tissue factor procoagulant activity by regulating endoplasmic reticulum calcium depletion in blood monocytes. Protective effects of APC treatment in severe sepsis. APC decreases phosphorylated eukaryotic translational initiation factor 2alpha and C/EBP homologous protein levels induced by thapsigargin. APC inhibits thapsigargin-induced ER Ca2+ flux and reactive oxygen species generation. Functionally, APC diminishes thapsigargin-induced caspase-3 activity and degradation of the nuclear factor kappaB inhibitor IkappaBalpha. Furthermore, APC dampens the induction of tissue factor procoagulant activity facilitated by thapsigargin, and APC dampens unfolded protein response activation
physiological function
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activated protein C promotes fibrinolysis while inhibiting coagulation and inflammation. Although aPC does not affect ET-1-dependent sinusoidal vasoconstriction, it induces hepatoprotective effects via enhanced red blood cell velocity. aPC ameliorates ET-1-dependent changes in hepatic microcirculation and improves hepatic function in the setting of sepsis in rats
physiological function
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activated protein C upregulates TF activity by endothelial cell protein C receptordependent shedding of the Kunitz 1 domain from membrane-associated TFPI. Exogenous or endogenously generated APC leads to increased TF-dependent factor Xa activity. Induction requires APC's proteolytic activity and binding to endothelial cell protein C receptor but not protease activated receptors, mechanism, overview. APC does not affect total TF antigen expression or the availability of anionic phospholipids on the apical cell membrane
physiological function
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APC inhibits activation of caspase-3, -8, and -9 by hypoxia
physiological function
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protein C is the central enzyme of the natural anticoagulant pathway, its activated form activated protein C is able to proteolyse non-active as well as active coagulation factors V and VIII in a protein S and factor V dependent manner, mechanism, overview. Proteolysis renders these cofactors inactive, resulting in an attenuation of thrombin formation and overall downregulation of coagulation. The activated enzyme also has direct cytoprotective effects on cells, since it is able to protect the endothelial barrier function and expresses anti-inflammatory and anti-apoptotic activities. Both the protease activated receptor 1 and EPCR are essential for the cytoprotective activity of APC. Also other receptors like sphingosine 1-phosphate receptor 1, Cd11b/CD18 and tyrosine kinase with immunoglobulin-like and EGFlike domains 2 are likewise important for APC signalling. The N-terminal Gla-domain, residues 1-45, confers protein C its membrane and EPCR binding capacity and contributes to the binding between APC and protein S, the C-terminus of the Gla-domain, residues 25-45, and particularly D35, D36, L38 and A39 were shown to interact with protein S
physiological function
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treatment with recombinant activated protein C reduces the activation of splenic dendritic cells as well as systemic inflammation in MRL-Fas(lpr) mice. Activated protein C attenuates systemic lupus erythematosus and lupus nephritis in autoimmune female MRL-Fas(lpr) mice injected with recombinant human activated protein C, overview. Activated protein C treatment significantly suppresses lupus nephritis as evidenced by decrease in activity index, glomerular IgG and complement C3 deposits, macrophage counts, as well as intrarenal IL-12 expression. Further, activated protein C attenuates cutaneous lupus and lung disease as compared with vehicle-treated MRL-Fas(lpr) mice. In addition, parameters of systemic autoimmunity, such as plasma cytokine levels of IL-12p40, IL-6, and CCL2/MCP-1, and numbers of B cells and plasma cells in spleen are suppressed by activated protein C
physiological function
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activated protein C has a protective efficacy against ischemia-reperfusion injury in several organs, e.g. in myocardium, possible mechanism, overview. The enzyme improves ischemia-reperfusion injury in spinal cord as neuroprotective effect through insulin like growth factor and AKT1 cascade. AKT1 is one of signals that prevent from heart failure
physiological function
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activated protein C induces endoplasmic reticulum stress and attenuates lipopolysaccharide-induced apoptosis both mediated by glycogen synthase kinase-3beta. Activated protein C elicits a rise in glucose-regulated protein 78 and glycogen synthase kinase-3beta and inhibits apoptosis in human umbilical vein endothelial cells induced by lipopolysaccharide. Calcium inhibition does not alter the antiapoptotic effect of activated protein C
physiological function
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activated protein C is a natural anticoagulant that exerts anti-inflammatory and cytoprotective effects in various diseases via endothelial protein C receptor and proteinase-activated receptor-mediated pathways. Activated protein C inhibits proliferation and tumor necrosis factor alpha-stimulated activation of p38, c-Jun NH2-terminal kinase, and Akt in rheumatoid synovial fibroblasts. The enzyme induces the phosphorylation of extracellular signal-regulated protein kinase and enhances expression of p21 and p27 in a dose-dependent manner in rheumatoid synovial fibroblasts. The enzyme stimulates proliferation of normal human dermal fibroblasts by up to 60%, but robustly downregulates proliferation of rheumatoid synovial fibroblasts
physiological function
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activated protein C is a natural anticoagulant with strong cyto-protective and anti-inflammatory properties and inhibits pancreatic islet inflammation, stimulates T regulatory cells, and prevents diabetes when regularly injected into non-obese diabetic BALB/c mice, islets of which exhibit markedly increased expression of insulin, aPC/protein C, endothelial protein C receptor, and matrix metalloproteinase-2. Culture of non-obese diabetic mouse spleen cells with the recombinant human enzyme reduces the secretion of inflammatory cytokines interleukin-1beta and interferon-beta1 but increases interleukin-2 and transforming growth factor-beta1, two cytokines required for Treg differentiation, overview
physiological function
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activated protein C is an important factor in the anticoagulant system. It also regulates amyloid beta secretion by shifting amyloid beta precursor protein processing from the amyloidogenic pathway toward the nonamyloidogenic pathway. ADAM-10 expression is increased by the enzyme and inhibits amyloid beta secretion by stimulating activity of alpha-secretase, expression of presenilin-1 is not influenced by the enzyme in SH-SY5Ycells
physiological function
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direct cytoprotective activities of activated protein C on cells convey therapeutic, relevant, beneficial effects in injury and require the endothelial protein C receptor and protease activated receptor 3, PAR3. In vivo, the enzyme-derived PAR3 tethered-ligand peptide, but not the thrombin-derived PAR3 peptide, blunts vascular endothelial growth factor-induced vascular permeability
physiological function
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microvascular thrombosis occurs in severe acute pancreatitis, injection of recombinnat activated protein C in a rat model does not modify coagulation parameters or lead to hemorrhage but ameliorates pancreatic injury with preservation of IkappaB and reduction of NF-kappaB p65 and modulation of apoptosis, overview
physiological function
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the activated protein C plays a central role in physiological anticoagulation, and has potent anti-inflammatory mediator and cytoprotective properties. Activated protein C is a cytoprotective anticoagulant that can promote cutaneous healing. The enzyme favorably regulates MG63 viability and differentiation toward bone growth. Bisphosphonates alendronate, zoledronate or pamidronate induce MG-63 cell death in a dose- and time-dependent manner. Pamidronate- and zoledronate-related cell death is prevented by the enzyme treatment, but cell death induced by alendronate is accelerated by the enzyme. The enzyme induces MG-63 cell differentiation that is enhanced by alendronate, but inhibited by pamidronate or zoledronate. Endothelial protein C receptor is expressed by MG-63 cells and mediates the protective effect of the enzyme on zoledronate-induced viability. Expression of type 1 collagen and endothelial protein C receptor is induced by activated protein C treatment in MG-63 cells
physiological function
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the enzyme has anticoagulant function in the coagulation system counteracting apoptosis and inflammation in cells. the antiseptic activity of the enzyme is mediated by its binding to leukkocyte integrins, the integrin-binding motif of the enzyme locates at the N-terminus of the catalytic chain
physiological function
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the enzyme is a major regulator of blood coagulation by inactivating factors Va and VIIIa. O-ghrelin(15) has no effect
physiological function
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the enzyme is a major regulator of blood coagulation by inactivating factors Va and VIIIa. O-ghrelin(15) has no effect
physiological function
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the enzyme is a major regulator of blood coagulation by inactivating factors Va and VIIIa. O-ghrelin(15) has no effect
physiological function
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the enzyme significantly reduced thrombin-induced cell monolayer permeability, cell stiffening, and cell contraction. The enzyme reduces the disruption of barrier integrity induced by thrombin, thus contributing to alveolar epithelial barrier protection, overview
physiological function
activated protein C (APC) is a blood protease with anticoagulant activity and cell-signaling activities mediated by activation of protease-activated receptors 1 and 3 (PAR1, PAR3) via non-canonical cleavage1. Recombinant APC and/or its analogues with reduced by over 90% anticoagulant activity such as mutant 3K3A-APC (K191A/K192A/K193A), engineered to reduce APC-associated bleeding risk while retaining normal cell signaling activity, have shown benefits in preclinical models of ischemic stroke, brain trauma, multiple sclerosis, amyotrophic lateral sclerosis, sepsis, ischemic/reperfusion injury of heart, kidney and liver, pulmonary, kidney and gastrointestinal inflammation, diabetes, and lethal body radiation. Enzyme mutant 3K3A-APC stimulates neuronal production by human neural stem/progenitor cells (NSCs) in vitro via a PAR1-PAR3-sphingosine-1-phosphate receptor 1-Akt pathway. Effects of late post-ischemic 3K3A-APC treatment on the in vivo production of neurons from transplanted NSCs in C57BL/6J mice, and the effects of this combination therapy on long-term neurological recovery and restoration of disrupted neural circuitry in the post-ischemic murine brain, functional integration of NSCs into the host neuronal circuitry, overview
physiological function
Activated protein C (APC) is a vitamin K-dependent serine protease that plays a key role in the regulation of blood coagulation but also exerts a broad range of cytoprotective actions on endothelium including suppression of inflammation and stabilization of endothelial barrier function. Activated protein C (APC) is a natural anticoagulant with strong anti-inflammatory, anti-apoptotic, and barrier stabilizing properties. These cytoprotective properties of APC are thought to be exerted through its pathway involving the binding of APC to endothelial protein C receptor and cleavage of protease-activated receptors. APC enhances endothelial barrier integrity via a novel pathway, by binding directly to and activating Tie2, a transmembrane endothelial tyrosine kinase receptor. After binding, APC rapidly activates Tie2 to enhance endothelial barrier function. APC-mediated cytoprotective signaling requires endothelial protein C receptor (EPCR) and cleavage of protease-activated receptor (PAR)1 at Arg46, which may occur in caveolin-1-enriched lipid rafts. In addition, other receptors, such as sphingosine-1-phosphate receptor 1 (S1P1), epidermal growth factor receptor (EGFR), PAR3, and Tie2, may independently or co-operatively contribute to APC-mediated protective effects on endothelium. For example, APC protects against endothelial barrier disruption by cross-activating S1P1 or by stimulating Ang1 whilst inhibiting Ang2 to activateTie2, both these mechanisms require signaling through EPCR and PAR1. APC rapidly suppresses endothelial permeability via Tie2. APC signals through Tie2 to reverse vascular leakage in vivo. Tie2-I alone does not affect EBA leakage into the kidneys or lungs. The protective effect of APC is significantly reversed by Tie2-I in all experiments
physiological function
activated protein C (APC) is an anticoagulant protease that initiates cell signaling via protease-activated receptor 1 (PAR1) to regulate vascular integrity and inflammatory response. Importance of APC glycosylation in controlling the efficacy of PAR1 proteolysis by APC
physiological function
activated protein C (APC) is an anticoagulant protease that initiates cell signaling via protease-activated receptor 1 (PAR1) to regulate vascular integrity and inflammatory response. Importance of APC glycosylation in controlling the efficacy of PAR1 proteolysis by APC. Analysis of APC inhibition of cytokine secretion from RAW-264.7 cells. APC-beta exhibits superior inhibition of cerebral injury in murine ischemic stroke
physiological function
coagulation-independent cell signaling by aPC appears to be the predominant mechanism underlying its highly reproducible therapeutic efficacy in most animal models of injury and infection. Using a mouse model of Staphylococcus aureus sepsis,marked disease stage-specific effects of the anticoagulant and cell signaling functions of aPC are demonstrated. Factor V and protein S are required for sepsis mortality reduction and suppression of inflammatory gene expression by activated protein C. Procofactor V (cleaved by aPC at R506) and protein S are necessary cofactors for the aPC-mediated inhibition of inflammatory tissue-factor signaling. The antiinflammatory cofactor function of fV involves the same structural features that govern its cofactor function for the anticoagulant effects of aPC, yet its anti-inflammatory activities do not involve proteolysis of activated coagulation factors Va and VIIIa. Sepsis stage-related response to infusion of aPC variants, overview. Inhibition of tissue factor-EPCR-PAR2 signaling by enzyme aPC requires protein S and the factor V B domain. aPC inhibits PAR2 activation by the ternary tissue factor-factor VIIa-factor Xa complex
physiological function
protein C is a plasma serine protease zymogen whose active form, activated protein C (APC), exerts potent anticoagulant activity. In addition to its antithrombotic role as a plasma protease, pharmacologic APC is a pleiotropic protease that activates diverse homeostatic cell signaling pathways via multiple receptors on many cells. Enzyme APC shows cytoprotective and neurogenerative activities which most often, but not always, involve PAR1 and EPCR, often other receptors are required, such as PAR3, sphingosine phosphate 1 receptor 1 (S1P1), the integrin Mac-1 or other beta1 and beta3 integrins, apolipoprotein E receptor 2, epidermal growth factor receptor, and Tie-2 (tunica intima endothelial receptor tyrosine kinase 2). Neuroprotective effects of APC in the neurovascular space and in neurons, overview. APC's neuronal protective actions require PAR1 and PAR3. Enzyme mutant 3K3A-APC promotes neurogenesis in vitro as well as in vivo in the murine middle cerebral artery occlusion stroke model, using human fetal neural stem and progenitor cells
physiological function
protein C is a plasma serine protease zymogen whose active form, activated protein C (APC), exerts potent anticoagulant activity. In addition to its antithrombotic role as a plasma protease, pharmacologic APC is a pleiotropic protease that activates diverse homeostatic cell signaling pathways via multiple receptors on many cells. Enzyme APC shows cytoprotective and neurogenerative activities which most often, but not always, involve PAR1 and EPCR, often other receptors are required, such as PAR3, sphingosine phosphate 1 receptor 1 (S1P1), the integrin Mac-1 or other beta1 and beta3 integrins, apolipoprotein E receptor 2, epidermal growth factor receptor, and Tie-2 (tunica intima endothelial receptor tyrosine kinase 2). Neuroprotective effects of APC in the neurovascular space and in neurons, overview. APC's neuronal protective actions require PAR1 and PAR3. Enzyme mutant 3K3A-APC promotes neurogenesis in vitro as well as in vivo in the murine middle cerebral artery occlusion stroke model, using human fetal neural stem and progenitor cells
physiological function
the anticoagulant-activated protein C (APC) acts not solely as a crucial regulator of thrombus formation following vascular injury, but also as a potent signalling enzyme with important functions in the control of both acute and chronic inflammatory disease
physiological function
the anticoagulant-activated protein C (APC) acts not solely as a crucial regulator of thrombus formation following vascular injury, but also as a potent signalling enzyme with important functions in the control of both acute and chronic inflammatory disease. Distinct from its crucial role in regulating blood coagulation, APC initiates cell signalling via engagement with multiple cell surface receptors. Although APC triggers an array of signalling pathways via distinct receptor interactions on different cell types, APC signalling is invariably cytoprotective, conferring protection against exposure to pro-inflammatory and/or pro-apoptotic agents. Prototypical APC signalling on endothelial cells involves initial binding to EPCR that in turn facilitates proteolysis and activation of protease-activated receptor 1 (PAR1). APC binding to EPCR is a pre-requisite for PAR3 activation by APC, which mediates similar protective signalling outputs as PAR1 activation. The role of EPCR as an APC co-receptor for PAR1 signalling can also be assumed by the integrin alphaMbeta2 (macrophage-1 antigen, Mac-1)
physiological function
the anticoagulant-activated protein C (APC) acts not solely as a crucial regulator of thrombus formation following vascular injury, but also as a potent signalling enzyme with important functions in the control of both acute and chronic inflammatory disease. The proteolytic inactivation of FVa/FVIIIa by APC with protein S slows further thrombin generation and thus acts as a negative feedback loop to inhibit thrombus growth. Distinct from its crucial role in regulating blood coagulation, APC initiates cell signalling via engagement with multiple cell surface receptors. Although APC triggers an array of signalling pathways via distinct receptor interactions on different cell types, APC signalling is invariably cytoprotective, conferring protection against exposure to pro-inflammatory and/or pro-apoptotic agents. Prototypical APC signalling on endothelial cells involves initial binding to EPCR that in turn facilitates proteolysis and activation of protease-activated receptor 1 (PAR1). APC binding to EPCR is a pre-requisite for PAR3 activation by APC, which mediates similar protective signalling outputs as PAR1 activation. APC can also promote anti-inflammatory signalling on myeloid cells in a PAR-independent manner. APC binds apolipoprotein E receptor 2 (ApoER2) to trigger Dab1 phosphorylation and activate phosphoinositide 3-kinase (PI3K)/Akt/glycogen synthase kinase 3beta (GSK3beta)-dependent signalling in monocytic U-937 cells. APC might interact concurrently with other APC receptors on monocytes
physiological function
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activated protein C has a protective efficacy against ischemia-reperfusion injury in several organs, e.g. in myocardium, possible mechanism, overview. The enzyme improves ischemia-reperfusion injury in spinal cord as neuroprotective effect through insulin like growth factor and AKT1 cascade. AKT1 is one of signals that prevent from heart failure
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physiological function
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the enzyme is a major regulator of blood coagulation by inactivating factors Va and VIIIa. O-ghrelin(15) has no effect
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additional information
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a TFPI Lys86Ala mutation between the Kunitz 1 and 2 domains eliminates both cleavage and the enhanced TF activity in response to APC in overexpression studies
additional information
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APC generation is dependent on protein C binding to endothelial cell protein C receptor, EPCR, and thrombin binding to thrombomodulin
additional information
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function relationships of APC, overview. Presence of the APC cofactor, protein S, thrombomodulin, endothelial protein C receptor and a phospholipid surface are important for the expression of anticoagulant APC activity. Two or three cation binding-sites in the Gla-domain are occupied, resulting in a conformational change of the Gla-domain. Second, a group of four or five divalent cation binding sites with a high specificity for Ca2+ become occupied, enabling binding of the protein to acidic phosphalipid vesicles. Ca2+ interactions are essential for the anticoagulant functions of APC and are influenced by mutations in different regions of the Gla-domain. Residues R15, C22 and Gla-residues 6, 7, 16, 20, 25, 26 and 29 are thus absolutely required for APCs anticoagulant function
additional information
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residues Arg336 and Arg562 are involved in the catalytic mechanism
additional information
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enzyme peptide mass fingerprinting analysis
additional information
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molecular model of the complex of APC with alphaVbeta3 integrin obtained by protein-protein docking approach, molecular dynamics and docking simulation of natural mutant G216D of activated protein C with impaired protease activity, implications for integrin-mediated antiseptic function, overview
additional information
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enzyme peptide mass fingerprinting analysis
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D167F/D172G
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at saturating Ca2+ concentrations, the activation rates of the mutant and wild-type protein C by the thrombin-TM complex are comparable, but the mutant requires four-fold higher Ca2+ concentrations than wild-type APC to achieve half-maximal activation rates. When only thrombin is present, Ca2+ is not able to influence the activation of the D167F/D172G mutant, though Ca2+ effectively inhibits activation of wild-type protein C by thrombin
D222E
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mutation of the Arg-Gly-Asp sequence abolishes both integrin binding and inhibition of neutrophil migration
D35T/D36A
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site-directed mutagenesis, the mutant shows slightly increased factor Va proteolysis compared to the wild-type enzyme, the activation by protein S is reduced
E149A
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the cytoprotective effects of the APC mutant are severely diminished, despite a normal cleavage of PAR-1 and normal binding to EPCR. E149A-APC expresses only 6% of the anti-apoptotic activity of wild-type APC in a staurosporine-induced apoptosis model in endothelial cells and was unable to down-regulate IL-6 release in lipopolysaccharide treated U937 monocytes
E167A
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site-directed mutagenesis, the surface loop residue mutation eliminates the cytoprotective signaling properties of APC without affecting its anticoagulant activity, inability of E167A to exhibit significant protective activity in response to TNF-alpha-induced inflammatory events in endothelial cells
E16D
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site-directed mutagenesis, the mutation causes aberrant Ca2+ binding and Gla domain misfolding
E170A
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site-directed mutagenesis, the surface loop residue mutation eliminates the cytoprotective signaling properties of APC without affecting its anticoagulant activity, inability of E170A to exhibit significant protective activity in response to TNF-alpha-induced inflammatory events in endothelial cells
E20A/V34M
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the mutation is associated with thrombotic complications, despite the fact that carriers of these mutations have normal protein C antigen levels and APC amidolytic activity
E357Q
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E357 is involved in binding of macromolecular substrates. Engineered E357Q-APC shows two to threefold improved FVa inactivation, but slightly reduced anticoagulant activity in plasma compared to wild-type APC
E7D
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the mutation is associated with thrombotic complications, despite the fact that carriers of these mutations have normal protein C antigen levels and APC amidolytic activity
G216D
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a naturally occuring mutation, the mutant shows impaired protease activity, while preserving the overall protein fold. Superposition of the integrin binding motifs in wild-type and mutant forms suggests that the interaction with integrin can still occur and thus the mutant is likely to retain its antiseptic function related to the neutrophyl integrin binding
H10Q/S11G/S12N/D23S/Q32E/N33D/H44Y
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naturally occuring Gla-domain mutant, the mutant enzyme shows a higher anticoagulant effect compared to the wild-type enzyme, the combination with the B148 mutation in the serine protease domain even enhances the effect, overview
K174E
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site-directed mutagenesis, the activation rate of the mutant by thrombin is 12fold faster than that observed for wild-type protein C in the presence of Ca2+, and unchanged in the absence of Ca2+. Thrombin does not stimulate activation of the protein C variant
K191A
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Km- and kcat-value similar to wild-type, minor contribution to interaction with thrombin-thrombomodulin
K192A
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Km- and kcat-value similar to wild-type, major contribution to interaction with thrombin-thrombomodulin
K217A
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Km- and kcat-value similar to wild-type, minor contribution to interaction with thrombin-thrombomodulin
K218A
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Km- and kcat-value similar to wild-type, minor contribution to interaction with thrombin-thrombomodulin
K37S/K38Q/K39Q
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created by site-directed in vitro mutagenesis
K37S/K38Q/K39Q/K62N/K63D
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created by site-directed in vitro mutagenesis
K78A
prepared by PCR methods
L38D
site-directed mutagenesis, creation of an APC variant with individual amino acid substitutions within this region, L38D is the main source of lost anti-coagulant activity. Despite this, APC-L38D retains the ability to mediate PAR1-dependent signalling properties on endothelial cells
L8Q
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mutant variants L8Q and R9H show reduced affinity for EPCR and can contribute to the reduced anticoagulant activity
N33S/V34S/D35T/D36A/L38D/A39V
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site-directed mutagenesis, the mutant shows slightly increased factor Va proteolysis compared to the wild-type enzyme, no activation by protein S
P168V
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at saturating Ca2+ concentrations, the activation rates of the mutant and wild-type protein C by the thrombin-TM complex are comparable, but the mutant requires four-fold higher Ca2+ concentrations than wild-type APC to achieve half-maximal activation rates. When only thrombin is present, Ca2+ is not able to influence the activation of the P168V mutant, though Ca2+ effectively inhibits activation of wild-type protein C by thrombin
R15G
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the mutation leads to increased thrombotic tendency
R15W
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the mutation leads to increased thrombotic tendency
R177E
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site-directed mutagenesis, the activation rate of the mutant by thrombin is 12fold faster than that observed for wild-type protein C in the presence of Ca2+, and unchanged in the absence of Ca2+. Thrombin does not stimulate activation of the protein C variant
R178E
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site-directed mutagenesis, the activation rate of the mutant by thrombin is 12fold faster than that observed for wild-type protein C in the presence of Ca2+, and unchanged in the absence of Ca2+. Thrombin does not stimulate activation of the protein C variant
R222C/D237C
site-directed mutagenesis, manipulation of the APC serine protease domain via the introduction of a new disulfide bridge is found to disproportionately inhibit APC anti-coagulant activity compared with EPCR-PAR1 signalling function
R229A
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Km- and kcat-value similar to wild-type, major contribution to interaction with thrombin-thrombomodulin
R229A/R230A
site-directed mutagenesis
R229A/R230A/K191A/K192A/K193A
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site-directed mutagenesis, construction of an APC protease domain mutant, 5A-APC, the mutant has minimal anticoagulant activity but normal cytoprotective activities that are dependent on endothelial protein C receptor and protease-activated receptor-1 as compared to the wild-tpe enzyme, activation of thrombin activable fibrinolysis inhibitor is essentially unaffected by 5A-APC due to its low anticoagulant activity, a 1000fold higher concentration of 5A-APC is required to give a factor Va inactivation pattern similar to that of recombinant wild-type APC
R230A
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Km- and kcat-value similar to wild-type, major contribution to interaction with thrombin-thrombomodulin
R312A
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Km- and kcat-value similar to wild-type, minor contribution to interaction with thrombin-thrombomodulin
R67C/R82C
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site-directed mutagenesis, construction of a protein C variant in which an engineered disulfide bond between two beta-sheets stabilizes the functionally critical Ca2+-binding 70-80 loop of the molecule. The 70-80 loop of this mutant no longer binds Ca2+, and the activation of the mutant by thrombin is enhanced 60-80fold independently of thrombomodulin, the anticoagulant activity of the activated protein C mutant is nearly eliminated. The endothelial protein C receptor- and protease activated receptor-1-dependent protective signaling properties of the mutant are minimally altered compared to the wild-type enzyme. The mutant loses its ability to interact with the procoagulant cofactors but not with the protective signaling molecules. The binding of EPCR is 2fold reduced compared to the wild-type enzyme
R74A
prepared by PCR methods
R74E/R75E/K78E
triple mutant, Gla-domainless form of APC
R74Q
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created by site-directed in vitro mutagenesis
R75A
prepared by PCR methods
R9H
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mutant variants L8Q and R9H show reduced affinity for EPCR and can contribute to the reduced anticoagulant activity
S11G/S12N
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site-directed mutagenesis, the mutant shows slightly increased factor Va proteolysis compared to the wild-type enzyme
S190A
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Km- and kcat-value similar to wild-type, minor contribution to interaction with thrombin-thrombomodulin
S195A
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site-directed mutagenesis, inactive mutant
S360C
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site-directed mutagenesis, the active site residue mutant shows no amidolytic activity
W231A
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Km- and kcat-value similar to wild-type, minor contribution to interaction with thrombin-thrombomodulin
K191A/K192A/K193A
engineering of APC by site-directed mutagenesis provided a signaling selective APC mutant with 3 Lys residues replaced by 3 Ala residues, 3K3A-APC, that lacks over 90% anticoagulant activity but retains normal cell signaling activities. The 3K3A-APC mutant exerts multiple potent neuroprotective activities, which require the G-protein-coupled receptor, protease activated receptor 1 (PAR1). Potent neuroprotection in murine ischemic stroke models is linked to 3K3A-APC-induced signaling that arises due to APC's cleavage in protease activated receptor 1 at a noncanonical Arg46 site
N329Q
the recombinant APC variant APCN329Q mimics the glycosylation pattern of the endogenous plasma APC-beta glycoform and exhibits significantly enhances PAR1-dependent cytoprotective activity on endothelial cells compared with wild-type APC, determination of the molecular basis for superior APC-beta cytoprotective signaling
R506Q
site-directed mutagenesis, the Leiden mutation, abrogates the anti-inflammatory cofactor function of factor V for activated protein C
D36A/L38D/A39V
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site-directed mutagenesis, the mutant shows no activation by protein S
D36A/L38D/A39V
site-directed mutagenesis, substitution of APC amino acid residues within the C-terminal end of the gamma-carboxyglutamic acid (Gla) domain with those of prothrombin result in an APC variant (APC-36A/L38D/A39V) with diminished capacity to inhibit thrombin generation. FVa degradation by this APC variant is normal in the absence of protein S, but completely defective when FVa degradation is dependent upon protein S cofactor activity
K191A/K192A/K193A
site-directed mutagenesis, mutant APC-K191A/K192A/K193A (APC-3K3A) is assessed in a phase II clinical trial as an adjunctive neuroprotective therapy in combination with t-PA (EC 3.4.21.68) postischaemic stroke
K191A/K192A/K193A
site-directed mutagenesis, the mutant is engineered to reduce APC-associated bleeding risk while retaining normal cell signaling activity. Enzyme mutant 3K3A-APC stimulates neuronal production by human neural stem/progenitor cells (NSCs) in vitro via a PAR1-PAR3-sphingosine-1-phosphate receptor 1-Akt pathway. Effects of late post-ischemic 3K3A-APC treatment on the in vivo production of neurons from transplanted NSCs in mice, and the effects of this combination therapy on long-term neurological recovery and restoration of disrupted neural circuitry in the post-ischemic murine brain, functional integration of NSCs into the host neuronal circuitry, overview
N329Q
site-directed mutagenesis, recombinant APC variant in which this N-linked glycosylation sequon is disrupted possessing markedly enhanced PAR1-dependent cytoprotective activity on endothelial cells. PAR1-dependent maintenance of endothelial cell barrier integrity is also achieved at approximately 5fold lower APC-N329Q concentration than wild-type APC. APC-N329Q also blocks staurosporine-induced endothelial cell apoptosis at about 20fold lower APC-N329Q than occurs when wild-type APC is used
N329Q
the recombinant APC variant mimics the glycosylation pattern of the endogenous plasma APC-beta glycoform and exhibits 4fold enhanced PAR1-dependent cytoprotective activity on endothelial cells compared to wild-type APC, determination of the molecular basis for superior APC-beta cytoprotective signaling
S360A
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site-directed mutagenesis, catalytic site residue mutation, mutant thrombin W215A/E217A induces protective signaling only in the presence of wild type protein C but not mutant protein C S360A
S360A
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site-directed mutagenesis, the active site residue mutant shows no amidolytic activity
S360A
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the active site mutant lacks proteolytic activity but exhibits anticoagulant activity. APC(S360A), and not its zymogen protein C(S360A), expresses anticoagulant activities by competing with activated coagulation factors X and IX for binding to FVa and FVIIIa, respectively. APC(S360A) binding to FVa is critically dependent upon the presence of Arg506 and not Arg306. Inhibition of FVIIIa activity by APC(S360A) is 100fold less efficient than inhibition of FVa. Binding of APC(S360A) to FVa is almost completely dependent on Arg506 interacting with APC(S360A) to form a nonproductive Michaelis complex. No binding to the substrate FVa Gln506 mutant
additional information
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enzyme variant with seven point-mutations in Gla domain, enhanced affinity for negatively charged phospholipid and increased anticoagulantic potential. Degradation of Factor Va yields similar fragments from wild-type and mutant, mutant is more efficient in absence and presence of protein S
additional information
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replacement of autolysis loop of protein by the corresponding loop of factor X. Mutant is activated by thrombin with 5fold higher rate in presence of Ca2+, Ca2+-affinity of mutant is impaired 3fold and anticoagulation function of mutant is improved 4-5fold in the absence, but not in the presence of protein S. Plasma half-life of mutant is markedly shortened
additional information
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substitution of the autolysis loop of APC with the corresponding loop of trypsin has no influence on the proteolytic activity of the protease towards factor Va, however, this substitution increases the reactivity of APC with plasma inhibitors so that the mutant exhibits no anticoagulant activity in plasma, the mutant APC cannot interact with protein S as cofactor, overview
additional information
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a thrombin derivative containing the Gla-domain of APC recapitulates all protective effects of APC with a 20 to 50fold higher efficacy
additional information
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proteolysis at Arg336 occurs 25-fold faster than at Arg562. Replacing residues flanking Arg336 en bloc with the corresponding residues surrounding Arg562 markedly reduces the rate of cleavage at Arg336
additional information
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single mutations of Gla domnain residues at positions 6, 7, 16, 20, 26 or 29 result in APC variants with less than 10% of the anticoagulant activity of wild-type APC
additional information
APC variants specifically designed to possess divergent anti-coagulant and signalling properties are created by ablation of a substrate-binding exosite for FVa on the surface of the APC serine protease domain (APC-R229A/R230A, APC-K191A/K192A/K193A and a combination of these mutations, termed 5A-APC). These variants signal normally via EPCR-PAR1 on endothelial cells, but possess severely attenuated ability to degrade FVa and thus inhibit coagulation. In animal models of endotoxemia, APC-5A exhibits comparable ability to protect mice from LPS-induced lethality as wild-type APC, illustrating the limited requirement for APC anti-coagulant function to reduce LPS-mediated mortality, at least in mice. These mutant variants are also shown to be equally protective in rodent models of ischaemic stroke and APC-K191A/K192A/K193A (APC-3K3A) is assessed in a phase II clinical trial as an adjunctive neuroprotective therapy in combination with t-PA (EC 3.4.21.68) postischaemic stroke. Bio-engineering approaches to modify APC for maximum therapeutic activity, overview. Methods to improve recombinant APC as a plausible therapeutic agent focuse on the removal of unwanted anti-coagulant activity, either by disruption of FVa substrate recognition in the serine protease domain or reduced sensitivity to its obligate anti-coagulant co-factor protein S by modification of the N-terminal Gla domain. Generation of APC variants with diminished interaction with its inhibitor alpha1-anti-trypsin and therefore longer plasma half-life. APC variants with enhanced ability to initiate cytoprotective signalling at lower APC concentrations via modification of specific N-linked glycan sequons are described
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engineering of APC by site-directed mutagenesis provides a signaling selective APC mutant with 3 Lys residues replaced by 3 Ala residues, 3K3A-APC, that lacks over 90% anticoagulant activity but retains normal cell signaling activities. The 3K3A-APC mutant exerts multiple potent neuroprotective activities, which require the G-protein-coupled receptor, protease activated receptor 1 (PAR1)
additional information
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engineering of APC by site-directed mutagenesis provides a signaling selective APC mutant with 3 Lys residues replaced by 3 Ala residues, 3K3A-APC, that lacks over 90% anticoagulant activity but retains normal cell signaling activities. The 3K3A-APC mutant exerts multiple potent neuroprotective activities, which require the G-protein-coupled receptor, protease activated receptor 1 (PAR1)
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knockout mice show perinatal lethality, reduced enzyme levels permit birth and growth but lead to thrombosis and inflammation with an early onset
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a signaling-selective 5A-aPC variant lacks deleterious effects upon early administration
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a signaling-selective 5A-aPC variant lacks deleterious effects upon early administration
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human APC variants specifically designed to possess divergent anti-coagulant and signalling properties are created by ablation of a substrate-binding exosite for FVa on the surface of the APC serine protease domain (APC-R229A/R230A, APC-K191A/K192A/K193A and a combination of these mutations, termed 5A-APC). These variants signal normally via EPCR-PAR1 on endothelial cells, but possess severely attenuated ability to degrade FVa and thus inhibit coagulation. In animal models of endotoxemia, APC-5A exhibits comparable ability to protect mice from LPS-induced lethality as wild-type APC, illustrating the limited requirement for APC anti-coagulant function to reduce LPS-mediated mortality, at least in mice. These mutant variants are also shown to be equally protective in rodent models of ischaemic stroke and APC-K191A/K192A/K193A (APC-3K3A) is assessed in a phase II clinical trial as an adjunctive neuroprotective therapy in combination with t-PA (EC 3.4.21.68) postischaemic stroke
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neuroprotective activity of a murine APC variant with limited anticoagulant activity (mAPCPS) is compared with an identical APC variant except for the absence of glycosylation at the APC-beta sequon (mAPCPS/N329Q). mAPCPS/N329Q limits cerebral ischemic injury and reduces brain lesion volume significantly more effectively than mAPCPS
additional information
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neuroprotective activity of a murine APC variant with limited anticoagulant activity (mAPCPS) is compared with an identical APC variant except for the absence of glycosylation at the APC-beta sequon (mAPCPS/N329Q). mAPCPS/N329Q limits cerebral ischemic injury and reduces brain lesion volume significantly more effectively than mAPCPS
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