Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.21.69 (APC)
 16,337 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The two-way and three-way interactions among active-site-blocked bovine thrombin, bovine protein C, and the elastase fragment of rabbit thrombomodulin (elTM) were examined by analytical ultracentrifugation at 23.3 degrees C in 100 mM NaCl, 50 mM Tris (pH 7.65), and 1 mM benzamidine, in the presence of 0 to 5 mM calcium chloride. Thrombin and elTM form a tight (Kd less than 10(-8) M) 1:1 complex in the absence of Ca2+ that weakens with the addition of Ca2+ (Kd approximately 4 microM in 5 mM Ca2+). Without Ca2+, thrombin and protein C form a 1:1 complex (Kd approximately 1 microM) and what appears to be a 1:2 thrombin-protein C complex. The Kd for the 1:1 complex weakens over 100-fold in 5 mM CaCl2. Protein C and elTM form a Ca(2+)-independent 1:1 complex (Kd approximately 80 microM). Nearly identical binding to thrombin and elTM is observed when active-site-blocked activated bovine protein C is substituted for protein C. Thrombin inhibited by diisopropyl fluorophosphate and thrombin inhibited by a tripeptide chloromethyl ketone exhibited identical behavior in binding experiments, suggesting that the accessibility of protein C to the substrate recognition cleft of these two forms of thrombin is nearly equal. Human protein C binds with lower affinity than bovine protein C. Ternary mixtures also were examined. Protein C, elTM, and thrombin form a 1:1:1 complex which dissociates with increasing [Ca2+]. In the absence of Ca2+, protein C binds to the elTM-thrombin complex with an apparent Kd approximately 1 microM.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Ca2+ dependence of the interactions between protein C, thrombin, and the elastase fragment of thrombomodulin. Analysis by ultracentrifugation. 131 45

Protein C is a plasma, vitamin K-dependent zymogen of a serine protease that can inhibit blood coagulation. Protein C is regulated by a series of reactions known as the protein C pathway. The importance of this pathway is seen in the occurrence of thrombosis in individuals with deficiencies in elements of the pathway like protein C and protein S. Work on several steps in this pathway has revealed that mechanisms involved in activation of protein C and the expression of its anticoagulant activity have features that allow for the expression of the anticoagulant activity away from sites in which procoagulant reactions occur, but not systemically. Thrombin, the principal procoagulant enzyme at the site of an injury, is converted to an anticoagulant enzyme at distant sites through its interaction with the endothelial cell protein thrombomodulin. Structural and functional studies have revealed the importance of several domain structures in the modulation of thrombin activity. Structural features of both activated protein C and its substrates (coagulation factors V and VIII) are such that they require the localization of enzyme and substrate on the surface of phosphatidyl serine containing membranes for optimum activity.
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PMID:Regulation of blood coagulation by the protein C system. 131 8

Protein C is lower in newborn infants than in adults. There are conflicting reports regarding functional activity and the presence of des-gamma carboxylated species in the newborn. We have compared protein C activity and antigenic level in newborn infants and found the activity: antigen ratio to be lower than in adults (0.69 versus 1.0). We discuss this finding in relation to the previously published reports.
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PMID:Functional activity of protein C in newborn infants. A report of a study and a review of the literature. 132

Protein C activation is catalyzed on endothelium by a complex between thrombin and thrombomodulin. Ca2+ stimulates protein C activation in the presence, and inhibits in the absence, of thrombomodulin. Protein C has Asp residues at the P3 and P3' positions relative to the scissile bond at Arg169-Leu. To determine the contribution of these residues to the Ca2+ effect on activation, we have expressed human 4-carboxyglutamic acid (Gla)-domainless protein C and 3 mutants with Asp-->Gly substitutions at P3, P3', and both positions. Ca2+ interaction with the protein C derivatives was monitored by changes in intrinsic fluorescence, and the Ca2+ dependence of activation by thrombin and a complex of thrombin-thrombomodulin with a soluble thrombomodulin derivative (the fourth through sixth epidermal growth factor domains). The affinity for Ca2+ of the mutants was reduced 3-6-fold, which was reflected by a comparable change in the Ca2+ concentration required for the half-maximal rate of activation by the thrombin-thrombomodulin complex. However, Ca2+ no longer effectively inhibited activation of the mutants by thrombin alone. We conclude that 1) the Asp residues play a specific role in the Ca(2+)-dependent inhibition of protein C activation by thrombin; 2) these mutations alter the affinity of Ca2+ for the high affinity binding site; and 3) the Asp residues in the P3 and P3' sites do not contribute in a positive fashion to rapid activation by the thrombin-thrombomodulin complex.
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PMID:The function of calcium in protein C activation by thrombin and the thrombin-thrombomodulin complex can be distinguished by mutational analysis of protein C derivatives. 133 92

Three patients with an acute exacerbation of ulcerative colitis (a 40-year-old and a 31-year-old man and a 30-year-old woman) developed a protein C deficiency (serum protein C activity between 32 and 48%). In the two men the protein C deficiency was diagnosed only after the onset of severe thromboembolic complications (cavernous sinus thrombosis; pulmonary embolism) during heparin treatment. But in the woman protein C activity was measured immediately after hospital admission (in the knowledge of the first two cases) even before heparin administration was started. All three patients received treatment with sulphasalazine (3 g daily) and fluocortolone (60 mg daily), as well as full heparinization (22,500-36,000 IU daily). Protein C activity returned to normal on remission of the ulcerative colitis (in one case only after subtotal colectomy). These case reports show that acquired protein C deficiency can be reversed by rigorous treatment of the underlying disease.
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PMID:[Acquired protein C deficiency in ulcerative colitis. The cause of thromboembolic complications]. 162 40

1. Guinea-pig blood clots rapidly and the clots retract in glass tubes. The prothrombin time is long and the activated partial thromboplastin time short compared to human. The Russel viper venom time is similar to human. 2. Factors VII and X assay at levels far below and factors V, VIII and XII assay far above human levels. Other coagulation factors (fibrinogen, II, IX, XI, Fletcher and Fitzgerald) assay within or close to the human range. 3. The thromboplastin generation test results for guinea-pigs and humans are similar. 4. Platelets are numerous and small. They aggregate with ADP, arachidonic acid and pig plasma, variably with ristocetin and poorly with bovine collagen or thrombin. On electron microscopy, platelets appear small with many dark granules (dense bodies). There is an open canicular system. Glycogen particles are sparse. Microtubules are occasionally seen, mitochondria are rare and alpha-granules are not readily distinguished from dark granules. 5. Ristocetin cofactor is very low, assaying at < 16% of human (< 0.16 U/ml). 6. Leukocyte counts are variable (6300-17,000 per microliters) and differential counts show neutrophils slightly lower and lymphocytes slightly higher than average human counts. 7. Guinea-pig erythrocyte parameters fall within human ranges. 8. Protein electrophoresis shows total protein and albumin to be slightly lower than human. 9. Antithrombin III, Protein C and alpha 2-antiplasmin assay within the human range and plasminogen at very low levels. 10. Bleeding times are consistently about 4 min.
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PMID:Comparative hematology: studies on guinea-pigs (Cavia porcellus). 135 40

Human Protein C (HPC), an antithrombotic factor with potential clinical utility, is a vitamin K-dependent protein that has several complex post-translational modifications. In an effort to define the functional roles of these modifications, recombinant HPC (rHPC) was expressed in and characterized from 3 adenovirus-transformed cell lines. The rHPC in crude culture medium from the 3 cell lines displayed anticoagulant activities that were either higher, slightly lower or much lower than that of plasma HPC. The rHPC from each cell line was purified and characterized using a novel, but simple chromatographic method, termed "pseudo-affinity", capable of resolving molecules differing by only very slight modifications. We demonstrate the critical dependence of full gamma-carboxylation on the function of this protein. In addition, our data indicate that both the gamma-carboxyglutamate and glycosyl contents affect the functional activities of rHPC.
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PMID:Characterization and novel purification of recombinant human protein C from three mammalian cell lines. 136 28

A new bioreactor for animal cell cultivation employs two compartments for cells and medium respectively. The two chambers are separated by an ultrafiltration membrane. Cells and solution of collagen or collagen/chitosan mixture were loaded to the cell chamber and were allowed to form gel inside. Contraction of the cell-laden gel occurred subsequently to create a new zone in the cell chamber. In such a bioreactor cells are retained in the reactor, the high molecular product(s) accumulate in the cell chamber, while the small molecular weight nutrients and metabolites are replenished and removed from the medium chamber. By adjusting the flow rates for cell and medium chambers, the resident time for cells, high and low molecular weight components of the system can be manipulated separately. The new bioreactor, in both flat-bed and hollow-fiber configurations, was used to cultivate recombinant human cell, 293, for Protein C production over 60 to 90 days.
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PMID:A two-compartment cell entrapment bioreactor with three different holding times for cells, high and low molecular weight compounds. 136 40

We have studied the behaviour of total protein S, free protein S, protein C and C4b-binding protein fifteen neonates with severe infections, eight with septic shock and in a group of ten healthy newborns. Protein C was decreased in shock and septic patients, but only the shock group showed significant differences compared to normal neonates. Total protein S was normal in both groups of patients, although free protein S had significantly lower values in shock and nonshock infants. C4b-binding protein was higher than normal in septic and shock patients compared to the control group. Decreased values of protein C and free protein S can be explained by the activation of coagulation and their subsequent consumption. On the other hand, the increased levels of C4b-binding protein can affect the distribution of protein S in plasma, producing a shift in protein S to the complexed inactive form. These findings can contribute to an increased risk of microthrombosis during neonatal sepsis.
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PMID:Protein C, protein S and C4b-binding protein in neonatal severe infection and septic shock. 138 81

Protein C inhibits coagulation and promotes fibrinolysis. This New England study investigated the association between protein C deficiency and pregnancy loss, thrombosis in pregnancy, and thrombosis with oral contraceptives (OCs). 15 protein C-deficient patients and 37 controls from a single kindred were studied. An obstetric history was obtained by telephone. Data were analyzed by logistic regression, Fisher's exact test, and Student t test. The protein C-deficient women experienced a 33% pregnancy loss vs 19% among the controls (not significant). Thromboembolism during pregnancy in protein C-deficient women was 33% (45% in those not receiving prophylactic anticoagulation) vs 5% in the controls (odds ration 7.37, p=0.026). 5 of 12 protein C-deficient women using OCs developed thrombosis vs. none of the 33 controls. The risk of thrombosis for protein C-deficient women using OCs is increased (p0.001). Perinatal outcome is not statistically different with protein C deficiency. Protein C deficiency increases the risk of thrombosis during pregnancy and while taking OCs. Prophylactic heparin is suggested during pregnancy for protein C-deficient women with personal or family histories of thrombosis. Oral contraception is not advised.
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PMID:Pregnancy loss and thrombosis with protein C deficiency. 141 34


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