Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.21.6 (thromboplastin)
13,278 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

An essential step in paramyxovirus fusion (F) glycoprotein biosynthesis is the posttranslational endoproteolytic cleavage of the inactive precursor glycoprotein Fo by host cell proteases. When the Fo possesses a pair or a cluster of basic residues at the cleavage site, cleavage is catalyzed by a ubiquitous protease(s) and the infection is consequently pantropic. When the site is monobasic with a single arginine, cleavage is allowed to occur only by the enzyme(s) expressed in limited tissue types and the infection is localized there. We have isolated from chick embryo an example of the latter type of endoprotease specific for the single arginine motif and demonstrate its identity with the clotting factor Xa. The ectopic expression of the FXa appeared to be the sole determinant for the viral tropism in chick embryo. The latter type of protease specific for a paired or multiple basic cleavage motif have neither been identified nor characterized extensively. We show here that this cleavage can be induced by the yeast KEX2 protease, a unique subtilisin-like serine protease, responsible for pro factor processing at the paired basic sites.
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PMID:Paramyxovirus tropism dependent on host proteases activating the viral fusion glycoprotein. 193 Jan 2

Colburn and Buonassisi (In Vitro Cell Dev. Biol. 24, 1133-1136, 1988) have isolated a single chain sulfated glycoprotein inhibitor of factor VIIa/tissue factor-catalyzed activation of factor X from conditioned media of an established rabbit endothelial cell line. We report herein that their endothelial cell-derived inhibitor and extrinsic pathway inhibitor (EPI) isolated from rabbit plasma have identical functional properties with respect to their interactions with factor Xa and with factor VIIa/tissue factor. In addition, the endothelial cell inhibitor and rabbit plasma EPI migrate with the same apparent molecular weights on non-reduced SDS-PAGE and contain similar amounts of N-linked carbohydrate. Like the endothelial cell inhibitor the EPI of rabbit plasma exists as a single chain molecule. Furthermore, the endothelial cell inhibitor is recognized and neutralized by a polyclonal antibody raised against rabbit plasma EPI. We therefore conclude that cultured rabbit endothelial cells produce an inhibitor of factor VIIa/tissue factor activity that is functionally and immunologically identical to rabbit plasma EPI.
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PMID:A sulfated rabbit endothelial cell glycoprotein that inhibits factor VIIa/tissue factor is functionally and immunologically identical to rabbit extrinsic pathway inhibitor (EPI). 202 53

A novel inhibitor of blood coagulation has been isolated from the intima of bovine aorta. The inhibitor, vascular anticoagulant (VAC), has been purified to an active fraction that contains two Coomassie-blue-staining bands (Mr = 34,000 and Mr = 32,000, as judged by sodium dodecyl sulfate/polyacrylamide electrophoresis). Both bands are single-chain proteins, having no glycoprotein features. Furthermore, they do not contain any detectable 4-carboxyglutamic acid residues. Both proteins have an identical isoelectric pH of approximately 4.5. VAC binds in the presence of calcium ions to a bilayer consisting of 20% dioleoylglycerophosphoserine and 80% dioleoylglycerophosphocholine with a Kd = 6 nM. The binding is dependent on the calcium concentration: half-saturation of binding occurs at a calcium concentration of 0.8 mM. The binding is completely reversible with EDTA. Furthermore the phospholipid/VAC ratio at saturation was n = 112 and n = 32 mol/mol for 0.5 mM Ca2+ and 2 mM Ca2+, respectively. Binding does not occur between VAC and pure dioleoylglycerophosphocholine. In a system with purified coagulation factors VAC inhibits the activation of prothrombin by factor Xa and calcium only in the presence of negatively charged phospholipids. VAC decreases the Vmax and increases the Km of the factor-Xa-catalyzed prothrombin activation. Based on these results, we conclude that we have purified from bovine aortic intima an anticoagulant protein, which exerts its activity through a calcium-dependent binding to negatively charged phospholipids, and thus interferes with the assembly of prothrombinase on the phospholipid surface.
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PMID:Purification and characterization of a novel protein from bovine aorta that inhibits coagulation. Inhibition of the phospholipid-dependent factor-Xa-catalyzed prothrombin activation, through a high-affinity binding of the anticoagulant to the phospholipids. 296 40

Tissue factor (thromboplastin or Factor III), a glycoprotein cofactor, is required for Factor VII to express its catalytic activity, thereby initiating the extrinsic as well as intrinsic pathway of blood coagulation. Human brain tissue factor was purified 2,500-fold to 98% homogeneity from 2% Triton X-100 extraction of acetone dried brain powder with an overall yield of 36%. The method was based upon affinity chromatography utilizing the high affinity binding of tissue factor to Factor VII noncovalently complexed to immobilized anti-Factor VII-agarose beads. The apparent molecular weight of the purified tissue factor is 45,000 as judged by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and its isoelectric point is 4.8-5.1 by column chromatofocussing and flat bed agarose isoelectric focussing.
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PMID:Purification of human brain tissue factor. 318 30

Three hydrolases from the crude venom of the Malayan pit viper (Akistrodon rhodostoma) can be differentiated. The first, which we designate ARH alpha, is the well-known fibrinogenolytic enzyme ancrod. The second, ARH beta, which has not been described previously, is identified by its electrophoretic mobility after sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), by its ability to hydrolyze H-D-phenylalanyl-L-piperyl-L-arginyl-rho-nitroanilide, and by inhibition of its activity by diisopropyl phosphorofluoridate. The third, ARH gamma, also previously not described, has been purified by using gel permeation and ion-exchange chromatography and preparative PAGE. Chemical, electrophoretic, and hydrodynamic data indicate that it is a single-chain, nonglobular glycoprotein with a molecular weight of 25,600. ARH gamma catalyzes the degradation of several plasma vitamin K dependent coagulation factors, including factor IX, factor X, prothrombin, and protein C. The products are electrophoretically similar to factor IXa beta, factor Xa, thrombin, and activated protein C, respectively. However, these products contain little or no enzymatic activity. ARH gamma-degraded factor IX, factor X, prothrombin, and protein C can be subsequently activated by factor XIa, Russell's viper venom X coagulant protein, crude taipan snake venom, and thrombin, respectively. The N-terminal sequence of the peptides resulting from the ARH gamma digest of porcine factor IX shows that at least three bonds are hydrolyzed: (1) at position 152, seven residues from the Arg145-Ala146 factor XIa cleavage site; (2) at position 167 within the factor IX activation peptide; and (3) at position 177, three residues from the Arg180-Val181 factor XIa cleavage site. The degradation of factor IX by ARH gamma is not affected by several serine protease inhibitors. ARH gamma catalyzes the degradation of both the heavy and light chains of porcine factor VIII which results in the inability of thrombin to activate factor VIII. ARH gamma also catalyzes the degradation of porcine antithrombin III which abolishes its ability to inhibit thrombin. These findings may have relevance to studies of hemostatic derangements following envenomation by this snake. Additionally, several novel coagulation factor derivatives have been generated for structure-function studies.
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PMID:Degradation of coagulation proteins by an enzyme from Malayan pit viper (Akistrodon rhodostoma) venom. 332 4

The protein C activator (PCA) detectable in the venom of Agkistrodon Contortrix Contortrix (ACCV, Southern Copperhead) by specific immunochromometric assay and anticoagulant activity has been isolated and partially characterized. Chromatography of the crude venom on SP-Sephadex followed by Con A Sepharose and finally on hydroxylapatite was necessary to achieve an electrophoretically - pure product. The isolated PCA is a single chain glycoprotein with strong positive charge and an apparent molecular weight of 36,000. It had an immediate-inhibiting effect on the activated partial thromboplastin time (APTT) of normal plasma with no noticeable effect on the prothrombin time. Its prolonging effect on the APTT was dependent on protein C and it appeared to interfere with the contact mechanism rather than with factors V and VIII. It had enzymatic activity on some tripeptide chromogenic substrates sensitive to thrombin and kallikrein. When mixed with normal plasma it generated activity on substrates sensitive to activated protein C and should be useful for studies of protein C.
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PMID:Characterisation and some properties of the protein C activator from Agkistrodon Contortrix Contortrix venom. 336 32

In the present paper the influence of beta 2-glycoprotein-I, also known as apolipoprotein H, upon the prothrombinase activity of platelets and phospholipid vesicles was investigated. The results can be summarized as follows. 1. The prothrombinase activity of resting, non-activated platelets, lysed platelets and vesicles composed of phosphatidylserine and phosphatidylcholine at different molar ratios is inhibited by beta 2-glycoprotein-I in a dose-dependent manner. The concentration of glycoprotein which produces marked inhibition is within the physiological plasma concentration range of beta 2-glycoprotein-I. 2. The time dependence of this inhibition is a relatively slow process, which is not fully expressed before 1 h of incubation. 3. The effect of the glycoprotein is not due to a direct interaction with the components of the prothrombinase complex, i.e. factors Xa, Va, Ca2+ or prothrombin, nor is the inhibitory action abolished by increasing concentrations of coagulation factors Xa and Va. This suggests that beta 2-glycoprotein-I causes a reduction of the prothrombinase binding sites of these coagulation factors to platelets or phospholipid vesicles. 4. The prothrombinase activity of platelets stimulated with ionophore A23187 or with collagen plus thrombin is also inhibited by beta 2-glycoprotein-I in a manner similar to that observed for phospholipid vesicles or for lysed platelets. These findings suggest a regulatory role for beta 2-glycoprotein-I in the pathway of blood coagulation.
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PMID:Prothrombinase activity of human platelets is inhibited by beta 2-glycoprotein-I. 376 9

This study was performed on patients (n = 18) suffering from strictly defined hyperdynamic septic shock. Plasma factors (C-reactive protein, acid alpha 1-glycoprotein, fibrinogen, fibrinopeptide A, fibrinogen-fibrin split products, factor XIII, antithrombin III, complement factors C3 and C4, inter-alpha-trypsin-inhibitor and alpha 2-macroglobulin) measured during hyperdynamic septic shock were highly abnormal. The activation and consumption of clotting, fibrinolytic and complement factors due to system-specific proteinases (such as thrombokinase or plasminogen activators) seemed to be intensified by the nonspecific proteolytic activity of granulocytic proteinases probably released by the action of endotoxins. Possible therapeutic measures to maintain the endogeneous defence mechanism against enhanced proteolysis during septic shock are discussed.
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PMID:Disturbances of selected plasma proteins in hyperdynamic septic shock. 618 74

The function of fibrinolysis is to dissolve fibrin clots. The agent of fibrinolysis is plasmin, a glycoprotein with gram molecular weight (GMW) of 90,000. Under natural conditions, plasminogen is converted to plasmin by tissue plasminogen activator (TPA). Activation occurs on the fibrin surface, thus confining proteolytic activity to the appropriate site. Tissue plasminogen activator, produced by monoclonal methods, has recently been made available for limited therapeutic use. Currently streptokinase and urokinase are widely used therapeutically to activate plasminogen. These agents cause plasmin to be formed which is free in the circulation as well as bound to fibrin, resulting in proteolysis of circulating plasminogen and clotting factors. Fibrinolytic therapy has proven to be more beneficial than anticoagulation alone for deep vein thrombi and for pulmonary emboli. During therapy, laboratory studies demonstrate reduced concentrations of plasminogen, fibrinogen, and of alpha-2 plasmin inhibitor, and prolongation of activated partial thromboplastin time and thrombin time. Laboratory findings must be correlated with the clinical course. Demonstration of circulating plasmin-antiplasmin complex may be a useful indicator of active fibrinolysis.
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PMID:Fibrinolysis--a review. 623 87

Human factor IX circulates as a single-chain glycoprotein. Upon activation in vitro, it is cleaved into disulfide-linked light and heavy chains and an activation peptide. After reduction of activated 125I-factor IX, the heavy and light chains are readily identified by gel electrophoresis. A direct, immunoradiometric assay for factor IXa was developed to assess activation of factor IX for proteases that cleaved it. The assay utilized radiolabeled antithrombin III with heparin to identify the active site and antibodies to distinguish factor IX. After cleavage of factor IX by factor XIa, factor VIIa-tissue thromboplastin complex, or the factor X-activating enzyme from Russell's viper venom, antithrombin III bound readily to factor IXa. Cleavage of 125I-factor IX by trypsin, chymotrypsin, and granulocyte elastase in the presence of calcium yielded major polypeptide fragments of the sizes of the factor XIa-generated light and heavy chains. Kallikrein did not cleave the zymogen. Nonactivation cleavage was noted by thrombin, but only in the absence of calcium. When the immunoradiometric assay was used to assess trypsin-cleaved factor IX, the product bound antithrombin III, but not maximally. After digesting with insolubilized trypsin, clotting activity confirmed activation. In contrast, incubation of factor IX with elastase (Takaki A et al, J Clin Invest 71:1706, 1983) or chymotrypsin did not lead to generation of an antithrombin III-binding site, despite their digestion of 125I-factor IX into heavy and light chain-sized fragments. In evaluating activation of factor IX, physical evidence of activation cleavages does not necessarily correlate with generation of an active site.
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PMID:Cleavage and activation of human factor IX by serine proteases. 638 97


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