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:3.4.21.7 (plasmin)
9,023 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The activation of factor IX purified from human plasma has been studied. Factor XIa and kallikrein separately activated factor IX to factor IXa. In both cases factor IXa had an apparent molecular wight of about 42-45000 in sodium dodecyl sulphate-polyacrylamide disc gel electrophoresis compared with a molecular weight of about 70000 for the native factor IX. The activation by XIa required Ca2+-ions, wherease Ca2+-in and factor VII or Russell's-viper venom alone did not activate factor IX. Trypsin activated and plasmin inactivated factor IX.
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PMID:The activation of human factor IX. 23 60

Partially purified human antihemophilic factor (AHF, factor VIII), when treated with high concentrations of salt, has been shown to dissociate into two components: one, of relatively low molecular weight, possesses procoagulant activity, and the other, of higher molecular weight, forms precipitates with heterologous antiserum against AHF and supports ristocetin-induced platelet aggregation. The ease of separation suggests that the two components in the native state might be held together by noncovalent bonds. Earlier observations do not exclude the possibility that the subunits may be covalently bonded in nature but might be severed by plasma proteolytic enzymes during laboratory manipulation. The issue was examined by preparing partially purified AHF from fresh human plasma in the presence of protease inhibitors, including benzamidine, soybean trypsin inhibitor, epsilon-aminocaproic acid, heparin, and hirudin. Under these conditons, gel filtration in the presence of 0.25 M calcium chloride and 0.001 M benzamidine resulted in its separation into two components, having properties identical to those separated in the absence of these protease inhibitors. The inhibitor mixture blocked generation and action of streptokinase- and kaolin-activated plasmin from plasma, and protected both plasma AHF and partially purified AHF from the action of thrombin. Surface-induced activation of PTA (factor XI) was partially inhibited, and that of Christmas factor (factor IX) was completely inhibited. This observation provides further evidence that in the native state the high- and low-molecular-weight components of preparations of antihemophilic factor are held together by noncovalent bonds.
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PMID:Evidence that functional subunits of antihemophilic factor (Factor VIII) are linked by noncovalent bonds. 94 7

A series of new compounds, 6-amino-1-naphthalenesulfonamides (ANSN), were used as fluorescent detecting groups for substrates of amidases. These compounds have a high quantum fluorescent yield, and the sulfonyl moiety permits a large range of chemical modification. Fifteen ANSN substrates with the structure (N alpha-Z)Arg-ANSNR1R2 were synthesized and evaluated for their reactivity with 8 proteases involved in blood coagulation and fibrinolysis. Thrombin, activated protein C, and urokinase rapidly hydrolyzed substrates with monosubstituted sulfonamide moieties (R1 = H). The maximum rate of substrate homologue). The hydrolysis rates for substrates with branched substituents were slower than their linear analogues. Monosubstituted (N alpha-Z)Arg-ANSNR1R2 possessing cyclohexyl or benzyl groups in the sulfonamide moiety were hydrolyzed by these three enzymes at rates similar to that of the n-butyl homologue (except the cyclohexyl compound for u-PA). Factor Xa rapidly hydrolyzed substrates with short alkyl chains, especially when R1 = R2 = CH3 or C2H5. Lys-plasmin and rt-PA demonstrated low activity with these compounds, and the best results were accomplished for monosubstituted compounds when R2 = benzyl (for both enzymes). Factor VIIa and factor IXa beta exhibited no activity with these substrates. A series of 14 peptidyl ANSN substrates were synthesized, and their reactivity for the same 8 enzymes was evaluated. Thrombin, factor Xa, APC, and Lys-plasmin hydrolyzed all of the substrates investigated. Urokinase, rt-PA, and factor IXa beta exhibited reactivity with a more limited group of substrates, and factor VIIa hydrolyzed only one compound (MesD-LGR-ANSN(C2H5)2). The substrate ZGGRR-ANSNH (cyclo-C6H11) showed considerable specificity for APC in comparison with other enzymes (kcat/KM = 19,300 M-1 s-1 for APC, 1560 for factor IIa, and 180 for factor Xa). This kinetic advantage in substrate hydrolysis was utilized to evaluate the activation of protein C by thrombin in a continuous assay format. Substrate (D-LPR-ANSNHC3H7) was used to evaluate factor IX activation by the factor VIIa/tissue factor enzymatic complex in a discontinuous assay. A comparison between the commercially available substrate chromozyme TH (p-nitroanilide) and the ANSN substrate with the same peptide sequence (TosGPR) demonstrated that aminonaphthalenesulfonamide increased the specificity (kcat/KM) of substrate hydrolysis by thrombin more than 30 times, with respect to factor Xa substrate hydrolysis.
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PMID:Aminonaphthalenesulfonamides, a new class of modifiable fluorescent detecting groups and their use in substrates for serine protease enzymes. 160 66

A low molecular weight platelet inhibitor of factor XIa (PIXI) has been purified 250-fold from releasates of washed and stimulated human platelets. Molecular weight estimates of 8400 and 8500 were determined by gel filtration and SDS-polyacrylamide gel electrophoresis, respectively, although a second band of Mr 5000 was present upon electrophoresis. The inhibitor does not appear to be one of the platelet-specific, heparin-binding proteins, since it neither bound to nor was affected by heparin. An amount of PIXI which inhibited by 50% factor XIa cleavage of the chromogenic substrate S2366 (Pyr-Glu-Pro-Arg-pNA-2H2O) only slightly inhibited (5-9%) factor XIIa, plasma kallikrein, plasmin, and activated protein C and did not inhibit factor Xa, thrombin, tPA, or trypsin, suggesting specificity for factor XIa. Kinetic analyses of the effect of PIXI on factor XIa activity demonstrated mixed-type, noncompetitive inhibition of S2366 cleavage and of factor IX activation with Ki's of 7 x 10(-8) and 3.8 x 10(-9) M, respectively. Immunoblot analysis showed that PIXI is not the inhibitory domain of protease nexin II, a potent inhibitor of factor XIa also secreted from platelets. Amino acid analysis showed that PIXI has no cysteine residues and, therefore, is not a Kunitz-type inhibitor. PIXI can prevent stable complex formation between alpha 1-protease inhibitor and factor XIa light chain as demonstrated by SDS-polyacrylamide gel electrophoresis. The inhibition by PIXI of factor XIa-catalyzed activation of factor IX and its capacity to prevent factor XIa inactivation by alpha 1-protease inhibitor, combined with the specificity of PIXI for factor XIa among serine proteases found in blood, suggest a role for PIXI in the regulation of intrinsic coagulation.
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PMID:A low molecular weight platelet inhibitor of factor XIa: purification, characterization, and possible role in blood coagulation. 173 24

Prothrombin complex concentrates (PCC), licensed for the treatment of hemophilia B, are known to carry a significant risk of thromboembolic complications. Although the reasons for thrombogenicity are not completely understood, several manufacturers have developed purified factor IX concentrates that contain negligible amounts of the other vitamin K-dependent factors. To evaluate whether or not the infusion of such a factor IX concentrate is followed by lesser activation of the hemostatic system than by the infusion of a PCC, we performed a series of coagulation assays on 11 hemophilia B patients before and after the administration of these two types of concentrate using a randomized cross-over design. The levels of prothrombin fragment F1 + 2, a sensitive measure of the in vivo cleavage of prothrombin by factor Xa, was significantly increased in plasma after PCC, but not after factor IX concentrate. Plasma fibrinopeptide A, a sensitive index of the enzymatic activity of thrombin on fibrinogen, also increased significantly after PCC but not after factor IX concentrate. The fragment B beta 15-42, a sensitive index of the enzymatic action of plasmin on fibrin II, did not change after either concentrate. There were also no differences in less sensitive coagulation measurements, such as plasma fibrinogen, antithrombin III, and fibrin monomers, nor in indices of platelet activation, such as beta-thromboglobulin and platelet factor 4. These findings show that the infusion of a purified factor IX concentrate can result in substantially less activation of the coagulation cascade than may be seen with PCC.
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PMID:Thrombin generation is not increased in the blood of hemophilia B patients after the infusion of a purified factor IX concentrate. 226 48

Studies of the clotting mechanisms in the plasma of a Burmese python (Python molurus bivittatus) confirm earlier information that both extrinsic and intrinsic pathways of thrombin formation participate in reptilian hemostasis. Plasma fibrinogen was present at a concentration comparable to that in human plasma. Other assays were hampered by the need to use nonreptilian reagents. The activated partial thromboplastin time was shorter than was that of human plasma, thus implying the presence of prothrombin in python plasma; however, this protein could be demonstrated only in trace amounts. Similarly, only small amounts of Hageman factor (factor XII) and antihemophilic factor (factor VIII) were detected, and none of plasma prekallikrein, high-molecular-weight kininogen, and Christmas factor (factor IX). The prothrombin time was slower than that of human plasma. Factor VII was not detected, but both proaccelerin (factor V) and Stuart factor (factor X) were present. Python plasma inhibited bovine thrombin and human plasmin, but it was deficient in fibrinolytic capacity.
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PMID:Notes on clotting in a Burmese python (Python molurus bivittatus). 234 66

Alteration of the coagulation-fibrinolysis system was examined in patients on maintenance hemodialysis. The mean values of fibrinogen, factor V, factor VII, factor VIII, vWF (activity and antigen), factor IX and factor XI were significantly higher in these patients than in control subjects (p less than 0.01), but factor XII alone was significantly lower. Fibrinolytic parameters (euglobulin lysis time, fibrin plate lysis, fibrin degradation products and alpha 2-plasmin inhibitor-plasmin complex) suggested a hyperfibrinolytic state and plasmin generation in the patients' circulation. These findings suggest that the alteration of the coagulation-fibrinolysis system is aggravated by repeated hemodialysis, either by the influence of the dialyzer itself or heparin.
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PMID:Coagulation and fibrinolysis in patients with chronic renal failure on maintenance hemodialysis. 274 46

A DEAE-Sephadex column chromatography step utilized to purify human Factor VII consistently yields a protein peak between the factor VII activity peak and prothrombin, factor X and factor IX activity peak (S.P. Bajaj, S.I. Rapaport, and S.F. Brown: J. Biol. Chem. 251, 253-259, 1981). We now report that this protein peak contains protein C and protein S. Preparative disc polyacrylamide gel electrophoresis of the proteins in this peak permitted a complete separation of protein C from protein S. Protein C at this step usually contained approximately 5-10% of Factor X, which could be removed by a goat anti-human Factor X antibody column. For a typical preparation, starting with 10L of plasma, the yield of Protein C was 5 mg and of protein S was 4 mg. Both proteins revealed apparent homogeneity in sodium dodecyl sulfate gel electrophoretic system. beta-Protein C and beta-protein S were not observed in our preparations starting with plasma collected directly into citrate anticoagulant containing benzamidine and soybean trypsin inhibitor, suggesting that these beta forms of protein C and protein S, isolated by other investigators, are slightly degraded forms of the native proteins. Antisera generated to these proteins were monospecific and could be used to monitor column fractions during purification. When examined by immunoelectrophoresis, the electrophoretic mobility of protein S in plasma was slower than that of isolated protein S. When exposed to plasmin, protein C was activated slightly and then rapidly degraded.
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PMID:A procedure for isolation of human protein C and protein S as by-products of the purification of factors VII, IX, X and prothrombin. 622 44

Experiments on animals in vitro showed that phosphatidylserine-containing anticoagulant (PhCA) inhibited factors X and VIII, restricted factor V activity and, to a less degree, that of factor VII, decreased the activity of fibrin-stabilizing factor, the degree of clot retraction and its tolerance to fibrinolysin. The activity of factor IX remained virtually unchanged under the influence of PhCA, whereas the contact phase was speeded up by 14%. Anticoagulant activity of PhCA was accounted for by the phosphatidyl molecule residue - glycerylphosphorylserine.
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PMID:[Mechanism of the hypocoagulemic effect and the active principle of a phosphatidylserine-containing anticoagulant]. 728

With advancing age, an increasing number of healthy individuals have laboratory signs of heightened coagulation enzyme activity. Such biochemical hypercoagulability might be the basis of either the increased thrombotic tendency occurring with age or a harmless manifestation of this process. To see whether these alterations are also present in the very elderly who had aged successfully, 25 healthy centenarians were studied and results of coagulation and fibrinolysis measurements were compared with those obtained in two control groups of healthy adults, 25 ranging in age from 18 to 50 years and 25 from 51 to 69 years. Older controls had, in general, slightly higher values of several coagulation and fibrinolysis measurements than younger controls. Centenarians had striking signs of heightened coagulation enzyme activity, as assessed directly by measuring activated factor VII in plasma (P < .01, compared with either control group) or indirectly by measuring the plasma levels of the activation peptides of prothrombin, factor IX, factor X, and thrombin-antithrombin complexes (all P < .001). Heightened coagulation enzyme activity was accompanied by signs of enhanced formation of fibrin (high fibrinopeptide A, P < .001) and secondary hyperfibrinolysis (high D-dimer and plasmin-antiplasmin complex, P < .001). Plasma concentrations of fibrinogen and factor VIII were higher than in controls, whereas other coagulation factors were not elevated. In conclusion, this study shows the very elderly do not escape the state of hypercoagulability associated with aging, but that this phenomenon is compatible with health and longevity. Hence, high plasma levels of the coagulation activation markers in older populations do not necessarily mirror a high risk of arterial or venous thrombosis.
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PMID:Hypercoagulability in centenarians: the paradox of successful aging. 775 46


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