Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.21.5 (thrombin)
 33,306 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The synthetic thrombin-inhibitor termed No. 205 (N-alpha-dansyl-L-arginine-4-ethyl-piperidine amide) found in our laboratories was studied kinetically using synthetic peptide substrates. The following results were obtained. 1. No. 205 inhibited thrombin competively with bz-Phe-Val-Arg-pNA and the Ki value obtained was extremely small, 3.7 x 10(-8) M. 2. No. 205 also inhibited trypsin competitively with bz-Phe-Val-Arg-pNA but the Ki value obtained was far larger than that for thrombin, 1.0 x 10(-5) M. 3. No. 205 inhibited F. Xa, plasmin and urokinase only to a small extent when estimated using 2 x 10(-4) M D-Val-Leu-Lys-pNA, bz-Ile-Glu-Gly-Arg-pNA and Glu-Gly-Arg-pNA, respectively. 4. No 205 differed from APPA in its specific inhibitory spectrum for thrombin as compared to trypsin, plasmin and F. Xa. The above results indicate that No. 205 is an extremely potent and highly selective reversible thrombin-inhibitor.
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PMID:Kinetic studies on the selectivity of a synthetic thrombin-inhibitor using synthetic peptide substrates. 15 13

Secondary generalized hyperfibrinolysis was induced by thrombin infusion or batroxobin injection in rats. To follow intravascular fibrinolysis quantitatively, an electroimmuno-assay was used for determination of the fibrin degradation products formed. Anticoagulants (heparin, hirudin), antifibrinolytics (EACA, PAMBA, AMCA), and synthetic (APPA) and naturally occurring (aprotinin) protease inhibitors were studied with regard to their influence on secondary fibrinolysis. The potency and duration of action of the antifibrinolytics tested correspond to their antifibrinolytic activity measured in vitro and to their pharmacokinetics. Formation of degradation products is initiated after the appearance of fibrin monomer or fibrin, respectively. Due to their antithrombin action heparin, hirudin, and APPA prevent the thrombin-induced fibrin formation and thus the induction of secondary fibrinolysis. In contrast, formation of fibrin monomers caused by batroxobin is not influenced by thrombin inhibitors so that in this case formation of degradation products is not prevented.
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PMID:[Pharmacologic influence on secondary generalized fibrinolysis]. 53 98

Based on studies of structure-activity relationship, trans-4-aminomethylcyclohexanecarbonyl-L-phenylalanine-4-carbox ymethylanilide (Tra-Phe-APAA) was designed as a selective plasma kallikrein inhibitor and synthesized. Tra-Phe-APAA inhibited plasma kallikrein with a Ki value of 0.81 microM, while it inhibited glandular kallikrein, plasmin, urokinase, factor Xa and thrombin with Ki values of greater than 500, 390, 200, greater than 500, and greater than 500 microM, respectively. However, its stereoisomer, Tra-D-Phe-APPA did not exhibit any detectable inhibitory activity against the above enzymes.
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PMID:Synthesis of trans-4-aminomethylcyclohexanecarbonyl-L- and -D-phenylalanine-4-carboxymethylanilide and examination of their inhibitory activity against plasma kallikrein. 139 97

The interactions of human thrombin and bovine trypsin with 4-amidinophenylpyruvate (p-APPA), 3-amidinophenylpyruvate (m-APPA) and benzamidine were studied by equilibrium binding and by stopped-flow kinetics with proflavin displacement. The excellent inhibitory properties of p-APPA with both enzymes are explained by a two-step transition-state mechanism in which the initial Michaelis complex E.I reacts rapidly to form a fairly stable, chemically bonded complex E-I, in which the keto group of p-APPA forms a hemiketal with the gamma-O-atom of Ser195 at the active site. The hemiketal complex of thrombin and p-APPA may be further stabilized by a hydrogen bond between a carboxylate oxygen of p-APPA and the N tau-atom (= N epsilon 2) of His57, as was previously shown for the trypsin-p-APPA complex by X-ray crystal structure analysis by J. Walter and W. Bode. m-APPA is apparently sterically incapable of forming a hemiketal with Ser195 O gamma; it does not bind to thrombin or trypsin in a time-dependent manner, and it displays KI values with both enzymes close to those obtained for benzamidine itself. In the p-APPA-thrombin reaction the overall binding constant KI (E-I) is 1.3 microM, while the initial binding displays a KM (E.I) estimated at least 100-fold higher (700 microM). The half-time for the formation of E-I is about 0.6 s at a p-APPA concentration of 1 microM.
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PMID:Transition-state inhibition of thrombin and trypsin by amidinophenylpyruvates. 407 1

The effects of two types of synthetic inhibitor of fibrinolytic enzymes (omega-aminocarboxylic acids, benzamidine derivatives) on intravascular fibrinolysis and fibrinogenolysis were studied in rats. Generalised primary fibrinogenolysis was produced by infusion of human plasminogen-streptokinase complex, secondary fibrinolysis was induced by infusion of the thrombin-like enzyme batroxobin. The inhibitors exerted different effects on the hyperfibrinolytic states. The omega-aminocarboxylic acids (PAMBA, AMCA) inhibited fibrinolysis more effective than fibrinogenolysis. In contrast, the benzamidines (APPA, NANP) were more potent inhibitors of fibrinogenolysis. Aprotinin examined for comparison behaved like the benzamidine derivatives.
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PMID:Chemical control of hyperfibrinolytic states by synthetic inhibitors of fibrinolytic enzymes. 660 48

Crystals of human alpha-thrombin complexed with hirugen and the alpha-keto acid thrombin inhibitor APPA (p-amidinophenylpyruvate) that diffract to 1.6 A resolution were obtained by soaking an alpha-thrombin-hirugen crystal in a solution of APPA. The crystal structure was determined using the difference Fourier method and refined to an R factor of 18.7% at 1.6 A resolution. This structure is the highest resolution structure of the thrombin molecule that is currently available. With the exception of the region near Arg77A-Asn78, the structures of the thrombin and hirugen molecules in the ternary complex are similar to those reported for the thrombin-hirugen binary complex. As previously determined for the APPA-trypsin complex, the carbonyl carbon atom of APPA forms a covalent bond with O gamma of Ser195 of thrombin to yield a "transition-state" analog of the tetrahedral intermediate. Comparison of the specificity pocket of the APPA complexes of thrombin and trypsin reveals differences in hydrogen bonding and shows for the first time that the S1 site of thrombin is larger than that of trypsin and as a result thrombin may be able to accommodate a bulkier P1 group than trypsin.
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PMID:Crystal structure of human alpha-thrombin complexed with hirugen and p-amidinophenylpyruvate at 1.6 A resolution. 757 75