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)

Protease-like activity which split plasminogen-free fibrin was demonstrated in 2 M KSCN extracts of the lung and spleen of conventional rats. The activity was virtually undetectable in tissue extracts from germ-free rats. The extracts from the conventional rat tissues split fibrin and fibrinogen remarkably at neutral pH, but not casein, when examined using fibrin, fibrinogen-agar and casein-agar plates. The fibrinolytic activity was inhibited by STI and DFP, indicating a serine protease nature. The activity was not inhibited by TLCK, t-AMCHA or dansyl-L-arginine-methylpiperidine amide (a selective synthetic thrombin inhibitor, OM189). It was neither activated nor inhibited by cysteine, KCN or iodoacetic acid. The results obtained indicate that the protease-like activity of the lung and spleen extracted with 2 M KSCN from conventional rats has properties which differ from those of trypsin, plasmin, plasminogen-activator, thrombin, and cathepsin A, B and C.
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PMID:Fibrinolytic activity of lung and spleen extracts observed in conventional but not in germ-free rats. 9 68

The jawed leech, Hirudinaria manillensis is closely related to Hirudo medicinalis, both belonging to the same family Arhynchobdellida. From Hirudo, two potent peptide inhibitors, hirudin (a thrombin inhibitor) and eglin (an elastase/chymotrypsin inhibitor) have been characterised in detail. During our studies to isolate thrombin inhibitor from the leech Hirudinaria a potent inhibitor, analogous to eglin, was also detected. Results indicate that this inhibitor, which we have named 'GELIN', is significantly different from eglin. Gelin was isolated and purified to homogeneity by ion exchange chromatography and reverse phase HPLC. The isoelectric point of Gelin was estimated to be 4.55, in contrast to 6.45 for eglin. The molecular weight of Gelin was similar to eglin, as estimated by SDS-PAGE. Amino-terminal sequence analysis of the first 29 residues show no sequence homology with eglin or any other serine protease inhibitors. Circular dichroism studies showed that the secondary structure of Gelin has no helix, 58% beta sheets and 42% random structures compared to 19% helix, 56% beta sheets and 25% random structures in eglin. Like eglin, Gelin inhibits elastase, cathepsin G and chymotrypsin but has little or no activity towards plasmin, thrombin, pepsin and trypsin. These data suggest that the elastase inhibitors from these two species of leech are fundamentally different in structure, indicative of independent evolutionary origin.
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PMID:Biochemical characterisation of a pancreatic elastase inhibitor from the leech Hirudinaria manillensis. 128 66

We investigated the effect of plasmin on the release of sulfated glycosaminoglycans (GAG) from cultured vascular smooth muscle cells. Confluent cultures of vascular smooth muscle cells from bovine aorta were labelled with [35S]sulfate and incubated at 37 degrees C for principally 60 min in a serum-free medium in the presence of plasmin. Plasmin at 10 mU/ml (approximately 2.7 micrograms/ml) and above significantly increased the release of [35S]sulfate-labeled GAG (35S-GAG) from the cell layer after a 60 min incubation. A time course study showed that plasmin at 10 mU/ml significantly increased the 35S-GAG release after 20 min and longer. However, plasminogen at 100 mU/ml and below did not cause a significant change of the 35S-GAG release after a 90 min incubation. A characterization of 35S-GAG revealed that plasmin increased both dermatan sulfate and the other 35S-GAG in the medium. Plasmin at 100 mU/ml enhanced the cell detachment significantly but only slightly. From these results, it was suggested that a endogenous thrombin inhibitor heparin cofactor II may be activated in the liquid phase by dermatan sulfate released from plasmin-stimulated vascular smooth muscle cells when the vascular is disrupted and plasma is exposed to extravessel.
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PMID:Plasmin stimulates the release of dermatan sulfate from vascular smooth muscle cells in culture. 138 67

Thrombin at concentrations as low as 20 pM (0.002 U ml-1) was found to stimulate inositol phosphate levels in cultured human non-pigmented ciliary epithelial cells. Several other proteases, including trypsin and plasmin, had little or no effect, of several protease inhibitors tested, only those with specificity for thrombin blocked the effect. Studies with active site-blocked thrombin suggested that the esterolytic active site of thrombin is required for inositol phosphate stimulation, while gamma-thrombin, which has reduced binding affinity to fibrinogen also showed reduced effectiveness in stimulating inositol phosphates. In the presence of 10 mM LiCl, thrombin stimulated inositol monophosphate, inositol bisphosphate and inositol trisphosphate formation, with a prolonged rise of the first and transient early rises in the latter two species. Thrombin also elevated intracellular Ca2+ levels as measured with the fluorescent calcium probe, indo-1-AM. This elevation could be blocked by prior addition to cells of the thrombin inhibitor, hirudin, and was dependent upon extracellular Ca2+ for the maintenance of an elevated level in the presence of thrombin. Incorporation of thymidine into DNA in confluent cultures was also stimulated by thrombin, with a four-fold increase in incorporation at 35 hr in thrombin-treated cells compared to controls. The half-maximal concentration for this process was 0.25 U ml-1. Pretreatment with 100 ng ml-1 pertussis toxin greatly reduced the thrombin effect, which is consistent with a role for a G-protein in stimulation of DNA synthesis by thrombin.
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PMID:Thrombin stimulates inositol phosphate formation, intracellular calcium fluxes and DNA synthesis in cultured fetal human non-pigmented ciliary epithelial cells. 148 37

Increase of TAT is reflected by the generation of thrombin in hypercoagulable state. TAT might increase in DIC characterized by the formation of disseminated micro-thrombosis. DIC was classified into three groups according to the results of screening tests (FDP, platelet count, fibrinogen, prothrombin time). TAT values significantly increased in the stage of pre-DIC compared with the control group consisting of DIC prone underlying disease. Pre-DIC was easily detected by an increase of TAT during the clinical course. Management of high TAT began with the use of an anticoagulant such as heparin under the condition of sufficient ATIII level. The lowering effect of TAT was easily obtained by the anticoagulant. In ATIII-deficient DIC, the high TAT reduced with the substitution of ATIII concentrate, though a transient increase of TAT was found during the administration of ATIII. To reduce the high TAT under the deficient state of ATIII, MD805, a synthetic thrombin inhibitor, was introduced to avoid further consumption of ATIII. The TAT was decreased by the use of MD805 without administration of ATIII. MD805 could be used as an effective anticoagulant in high TAT due to DIC under an ATIII-deficient state. Although the TAT improved with an adequate anticoagulation in DIC, spontaneous bleeding sometimes appeared as a complication associated with the high level of alpha 2 plasmin inhibitor plasmin complex. In this case, the combined use of tranexamic acid relieved the bleeding.
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PMID:[Thrombin.antithrombin III complex]. 192 Aug 62

Structural and functional properties of alpha-protease nexin I (alpha-PNI) expressed in Chinese hamster ovary cells were studied. All three cysteines were in the reduced form, showing that the potential disulfide bridge between residues Cys117 and Cys131 was not formed. Heparin association rate enhancements were from ka = 8.3 x 10(5) to 0.7-1.6 x 10(9) M-1 s-1 for the interaction of PNI with thrombin, from ka = 5.1 x 10(3) to 3.5 x 10(5) M-1 s-1 for interaction with Factor Xa, and from ka = 2.2 x 10(6) to 1.0 x 10(7) M-1 s-1 for interaction with trypsin; there was no rate enhancement of the plasmin interaction (ka = 1.0 x 10(5) M-1 s-1). The minimal heparin pentasaccharide had no effect on these interactions. Cleavage of the reactive center loop of PNI by three different proteases gave the typical stressed to relaxed change in thermal stability, but unlike with antithrombin III, there was no loss of heparin affinity. A similar difference from antithrombin was that PNI-thrombin complexes retained normal heparin affinity. These results are compatible with a role for protease nexin I as a cell-associated thrombin inhibitor that remains bound to the cell surface even after complexing with the protease, as compared with the role of antithrombin III as a circulating inhibitor of thrombin that becomes activated on binding to the microvasculature and is released on complex formation.
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PMID:Protease specificity and heparin binding and activation of recombinant protease nexin I. 193 53

Protease nexin-1 is a protein proteinase inhibitor that is secreted by a variety of cultured cells and rapidly forms complexes with thrombin, urokinase, and plasmin; the complexes then bind back to the cells and are internalized and degraded. In fibroblast cultures, protease nexin-1 is localized to the extracellular matrix. Here we report that protease nexin-1, which is bound to the surface of fibroblasts, forms complexes with thrombin, but not urokinase or plasmin. Experiments were conducted to determine directly if protease nexin-1 binding to the fibroblast surface alters its proteinase specificity. To do this, cell surface protease nexin-1 was inhibited using anti-protease nexin-1 monoclonal antibodies that stoichiometrically block its ability to form complexes with target proteinases. Then, purified protease nexin-1 was added to these cells; the cell-bound molecule formed complexes with thrombin, but not urokinase or plasmin. Similar experiments showed that protease nexin-1 bound to preparations of fibroblast extracellular matrix also formed complexes with thrombin, but not urokinase or plasmin. Components of the extracellular matrix other than heparin-like glycosaminoglycans are required for this regulation since heparin did not block the formation of complexes between protease nexin-1 and urokinase or plasmin. These results suggest that protease nexin-1 is primarily a thrombin inhibitor in interstitial fluids where much of it would be bound to cell surfaces.
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PMID:Binding of protease nexin-1 to the fibroblast surface alters its target proteinase specificity. 264 83

The three-dimensional structure of a thrombin inhibitor-trypsin complex has been determined by an X-ray analysis at 2.5 A resolution. The result has given experimental support to the mechanisms previously proposed by the authors for the selective inhibition of trypsin, thrombin, factor Xa, and plasmin by inhibitors with an arginine or lysine backbone. The differences in the amino acid sequences at the positions corresponding to Ilc63, Leu99, and Ser190 of trypsin give each enzyme different binding affinities toward inhibitors and result in the selective inhibition. Furthermore, the X-ray analysis has revealed a novel type of interaction between the inhibitor and trypsin. The hydrogen bonds between the inhibitor main chain and trypsin Gly216 play an essential role in the complex formation.
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PMID:X-ray analysis of a thrombin inhibitor-trypsin complex. 276 21

The tertiary structure of a thrombin inhibitor-trypsin complex has been predicted by a molecular modelling considering the van der Waals interactions between the inhibitor and the enzyme. The selective inhibition of trypsin, thrombin, factor Xa, and plasmin exhibited by arginine and lysine derivatives has been clearly explained based on the predicted structure and the homology in the amino acid sequences of these enzymes. The differences in the amino acid sequences at the positions corresponding to Ile63, Leu99, and Ser190 of trypsin give each enzyme different binding affinities toward inhibitors and result in the selective inhibition. The X-ray analysis of the inhibitor-trypsin complex is in progress to prove the predicted structure.
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PMID:A predicted tertiary structure of a thrombin inhibitor-trypsin complex explains the mechanisms of the selective inhibition of thrombin, factor Xa, plasmin, and trypsin. 296 79

Thrombin inhibitors have recently advanced to the stage of preclinical testing as anticoagulants. However, little is known about the effects of these inhibitors on the enzymes of the fibrinolytic system. In the present study we evaluated the effect of two protein and two synthetic inhibitors of thrombin on tissue plasminogen activator (tPA), urokinase, and plasmin. We found that hirudin inhibited the amidolytic activity of plasmin but had no effect on tPA or urokinase. Antithrombin III inhibited plasmin and urokinase but had no effect on tPA. D-Phe-Pro-Arg-CH2Cl inhibited plasmin and tPA but had no effect on urokinase. Thromstop inhibited all three fibrinolytic enzymes: plasmin, urokinase, and tPA. Thus each thrombin inhibitor tested had different inhibitory effects on the fibrinolytic enzymes. These effects should be carefully considered when thrombin inhibitors are used as antithrombotic drugs.
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PMID:Inhibition of fibrinolytic enzymes by thrombin inhibitors. 297 31


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