Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.73 (urokinase-type plasminogen activator)
 10,685 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Fibrinolytic therapy was carried out in 59 patients suffering from a total of 60 deep venous thromboses of the iliac segment (n = 24), the femoropopliteal segment (n = 18), the deep calf veins (n = 2), or the subclavian vein (n = 16). 46 patients received streptokinase (SK), 4 were given urokinase (UK), and 10 were treated with streptokinase followed by urokinase (SK + UK). The duration of fibrinolytic therapy was between 19 and 596 hours (x = 166 +/- 111 hrs). Phlebographic examination was used to determine the location of the thrombotic occlusion as well as to evaluate therapeutic results. To assure sufficient anticoagulatory protection during therapy with streptokinase the dose of streptokinase was either reduced by steps of 20,000 U/hr to a minimum of 40,000 U/hr or heparin was added as a continuous infusion. Urokinase was administered with a mean loading dose of 75,000 IU followed by an average maintenance dose of 40,000 IU/hr; it was always given in combination with heparin. When therapeutic success was graded as complete/partial/no recanalisation, the following results were obtained: thrombotic occlusion up to 1 week old 35%/48%/17%; up to 2 weeks old 57%/14%/29%; 3 or 4 weeks old 12%/38%/50%; older than 4 weeks 13%/37%/50%. The two most common side effects were a fall of the hemoglobin and a rise of body temperature. Treatment with SK had to be interrupted for bleeding in two cases. One patient diet after rupture of the liver and of the spleen following development of subcapsular hematoma in these organs, 3 patients survived pulmonary embolism without major long-term impairment. Considering medical and social aspects (preservation of capability for working in young adults) it appears justified to administer fibrinolytic agents up to a thrombus age of 14 days, in some cases even up to a thrombus age of 28 days. Good results in cases of deep vein thrombosis of the lower limbs are often obtained only when fibrinolytic therapy is extended beyond 96 hours. It should be performed in intensive care units only. Follow-up examinations of the venous drainage capacity up to 2 years after fibrinolytic therapy document the good therapeutic effect that is warrented by streptokinase or urokinase induced complete recanalisation.
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PMID:[Fibrinolytic therapy in deep venous thrombosis of the upper and lower extremity]. 84 72

Twelve amino acid sequences of kringle-forming polypeptides were compiled from the known sequences of urokinase A-chain (human), a tissue-type plasminogen activator (human), prothrombin (human and bovine), and plasminogen (human). Their sequence homologies with maximum match were examined by a computer program. A homology alignment and graphic matrix analyses did show that they had a great degree of homology. All the cysteine residues responsible for the kringle structures of urokinase and the tissue-type plasminogen activator were confidently preserved as well as other proteins. A phylogenetic tree was then reconstructed, and the A- and S-chain of bovine and human prothrombins were accounted for the measurement of the evolutionary time span. It was found that urokinase had a larger time span, as much as 60 million years (MY), than the tissue-type plasminogen activator. A common ancestral element of the kringle-related serine proteases was placed at around 500 MY ago, as old as the diversion of the alpha- and beta-chains of hemoglobin. Thus, the kringle-families have undergone a substantial evolutionary divergence. Moreover, they can be subgrouped into three subfamilies: plasminogen activators, plasminogen, and prothrombin A-chains, the last being the most distantly diverged prothrombin S-chains.
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PMID:Homology of kringle structures in urokinase and tissue-type plasminogen activator: the phylogeny with the related serine proteases. 393 78

Soluble highly active conjugates were obtained after complex formation or covalent binding of trypsin and urokinase with polymers of various chemical structure as well as by means of condensation of the enzyme molecules as a result of which oligo- and heterooligoproteins were produced. Pharmacological activity of the conjugates obtained was studied in the course of treatment of rabbits with experimental hyphemia. All the preparations produced exhibited high therapeutic efficiency: the time of hyphemia resorption was decreased, the effect of immobilized enzymes was prolonged as compared with controls. Dependence on the molecular mass and the dose of enzymatic preparations of the period of hyphemia resorption was studied using heteromers of urokinase and hemoglobin. Maximal activity was noted with the preparations of molecular mass 4.10(5) daltons; they maintained the optimal level of pharmacological activity even after 4-fold decrease in the dose used as compared with other immobilized preparations of trypsin and urokinase. The immobilized preparations were 20-fold more effective as compared with native unmodified enzymes.
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PMID:[Immobilized thrombolytic enzymes and their use in ophthalmology]. 404 87

Two components of the fibrinolytic system, plasminogen and the vascular plasminogen activator, have been isolated to apparent homogeneity from the post-venous occlusion plasma of three diabetic patients (hemoglobin A1C greater than 7%) and of one nondiabetic control person. Plasminogen activation was studied for each person separately in the absence and presence of CNBr fragments of fibrinogen. Activation of diabetic plasminogen by urokinase was not significantly altered as compared to the activation of control plasminogen. The same was found when diabetic plasminogen was activated by control vascular plasminogen activator in the presence of fibrinogen fragments but only at plasminogen concentrations below 10-30 nM; at higher substrate concentrations, however, plasminogen activation was impaired in a pattern resembling substrate inhibition. Activation of control plasminogen by diabetic vascular plasminogen activator was completely impaired in the absence of fibrinogen fragments. Addition of fibrinogen fragments stimulated plasmin formation by diabetic vascular plasminogen activator resulting in kinetic constants which were similar to the activation of control plasminogen by control vascular plasminogen activator in the absence of fibrinogen fragments (Km = 7.5 microM, kcat = 0.05 S-1). Addition of fibrinogen fragments in controls decreased Km values to less than 0.1 microM. Despite addition of fibrinogen fragments the rate of plasmin formation from diabetic plasminogen by diabetic vascular plasminogen activator isolated from the same diabetic donor was so small that kinetic constants could not be calculated.
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PMID:Plasminogen activation in diabetes mellitus. Kinetic analysis of plasmin formation using components isolated from the plasma of diabetic donors. 623 Mar 54

A proteinase which can activate human, dog and rat plasminogen to plasmin has been isolated from the urine of female rats, using affinity chromatography on benzamidine-coupled Sepharose. Inhibition by diisopropylfluorophosphate, tosyl-L-lysine chloromethylketone and benzamidine classified the enzyme as trypsin-like. The proteinase has weak activity on alpha-casein and hemoglobin, but will not lyse fibrin clots. It readily cleaves arginyl amides, including synthetic substrates specific for human glandular kallikrein and other serine proteinases. A chromogenic substrate for human urokinase (pyro Glu-Gly-Arg-pNA) is a poor substrate for the rat proteinase. Characteristics of the enzyme, such as its molecular weight (25 900), kinetic parameters and inhibition by aprotinin, indicate that this proteinase is esterase A, described by several investigators. Esterase A is shown not to be a true urinary plasminogen activator but rather is a unique arginine-specific proteinase. Urokinase-like and kallikrein-like activity are part of a broader proteolytic activity displayed by this enzyme.
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PMID:Esterase A is a proteinase from rat urine that can activate plasminogen. 623 43

Researchers compared data on women using the 2-rod Norplant implant system formulated with the Silastic elastomer 4092 (original system) with those using the 2-rod Norplant made with a different elastomer (Q74910) (reformulated system) to examine their hemostatic effects during 36 months of use. All 33 women lived in Singapore. Both systems released the same amount of levonorgestrel at the same rate. In most hemostatic parameters, prolonged use of both 2-rod Norplant implant systems effected similar changes: increased hemoglobin concentration and hematocrit values, increased fibrinogen levels, no increased platelet activation, no increased activation of coagulation or fibrinolysis/inhibitor, no significant changes in platelet numbers, no significant changes in tissue plasminogen activator, and decreased urokinase-like plasminogen activator. Factor VII was higher after 18 months than it was during the first 12 months in original Norplant users (p 0.001). The factor VII level at 36 months during reformulated Norplant use was significantly higher than it was during the first 24 months of use (p 0.001). None of the changes common to both systems suggested tissue breakdown. Plasminogen activator inhibitor antigen levels were significantly lower during 12-36 months than preinsertion levels in original Norplant users, while they fell insignificantly in reformulated Norplant users. The increased levels of fibrinogen and factor VII at 36 months are areas of concern since they are markers of hypercoagulation and are linked to increased arteriosclerotic and cardiovascular risks. Researchers of this on-going study will later publish the two systems' effects on hemostasis after 5 years of use.
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PMID:The effects of reformulated 2-rod Norplant implant on hemostasis after three years. 892 75

Polymer conjugation is of increasing interest in pharmaceutical chemistry for delivering drugs of simple structure or complex compounds such peptides, enzymes and oligonucleotides. For long time drugs, mainly with antitumoral activity, have been coupled to natural or synthetic polymers with the purpose of increasing their blood permanence time, taking advantage of the increased mass that reduces kidney ultrafiltration. However only recently complex constructs were devised that exploit the 'enhanced permeability and retention' (EPR) effect for an efficient tumor targeting, the high molecular weight for adsorption or receptor mediated endocytosis and finally a lysosomotropic targeting, taking advantage of acid labile bonds or cathepsin susceptible polypeptide spacers between polymer and drug. New original, very active conjugates of this type, as those based on poly(hydroxyacrylate) polymers, are already in advanced state of development. Labile oligonucleotides, including antisense drugs, were also successfully coupled to polymers in view of an increased cell penetration and stabilization towards nucleases. However, the most active research activity resides in the field of polypeptides and proteins delivery, mainly for the two following reasons: first of all because a great number of therapeutically interesting compounds are now being produced by genetic engineering in large quantity and, secondly, because these products are difficult to administer to patients for several inherent drawbacks. Proteins are in fact easily digested by many endo- and exo-peptidases present in blood or in other body districts; most of them are immunogenic to some extent and, finally, they are rapidly excreted by kidney ultrafiltration. Covalent polymer conjugation at protein surface was demonstrated to reduce or eliminate these problems, since the bound polymer behaves like a shield hindering the approach of proteolytic enzymes, antibodies, or antigen processing cell. Furthermore, the increase of the molecular weight of the conjugate allows to overcome the kidney elimination threshold. Many successful results were already obtained in peptides and proteins, conjugated mainly to water soluble or amphiphilic polymers like poly(ethylene glycol) (PEG), dextrans, or styrenemaleic acid anhydride. Among the most successful are the conjugates of asparaginase, interleukin-2 or -6 and neocarcinostatin, to remind some antitumor agents, adenosine deaminase employed in a genetic desease treatment, superoxide dismutase as scavenger of toxic radicals, hemoglobin as oxygen carrier and urokinase and streptokinase as proteins with antithrombotic activity. In pharmaceutical chemistry the conjugation with polymers is also of great importance for synthetic applications since many enzymes without loss of catalytic activity become soluble in organic solvents where many drug precursors are. The various and often difficult chemical problems encountered in conjugation of so many different products prompted the development of many synthetic procedures, all characterized by high specificity and mild condition of reaction, now known as 'bioconjugation chemistry'. Bioconjugation developed also the design of new tailor-made polymers with the wanted molecular weight, shape, structure and with the functional groups needed for coupling at the wanted positions in the chain.
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PMID:Bioconjugation in pharmaceutical chemistry. 1051 Aug 47

A fibrinolytic metalloprotease has been purified from the fruiting bodies of the edible honey mushroom (Armillariella mellea). The enzyme has a molecular weight of 18538.1508, as measured by MALDI-TOF mass spectrometry and includes Zn2+ ion as found by ICP/MS. The N-terminal amino acid sequence, XXYNGXTXSRQTTLV, do not match any known protein or open reading frame. It hydrolyzes fibrinogen as well as fibrin, but does not show any proteolytic activity for other blood proteins such as thrombin, human albumin, bovine albumin, human IgG, hemoglobin, or urokinase. This protease hydrolyzes both A alpha and B beta subunits of human fibrinogen with equal efficiency. The enzyme activity was strongly inhibited by EDTA and 1,10-phenanthroline, indicating that the enzyme is a metalloprotease. No inhibition was found with PMSF, E-64, pepstatin, and 2-mercaptoethanol. The activity of the purified enzyme was slightly increased by Mg2+, Zn2+, and Co2+, but the enzyme was totally inhibited by Hg2+. It has broad substrate specificity for synthetic peptides, and a pH optimum at 7, suggested that the purified enzyme was a neutral protease. It was thermally stable up to 60 degrees C and the maximum fibrinolytic activity was at 55 degrees C.
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PMID:A fibrinolytic metalloprotease from the fruiting bodies of an edible mushroom, Armillariella mellea. 1066 46

The expression of Vitreosilla hemoglobin gene (vgb) is regulated by oxygen consistence in E. coli. The gene transcription is activated under the condition of limited oxygen. A new system for expressing heterologous gene in E. coli regulated by dissolved oxygen consistence was constructed. It includes a host bacteria GJ100, which contained T7 RNA polymerase gene controlled by vgb promoter, and an expression vector on which the heterologous gene was under the control of a T7 promoter. The results indicated that E. coli thioredoxin A, IgG binding domain of Staphylococcus protein A(ZZ), snake neurotoxin, salmon calcitonin hexa-polymer, human interleukinII (IL2) and human pro-urokinase genes could be expressed efficiently. Expression level was more than 30% of the total cellular protein.
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PMID:A new system for expressing heterologous gene in Escherichia coli regulated by oxygen consistence in the environment. 1093 65

Two kinds of metalloendopeptidases from the fruiting bodies of Tricholoma saponaceum (TSMEP1 and TSMEP2) have been purified, and TSMEP1 has been characterized based on their fibrinolytic activity. The enzymes have the same N-terminal amino acid sequence, Ala-Leu-Tyr-Val-Gly-X-Ser-Pro-X-Gln-Gln-Ser-Leu-Leu-Val, but slightly different molecular weights of 18,147 and 17,947, as measured by matrix assisted laser desorption ionization time of flight (MALDI-TOF) mass spectrometry. The N-terminal sequence do not match with any known protein or open reading frame. TSMEP1 hydrolyzes fibrinogen as well as fibrin, but does not show any proteolytic activity for other blood proteins such as thrombin, human albumin, human IgG, hemoglobin, or urokinase. The enzyme hydrolyzes both A alpha and B beta subunits of human fibrinogen with equal efficiency but didn't show any reactivity for the gamma form of human fibrinogen. The enzymatic activity is strongly inhibited by EDTA and 1,10-phenanthroline, indicating that the enzymes are metalloproteases. No inhibition was found with phenylmethylsulfonyl fluoride (PMSF), L-trans-epoxysuccinyl leucylamido-(4-guanidino)-butane (E-64), pepstatin and 2-mercaptoethanol. The activity of the purified enzyme was increased by Mg2+, Fe2+, Zn2+, and Co2+, and slightly decreased by Ca2+, but the enzyme activity was dramatically decreased by Cu2+, and totally inhibited by Hg2+. It has broad substrate specificity for synthetic peptides, and keep the high activity from pH 7.5 to 9, suggesting that the purified enzyme was a basic protease. The enzyme was stable up to 30 degrees C and the maximum fibrinolytic activity was at 55 degrees C.
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PMID:Characterization of a metalloenzyme from a wild mushroom, Tricholoma saponaceum. 1130 69


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