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)

The plasma concentration of lipoprotein (a) [Lp(a)] is correlated with the risk of atherosclerosis. It is a lipoprotein particle consisting of apoprotein (a) [Lp(a)] is correlated with the risk of atherosclerosis. It is a lipoprotein particle consisting of apoprotein (a) [apo(a)], a protein showing considerable amino acid sequence identity with plasminogen. bound to low-density lipoprotein. The apo(a) portion of Lp(a) was recently shown to have serine-proteinase-type amidolytic activity and to be able to degrade the adhesive glycoprotein fibronectin. To characterize this enzyme activity further, we used chromogenic peptide substrates and inhibitors. Of the substrates tested, those with arginine at the scissile bond [N-alpha-benzoyl-L-Arg p-nitroanilide (pNA), N-alpha-benzoyl-Ile-Glu-Gly-Arg-pNA, N-alpha-benzyloxycarbonyl-Arg-Gly-Arg-pNA] gave the highest hydrolysis rates. Synthetic substrates with plasmin specificity (Val-Leu-L-Lys-pNA and Val-Phe-L-Lys-pNA) were not hydrolysed by Lp(a). Neither tissue plasminogen activator nor urokinase had any effect on the enzyme activity. The addition of antibodies to these plasminogen activators did not inhibit the enzyme activity of Lp(a). Inhibition experiments with phenylmethanesulphonyl fluoride, carbodi-imide, dichloroisocoumarin and competitive peptide inhibitors demonstrated that Lp(a) has enzyme activity that closely resembles that of serine proteinases. Whether this serine-proteinase activity of Lp(a) plays any role in the genesis of atherosclerosis remains to be established.
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PMID:Characterization of the enzyme activity of human plasma lipoprotein (a) using synthetic peptide substrates. 182 80

Lipoprotein (a) [Lp(a)] and plasminogen share a high degree of homology as recently evidenced by amino acid and deoxyribonucleic acid analysis. As Lp(a) is enzymatically inactive, it has been suggested that high levels of Lp(a) may suppress the profibrinolytic activity at the cell surface and increase the risk for arteriosclerosis and thrombosis by competitive inhibition of plasminogen. The present study evaluated whether high levels of Lp(a) influence thrombolytic therapy in patients with acute myocardial infarction. Forty-one patients with acute myocardial infarction received a combination low-dose thrombolytic therapy with recombinant tissue-type plasminogen activator (rt-PA) and human single-chain urokinase-type plasminogen activator (scu-PA). This regimen did not induce plasminemia or a lytic state as indicated by well-maintained levels of fibrinogen. Coronary patency was assessed angiographically 90 minutes after initiation of treatment. Thrombolysis was successful in 30 and unsuccessful in 11 patients. Patients with high Lp(a) levels (greater than or equal to 25 mg/dl) (n = 9) responded equally well to thrombolytic therapy (8 of 9, patency 89%) as did patients with normal or low levels of Lp(a) (22 of 32, patency 70%, difference greater than 0.1). Lp(a) levels did not differ significantly between patients with successful and unsuccessful thrombolysis. Our results demonstrate that high levels of Lp(a) do not affect thrombolysis in patients with acute myocardial infarction when low-dose pharmacologic concentrations of rt-PA and scu-PA are applied in combination.
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PMID:Effects of lipoprotein (a) on success rate of thrombolytic therapy in acute myocardial infarction. 182 24

The glycosaminoglycans (GAGs) heparin, heparan sulphate and chondroitin 6-sulphate stimulate the rate of urokinase activation of human plasminogen. Kinetic analysis of plasminogen activation demonstrates that heparin, heparan sulphate and chondroitin 6-sulphate increased the catalytic rate (Kcat) by 5.3-, 3.5- and 2.5-fold respectively. These stimulatory GAGs had no effect on the affinity of urokinase for plasminogen, since the Km of the reaction is unaltered by the GAGs. The GAGs may enhance the rate of plasminogen activation through an interaction with the catalytic domain of the urokinase, with dissociation constants of approx. 30 nM. Additionally, the lipoproteins, lipoprotein (a) [Lp(a)] and low-density lipoprotein (LDL) inhibit heparin and heparan sulphate stimulation of plasmin formation. Lp(a) is a competitive inhibitor (Kic 20 nM) and LDL is a mixed inhibitor of heparin-enhanced urokinase-mediated plasminogen activation (Kic 24 nM and Kiu 60 nM). These inhibition constants correlate with physiological concentrations of these lipoproteins. These data suggest that these GAGs and lipoproteins may play an important role in vivo in regulating urokinase-mediated plasmin formation.
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PMID:Kinetic analysis of the effects of glycosaminoglycans and lipoproteins on urokinase-mediated plasminogen activation. 182 7

Lipoprotein(a) [Lp(a)] is a low density lipoprotein whose plasma levels strongly correlate with the occurrence of atherosclerotic disease. Structural studies have demonstrated that Lp(a) contains two disulphide bonded subunits, one of which has structural similarity to plasminogen. This subunit, designed apo-lipoprotein(a), contains multiple repeat copies of a kringle homologous to kringle-4 of plasminogen, one copy of a kringle-5-like structure and a domain homologous to the catalytic light chain of plasmin. This subunit, however, lacks the site where plasminogen activators cleave plasminogen to generate the active proteinase. Recent studies demonstrate that Lp(a) competes with plasminogen for binding to endothelial cells and macrophages and thus prevents assembly of the fibrinolytic system on cell surfaces. Lp(a) also inhibits activation of plasminogen by streptokinase, urokinase-type plasminogen activator or tissue-type plasminogen activator (t-PA). Inhibition of plasminogen activation by t-PA requires the presence of a template on which activation occurs. This template can be either fibrin or heparin. This review considers the role of Lp(a) as an inhibitor of template-dependent activation of the fibrinolytic system.
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PMID:Lipoprotein(a) inhibits plasminogen activation in a template-dependent manner. 183 24

The lipoprotein Lp(a) is a cholesterol-rich plasma lipoprotein from the density fraction 1.06-1.21 g/ml. Numerous clinical and epidemiological studies have revealed a strong correlation between high plasma Lp(a) concentrations and the incidence of coronary heart disease. Furthermore, the Lp(a)-specific protein apo(a) has been detected in atherosclerotic lesions. Lp(a) is essentially an LDL-like lipoprotein particle to which the glycoprotein apo(a) is attached through a disulfide bridge with apo B-100. The elucidation of the amino acid sequence of apo(a) revealed a high homology to specific regions of human plasminogen. The latter consists of five tandemly arranged kringle domains followed by a C-terminal trypsin-like protease region. Apo(a) is composed of a large number of kringle domains, all highly homologous to kringle IV of plasminogen, followed by a kringle V-like protease-domain. The lipoprotein Lp(a), therefore, combines structural elements of both the lipoprotein and coagulation systems. In contrast to plasminogen, Lp(a) cannot be activated by TPA, streptokinase or urokinase to give proteolytic activity. However, in vitro studies have shown that Lp(a) can both inhibit endothelial cell induced fibrinolysis and can also bind to plasmin modified fibrin. These findings provide a pathobiochemical basis for the involvement of Lp(a) in atherosclerotic and thrombotic processes. The function of this lipoprotein is, however, still unclear.
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PMID:[Lipoprotein(a): characteristics of a special lipoprotein and its potential clinical significance]. 214 32

Lp(a) represents a genetically transmitted class of plasma LDL having apo B-100 linked by a disulfide bridge to a glycoprotein, apo(a). Lp(a) is heterogeneous in size and density. Apo(a) is also heterogeneous in size (molecular weight between approximately 300,000 and 700,000) due probably to the polymorphism of both polypeptide and carbohydrate chains. Recent studies have shown that apo(a) has a striking amino acid sequence homology with plasminogen, a serine protease zymogen that following activation to plasmin enters the fibrinolytic system. Apo(a) is severalfold larger than plasminogen (molecular weight approximately 90,000) and also differs from it because it fails to be activated to plasmin. This is due to the fact that arginine is replaced by serine at the site of cleavage by streptokinase, urokinase, or tissue plasminogen activator. A single gene locus appears to control the Lp(a) polymorphism as well as the concentration of the Lp(a) phenotypes in the plasma. Patients with high plasma levels of Lp(a) have been shown to have an increased incidence of cardiovascular disease but a causal relationship has not been firmly established. The information that is being rapidly acquired on the structure of Lp(a) should facilitate the understanding of the molecular basis of the polymorphism of this genetic variant and of the role that the various Lp(a) phenotypes play in atherosclerosis and thrombosis. The potential physiologic role of Lp(a) remains open to inquiry.
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PMID:Lipoprotein(a): a genetically determined lipoprotein containing a glycoprotein of the plasminogen family. 297 66

Apolipoprotein(a) [apo(a)] is a glycoprotein with Mr approximately equal to 280,000 that is disulfide linked to apolipoprotein B in lipoprotein(a) particles. Elevated plasma levels of lipoprotein(a) are correlated with atherosclerosis. Partial amino acid sequence of apo(a) shows that it has striking homology to plasminogen. Plasminogen is a plasma serine protease zymogen that consists of five homologous and tandemly repeated domains called kringles and a trypsin-like protease domain. The amino-terminal sequence obtained for apo(a) is homologous to the beginning of kringle 4 but not the amino terminus of plasminogen. Apo(a) was subjected to limited proteolysis by trypsin or V8 protease, and fragments generated were isolated and sequenced. Sequences obtained from several of these fragments are highly (77-100%) homologous to plasminogen residues 391-421, which reside within kringle 4. Analysis of these internal apo(a) sequences revealed that apo(a) may contain at least two kringle 4-like domains. A sequence obtained from another tryptic fragment also shows homology to the end of kringle 4 and the beginning of kringle 5. Sequence data obtained from two tryptic fragments show homology with the protease domain of plasminogen. One of these sequences is homologous to the sequences surrounding the activation site of plasminogen. Plasminogen is activated by the cleavage of a specific arginine residue by urokinase and tissue plasminogen activator; however, the corresponding site in apo(a) is a serine that would not be cleaved by tissue plasminogen activator or urokinase. Using a plasmin-specific assay, no proteolytic activity could be demonstrated for lipoprotein(a) particles. These results suggest that apo(a) contains kringle-like domains and an inactive protease domain.
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PMID:Partial amino acid sequence of apolipoprotein(a) shows that it is homologous to plasminogen. 347 6

The effect of a 17-kringle form of recombinant apo(a) [r-apo(a)] on in vitro fibrin clot lysis was studied. In these assays, fibrin clots were formed in the wells of microtiter plates, and lysis of the clots was monitored by measurement of the turbidity at 405 nm. The results indicate that r-apo(a) produces a dose-dependent antifibrinolytic effect in clots formed using either purified components or barium-adsorbed plasma. This effect was found to be independent of clot structure, since lysis of clots formed using both high and low concentrations of thrombin was prolonged by r-apo(a) to the same extent. The two components of the antifibrinolytic effect of r-apo(a) were determined to be (i) attenuation of tPA-mediated plasminogen activation (the major component) and (ii) inhibition of plasmin degradation of fibrin, although r-apo(a) did not directly attenuate plasmin activity, as measured by S-2251 hydrolysis. r-Apo(a) interfered most substantially with tPA-mediated activation of Glu-plasminogen and less substantially with tPA-mediated Lys-plasminogen activation and urokinase-mediated activation of plasminogen. In summary, we have demonstrated that apo(a) is able to attenuate fibrin clot lysis in vitro, primarily as a consequence of the interference by apo(a) with tPA-mediated Glu-plasminogen activation. These studies illuminate possible mechanisms by which Lp(a) may contribute to the development of vascular disease in vivo.
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PMID:Antifibrinolytic effect of recombinant apolipoprotein(a) in vitro is primarily due to attenuation of tPA-mediated Glu-plasminogen activation. 771 Oct 34

The relationship between lipoprotein (a) (Lp(a)) and atherosclerosis has been appreciated for a number of years. Only in recent years, however, has the structural relationship of Lp(a) to plasminogen resulted in studies of the effect of this lipoprotein on fibrinolysis. Lp(a) inhibits activation of plasminogen by tissue-type (t-PA) and urinary-type (u-PA) plasminogen activators. These inhibitory reactions are surface-dependent. When Lp(a) binds to fibrin, fibrinogen, heparin or cells it blocks activation of plasminogen by t-PA. u-PA-mediated activation of plasminogen is blocked on surfaces including heparin and chondroitin sulfate. Lp(a) also favors inhibition of plasmin by alpha 2-antiplasmin (alpha 2-AP). The ability of Lp(a) to compete with plasmin for fibrin binding displaces plasmin into solution where alpha 2-AP rapidly inhibits this proteinase. These effects are all antifibrinolytic. Lp(a) also exhibits one profibrinolytic effect, since it blocks inhibition of t-PA by plasminogen activator type 1 in the presence of fibrinogen or heparin. Thus, Lp(a) modulates most of the reactions involved in plasmin generation and inhibition. Its overall effect will depend primarily on the concentrations of Lp(a), PAI-1 and t-PA in vivo.
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PMID:Lipoprotein (a) regulates plasmin generation and inhibition. 818 36

Lipoprotein(a) (Lp(a)) and plasminogen share a high degree of structural homology. Therefore it has been suggested that elevated levels of Lp(a) may inhibit the profibrinolytic activity at the cell surface and increase the risk of thrombosis by competitive inhibition of plasminogen. In the present study we evaluated whether high levels of Lp(a) affect thrombolytic therapy in patients with acute myocardial infarction. Forty-one patients with acute myocardial infarction were treated with a combination of recombinant tissue-type plasminogen activator and human single-chain urokinase-type plasminogen activator. Coronary patency was assessed angiographically 90 min after initiation of treatment. Thrombolysis was successful in 30 and unsuccessful in 11 patients. Patients with high Lp(a) levels (> 25 mg/dl) (n = 9) responded equally well to thrombolytic therapy (8 of 9, patency 89%) as did patients with normal or low levels of Lp(a) (22 of 32, patency 70%, difference P > 0.1). The results demonstrate that high levels of Lp(a) do not influence thrombolysis in patients with acute myocardial infarction when low-dose pharmacologic concentrations of recombinant tissue-type plasminogen activator and human single chain urokinase-type plasminogen activator are applied in combination.
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PMID:Effects of lipoprotein(a) on thrombolysis. 818 38


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