Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.7 (plasmin)
 9,023 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pro-carboxypeptidase R (proCPR), also known as thrombin-activatable fibrinolysis inhibitor (TAFI), precursor of carboxypeptidase U and plasma carboxypeptidase B is present in plasma and following activation by thrombin/thrombomodulin and/or plasmin can remove arginine from the carboxyterminal of C3a and C5a. We have shown that this enzyme can remove terminal arginine from the C5a octapeptide much more efficiently than the classical anaphylatoxin inactivator, carboxypeptidase N (CPN). Since we have previously demonstrated that proCPR is significantly upregulated in the inflammatory state, this enzyme would appear to significantly contribute to the inactivation of C5a, the most potent of the complement derived anaphylatoxins.
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PMID:Inactivation of C3a and C5a octapeptides by carboxypeptidase R and carboxypeptidase N. 1193 78

Thrombin-activable fibrinolysis inhibitor (TAFI) is a procarboxypeptidase B-like zymogen that upon activation by thrombin, thrombin-thrombomodulin, or plasmin attenuates fibrin clot lysis by inhibiting positive feedback in the fibrinolytic cascade. The concentration of TAFI in plasma varies in the human population and thus may constitute a risk factor for thrombotic disorders. In addition, TAFI has been reported to be a positive acute phase reactant in mice. We have initiated molecular analysis of the human TAFI promoter to understand the mechanisms underlying regulation of TAFI gene expression. We identified a putative C/EBP-binding site between -53 and -40 of the promoter. Mutations in this site that abolish C/EBP binding decrease TAFI promoter activity in human hepatoma (HepG2) cells by approximately 80%. Gel mobility shift analyses indicated that C/EBP-beta present in HepG2 nuclear extracts and C/EBP-alpha and -beta present in adult rat liver nuclear extracts bind to the C/EBP site. C/EBP-alpha, -beta, and -delta isoforms are all capable of binding to the C/EBP site and activating the TAFI promoter. The identification of a functional C/EBP-binding site in the human TAFI promoter may have important implications for the regulation of expression of this gene during development and in response to inflammatory stimuli.
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PMID:A role for CCAAT/enhancer-binding protein in hepatic expression of thrombin-activable fibrinolysis inhibitor. 1200 Jul 65

Activated thrombin-activatable fibrinolysis inhibitor (TAFIa) attenuates the fibrin cofactor function of tissue-type plasminogen activator-mediated plasmin formation and subsequently fibrin degradation. In the present study, we focused on the role of plasmin in the regulation of TAFIa activity. Upon incubation with plasmin, TAFIa activity was generated, which was unstable at 37 degrees C. Analysis of the cleavage pattern showed that TAFI was cleaved at Arg(92), releasing the activation peptide from the 35.8-kDa catalytic domain. The presence of the 35.8-kDa fragment paralleled the time course of generation and loss of TAFIa activity. This suggested that, in the presence of plasmin, TAFIa is probably inactivated by proteolysis rather than by conformational instability. TAFI was also cleaved at Arg(302), Lys(327), and Arg(330), resulting in a approximately 44.3-kDa fragment and several smaller fragments. The 44.3-kDa fragment is no longer activatable since it lacks part of the catalytic center. We concluded that plasmin can cleave at several sites in TAFI and that this contributes to the regulation of TAFI and TAFIa.
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PMID:Plasmin-mediated activation and inactivation of thrombin-activatable fibrinolysis inhibitor. 1202 72

Carboxypeptidase U (CPU,TAFIa) recently gained interest as a significant player in dampening the fibrinolytic rate. The aim of this study was to investigate the time course of the generation of CPU activity during coagulation and fibrinolysis using an in vitro clot lysis model in human plasma. A first peak of CPU activity appeared after initiation of the coagulation phase and a second rise in CPU activity was observed during the fibrinolysis. The decrease in the proCPU plasma concentration followed the same trend as the appearance of the CPU activity. The direct thrombin inhibitor inogatran eliminated the CPU generation during coagulation but not during fibrinolysis. Addition of the plasmin inhibitor aprotinin during fibrinolysis resulted in a decrease in CPU activation during the lysis phase. These results demonstrate that proCPU was activated during coagulation by thrombin and during fibrinolysis by plasmin. Addition of a CPU inhibitor before initiation of clotting decreased the clot lysis time as expected. However, addition in the time period between the two peaks of CPU activity had no apparent effect on the clot lysis time.
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PMID:Different mechanisms contribute to the biphasic pattern of carboxypeptidase U (TAFIa) generation during in vitro clot lysis in human plasma. 1257 5

We have previously confirmed, using a rat mesenteric arteriole thrombolysis model, that thrombin inhibition induces endogenous thrombolysis in vivo. In addition, we have shown that thrombin-activatable fibrinolysis inhibitor (TAFI) plays a role in the down regulation of endogenous thrombolysis. However, the mechanism of endogenous thrombolysis or spontaneous plasmin generation in vivo remains unclear. It has been shown in an in vitro system that plasma kallikrein activates pro-urokinase (pro uPA) and/or plasminogen, resulting in plasmin generation. These findings suggest that spontaneous fibrinolysis might be mediated by tPA and plasma kallikrein-dependent uPA. The aim of the present study was to examine whether these mechanisms play a dominant role in endogenous thrombolysis in vivo, using our rat mesenteric arterial thrombolysis model. Argatroban infusion enhanced endogenous thrombolysis. PKSI-527, anti uPA and anti tPA IgGs suppressed argatroban-induced thrombolysis. Also, the antibody IgG preparations suppressed endogenous thrombolysis in the absence of argatroban. In the presence of PKSI-527, anti tPA IgG was more effective than anti uPA IgG in suppressing argatroban-induced thrombolysis. The results suggested that both tPA and plasma kallikrein-mediated uPA activation and tPA release contribute to endogenous fibrinolytic or thrombolytic mechanisms.
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PMID:Suppression of argatroban-induced endogenous thrombolysis by PKSI-527, and antibodies to TPA and UPA, evaluated in a rat arterial thrombolysis model. 1271 78

Thrombin-activable fibrinolysis inhibitor (TAFI) is a zymogen that inhibits the amplification of plasmin production when converted to its active form (TAFIa). TAFI is structurally very similar to pancreatic procarboxypeptidase B. TAFI also shares high homology in zinc binding and catalytic sites with the second basic carboxypeptidase present in plasma, carboxypeptidase N. We investigated the effects of altering residues involved in substrate specificity to understand how they contribute to the enzymatic differences between TAFI and carboxypeptidase N. We expressed wild type TAFI and binding site mutants in 293 cells. Recombinant proteins were purified and characterized for their activation and enzymatic activity as well as functional activity. Although the thrombin/thrombomodulin complex activated all the mutants, carboxypeptidase B activity of the activated mutants against hippuryl-arginine was reduced. Potato carboxypeptidase inhibitor inhibited the residual activity of the mutants. The functional activity of the mutants in a plasma clot lysis assay correlated with their chromogenic activity. The effect of the mutations on other substrates depended on the particular mutation, with some of the mutants possessing more activity against hippuryl-His-leucine than wild type TAFIa. Thus mutations in residues around the substrate binding site of TAFI resulted in altered C-terminal substrate specificity.
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PMID:Mutations in the substrate binding site of thrombin-activatable fibrinolysis inhibitor (TAFI) alter its substrate specificity. 1279 75

Recently, a new inhibitor of fibrinolysis was described, which downregulated fibrinolysis after it was activated by thrombin, and was therefore named TAFI (thrombin-activatable fibrinolysis inhibitor; EC 3.4.17.20). TAFI turned out to be identical to the previously described proteins, procarboxypeptidase U, procarboxypeptidase R, and plasma procarboxypeptidase B. Activated TAFI (TAFIa) downregulates fibrinolysis by the removal of carboxy-terminal lysines from fibrin. These carboxy-terminal lysines are exposed upon limited proteolysis of fibrin by plasmin and act as ligands for the lysine-binding sites of plasminogen and tissue-type plasminogen activator (t-PA). Elimination of these lysines by TAFIa abrogates the fibrin cofactor function of t-PA-mediated plasminogen activation, resulting in a decreased rate of plasmin generation and thus downregulation of fibrinolysis. In this review, the characteristics of TAFI are summarized, with an emphasis on the pathways leading to activation of TAFI and the role of TAFIa in the inhibition of fibrinolysis. However, it cannot be ruled out that TAFI has other, as yet undefined, functions in biology.
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PMID:Thrombin-activatable fibrinolysis inhibitor (TAFI, plasma procarboxypeptidase B, procarboxypeptidase R, procarboxypeptidase U). 1287 Dec 92

Plasmin and other components of the plasminogen activation system play an important role in tissue repair by regulating extracellular matrix remodeling, including fibrin degradation. Thrombin-activatable fibrinolysis inhibitor (TAFI) is a procarboxypeptidase that, after activation, can attenuate plasmin-mediated fibrin degradation by removing the C-terminal lysine residues from fibrin, which play a role in the binding and activation of plasminogen. To test the hypothesis that TAFI is an important determinant in the control of tissue repair, we investigated the effect of TAFI deficiency on the healing of cutaneous wounds and colonic anastomoses. Histological examination revealed inappropriate organization of skin wound closure in the TAFI knockout mice, including an altered pattern of epithelial migration. The time required to completely heal the cutaneous wounds was slightly delayed in TAFI-deficient mice. Healing of colonic anastomoses was also impaired, as reflected by decreased strength of the tissue at the site of the suture, and by bleeding complications in 3 of 14 animals. Together, these abnormalities resulted in increased mortality in TAFI-deficient mice after colonic anastomoses. Although our study shows that tissue repair, including re-epithelialization and scar formation, occurs in TAFI-deficient mice, TAFI appears to be important for appropriate organization of the healing process.
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PMID:Impaired healing of cutaneous wounds and colonic anastomoses in mice lacking thrombin-activatable fibrinolysis inhibitor. 1452 86

The latent plasma carboxypeptidase thrombin-activable fibrinolysis inhibitor (TAFI) is activated by thrombin/thrombomodulin on the endothelial cell surface, and functions in dampening fibrinolysis. In this study, we examined the effect of activated TAFI (TAFIa) in modulating the proinflammatory functions of bradykinin, complement C5a, and thrombin-cleaved osteopontin. Hydrolysis of bradykinin and C5a and thrombin-cleaved osteopontin peptides by TAFIa was as efficient as that of plasmin-cleaved fibrin peptides, indicating that these are also good substrates for TAFIa. Plasma carboxypeptidase N, generally regarded as the physiological regulator of kinins, was much less efficient than TAFIa. TAFIa abrogated C5a-induced neutrophil activation in vitro. Jurkat cell adhesion to osteopontin was markedly enhanced by thrombin cleavage of osteopontin. This was abolished by TAFIa treatment due to the removal of the C-terminal Arg168 by TAFIa from the exposed SVVYGLR alpha 4 beta 1 integrin-binding site in thrombin-cleaved osteopontin. Thus, thrombin cleavage of osteopontin followed by TAFIa treatment may sequentially up- and down-modulate the pro-inflammatory properties of osteopontin. An engineered anticoagulant thrombin, E229K, was able to activate endogenous plasma TAFI in mice, and E229K thrombin infusion effectively blocked bradykinin-induced hypotension in wild-type, but not in TAFI-deficient, mice in vivo. Our data suggest that TAFIa may have a broad anti-inflammatory role, and its function is not restricted to fibrinolysis.
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PMID:Thrombin activatable fibrinolysis inhibitor, a potential regulator of vascular inflammation. 1452 95

Kidney transplant recipients are not only prone to dyslipidemia but also have a high risk of cardiovascular death. Impairment of the fibrinolytic system is thought to be one factor playing a role in development of thrombotic complications. Thrombin-activatable fibrinolysis inhibitor (TAFI) is a glycoprotein, linking coagulation and fibrinolysis. The purpose of this study was to assess TAFI concentrations and activities in renal transplant recipients stratified based upon serum cholesterol values above 220 mg/dL or below 200 mg/dL. The groups did not differ regarding age, creatinine clearance, BMI, time after transplantation, albumin, fibrinogen, thrombomodulin, or PAP. Additionally, we evaluated thrombin activity (thrombin-antithrombin complex TAT, prothrombin fragments 1 + 2); TAFI activator; thrombomodulin (TM), catalyzer of TAFI activation; and the degree of plasmin generation (plasmin-antiplasmin complex PAP) using commercially available kits. In patients with hyperlipidemia significantly higher TAFI concentrations and activities may contribute to prolonged ECLT and lowered fibrinolytic activity index (FAI). Increased levels of F1 + 2 and TAT were observed in hypercholesterolemic patients, indicating enhanced thrombin generation. Elevated TAFI concentration, and activities and enhanced thrombin generation observed in hypercholesterolemic kidney transplant recipients may contribute to hypofibrinolysis and progression of atherosclerosis in this group of patients.
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PMID:Thrombin-activatable fibrinolysis inhibitor in kidney transplant recipient with dyslipidemia. 1452 94


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