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)

Linear tri- and tetrapeptide precursors of 2,5-piperazinedione were prepared and their conversion to spirocyclic dipeptidase enzymes, the spirocyclic dipeptides (SpDp) were generated from the precursors by a two-step mechanism consisting in the proteolytic release of the C-terminal dipeptide ethyl ester and its subsequent spontaneous cyclization. After intraperitoneal administration of urokinase and Ac-Leu-Lys-Gly-Acp-OEt, a SpDp precursor targeted to endogenous plasmin, or the administration of the activated Hageman factor fragment and Ac-Leu-Arg-Ala-Acp-OEt, a SpDp precursor, targeted to endogenous kallikrein, the generated corresponding C-terminal dipeptide ethylester intermediates and SpDp, cyclo(Gly-Acp) and cyclo (Ala-Acp), respectively, were detected in the blood serum of C57B1 mice. Suppression of partial amnesia induced by sodium nitrite was observed in rats where it was subcutaneously administered with H-Leu-Ala-Acp-OEt, a peptide precursor of alaptide, the active SpDp, i.e. cyclo(1-amino-1-cyclopentanecarbonyl-L-alanyl).
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PMID:Two-step generation of spirocyclic dipeptides from linear peptide ethyl ester precursors. 153 Sep 83

A decreased fibrinolytic activity induced by bacterial products and some muramyl peptides has been previously demonstrated in macrophages preparations. Since vascular endothelial cells are important for the fibrinolytic balance, we have studied the effects of MDP derivatives on cultured endothelial cells. The supernatant of MDP and murabutide treated cell cultures exhibited an increased fibrinolytic inhibitory activity when tested with urokinase. The MDP(D-D)-treatment had no effect. This increased inhibitory activity was detectable in the supernatant after a 6 h treatment and was suppressed by the addition of puromycin to the cell cultures. Furthermore, the endothelial cell culture supernatant also reduced the lytic activity of the human plasma plasminogen activator induced by venostasis. This was enhanced by MDP treatment of the cultures. These in vitro results suggested that adjuvant-active muramyl peptides may regulate the fibrinolytic balance at the vessel wall level. This could be of possible significance in the transendothelial cell migration where the role of plasminogen activator(s) has been involved.
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PMID:Increased synthesis of fibrinolytic inhibitor induced by muramyl dipeptide derivatives in human cultured endothelial cells. 392 45

Human lung macrophages express all four of the known lysosomal thiol proteases: cathepsins B, H, L, and S. These enzymes share a similar size and targeting mechanism for lysosomal accumulation and all have relatively indiscriminate substrate specificity in comparison with such highly selective serine proteases as urokinase or thrombin. These enzymes do have distinctive properties: only cathepsin B has C-terminal dipeptidase activity, only cathepsin H has potent aminopeptidase activity, and only cathepsin L and S are elastolytic. Cathepsin S is unique in that it is stable at neutral pH; indeed, at neutral pH it has elastolytic activity roughly comparable with that of neutrophil elastase. Recent studies of the differential expression of these cathepsins suggest they not only cooperate in terminal degradation of endocytized protein but also have specific functions such as proenzyme activation, antigen processing, and tissue remodeling, especially bone matrix resorption. Lysates of lung macrophages degrade elastin at neutral pH, suggesting that necrosis of macrophages at sites of macrophage accumulation, e.g., caseation necrosis, could contribute to tissue destruction. Tissue destruction and remodeling by thiol proteases expressed by live macrophages, however, is limited by tight compartmentalization of cathepsins to lysosomes. Nonetheless, macrophages accumulate at sites of known injury in cigarette smokers. Because these cells contain potent elastases, and because lysosomal enzyme release and cell surface acidification are regulated events, dysregulation of thiol protease expression in stimulated macrophages may contribute to the injury observed in cigarette smokers with non-alpha-1-protease inhibitor-type emphysema.
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PMID:The role of thiol proteases in tissue injury and remodeling. 795 52

The CC chemokine CCL14a is constitutively expressed in a large variety of tissues and its inactive proform CCL14a(1-74) circulates in high concentrations in plasma. CCL14a(1-74) is converted into CCL14a(9-74) by the proteases urokinase-type plasminogen activator and plasmin and is a highly active agonist for the chemokine receptors CCR1 and CCR5. In this study, a new CCL14a analog, CCL14a(12-74), was isolated from blood filtrate. To elucidate the functional role of the N terminus, a panel of N-terminally truncated CCL14a analogs were tested on the receptors CCR1 to CCR5 and on the human cytomegalovirus (HCMV)-encoded chemokine receptor US28. The rank order of binding affinity to these receptors and of the activation of CCR1 and CCR5-mediated intracellular Ca(2+) concentration mobilization is CCL14a(6-74)<(7-74)<(8-74)<<(9-74) = (10-74)>>(11-74)>>(12-74). The almost identical affinities of CCL14a(7-74), CCL14a(9-74), and CCL14a(10-74) for the US28 receptor and the inhibition of US28-mediated HIV infection of 293T cells by all of the N-terminally truncated CCL14a analogs support the promiscuous nature of the viral chemokine receptor US28. In high concentrations, CCL14a(12-74) did reveal antagonistic activity on intracellular Ca(2+) concentration mobilization in CCR1- and CCR5-transfected cells, which suggests that truncation of Tyr(11) might be of significance for an efficient inactivation of CCL14a. A putative inactivation pathway of CCL14a(9-74) to CCL14a(12-74) may involve the dipeptidase CD26/dipeptidyl peptidase IV (DPPIV), which generates CCL14a(11-74), and the metalloprotease aminopeptidase N (CD13), which displays the capacity to generate CCL14a(12-74) from CCL14a(11-74). Our results suggest that the activity of CCL14a might be regulated by stringent proteolytic activation and inactivation steps.
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PMID:Significance of N-terminal proteolysis of CCL14a to activity on the chemokine receptors CCR1 and CCR5 and the human cytomegalovirus-encoded chemokine receptor US28. 1955 44