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:3.4.15.1 (ACE)
18,300 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Bradykinin is susceptible to degradation by a variety of endo- and exopeptidases. These include aminopeptidase P, meprin, endopeptidase 24.15, prolyl endopeptidase, neutral endopeptidase 24.11, angiotensin I-converting enzyme, carboxypeptidase N, carboxypeptidase M, and deamidase. These peptidases are widely distributed in various tissues and cells in the body, and their subcellular locations vary as well. Because bradykinin is inactivated (for binding the B2 receptor) when any of its peptide bonds are cleaved, all of these enzymes qualify as potential "kininases" in vivo; however, the importance of a particular enzyme as a kininase will depend on its localization, access to bradykinin, and the presence of other peptidases. In addition, these peptidases can cleave a variety of other peptide hormone substrates. Determination of the importance of a peptidase in the inactivation of bradykinin during a particular physiological response can be difficult, but specific peptidase inhibitors and kinin receptor antagonists are useful tools in investigating these questions.
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PMID:Bradykinin-degrading enzymes: structure, function, distribution, and potential roles in cardiovascular pharmacology. 128 29

The expression of cell-surface peptidases was examined in two human colon carcinoma cell lines, Caco-2 and HT-29. Enzymic assays revealed the presence of eight cell-surface peptidases on a Caco-2 cell line (passage number 82-88), namely aminopeptidase N, dipeptidyl peptidase IV, peptidyl dipeptidase A (angiotension-converting enzyme), aminopeptidase P, aminopeptidase W, endopeptidase-24.11, gamma-glutamyl transpeptidase and membrane dipeptidase. The presence of dipeptidyl peptidase IV and endopeptidase-24.11 was also confirmed immunochemically. After 15 days culture, the activities of aminopeptidase P, peptidyl dipeptidase A and alkaline phosphatase activities on Caco-2 cells reached a plateau, and that of membrane dipeptidase began to decline. In contrast, aminopeptidase N, dipeptidyl peptidase IV and endopeptidase-24.11 activities were still rising after 26 days in culture. Caco-2 cells of passage number 181-183 were found to lack endopeptidase-24.11, but maintained dipeptidyl peptidase IV expression. Two populations of HT-29 cells were surveyed. Both the standard, undifferentiated population and a differentiated population expressed only three peptidases: dipeptidyl peptidase IV, aminopeptidase W and carboxypeptidase M. In the differentiated HT-29 cells the activity of dipeptidyl peptidase IV after 14-21 days was beginning to plateau whereas aminopeptidase W activity was still rising and that of carboxypeptidase M had begun to decline. These differences in activity profiles observed among this group of cell-surface peptidases indicate that these cell lines, especially Caco-2, are useful models to study the regulation of their expression.
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PMID:A survey of membrane peptidases in two human colonic cell lines, Caco-2 and HT-29. 131 37

We investigated the effect of inhibition of carboxypeptidase, neutral endopeptidase, or angiotensin converting enzyme on airway reactivity to intravenous bradykinin in guinea pigs. Bradykinin reactivity in intact, unanesthetized, spontaneously breathing animals was determined by measuring specific airway resistance in response to increasing doses of intravenous bradykinin or acetylcholine. We found that phosphoramidon and/or captopril (specific antagonists of neutral endopeptidase and angiotensin converting enzyme, respectively) increased airway reactivity to bradykinin, but the combination had no effect on muscarinic reactivity. Although 2-mercaptomethyl-3-guanidinoethylthiopropanoic acid (MGTA, a carboxypeptidase inhibitor) alone did not alter bradykinin reactivity, MGTA in the presence of both phosphoramidon and captopril significantly potentiated bradykinin-induced airway reactivity. In comparison, this did not affect reactivity to acetylcholine. Having found that carboxypeptidase inhibition could augment kinin-induced airway reactivity, we subsequently assayed for and identified carboxypeptidase M activity in guinea pig lung. We found considerable carboxypeptidase M activity in guinea pig lung subcellular fractions, the 100,000 x g membrane pellet having the highest specific activity. Our data indicate that airway reactivity to intravenous bradykinin is modulated by the activity of endogenous neutral endopeptidase, angiotensin converting enzyme, and carboxypeptidase, all of which are present in lung cell membranes. This study also suggests that the influence of carboxypeptidase per se may be substantially enhanced if endogenous pulmonary neutral endopeptidase and angiotensin converting enzyme activities are reduced.
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PMID:Lung peptidases, including carboxypeptidase, modulate airway reactivity to intravenous bradykinin. 192 64

A comprehensive survey of 11 peptidases, all of which are markers for renal microvillar membranes, has been made in membrane fractions prepared from pig choroid plexus. Two fractionation schemes were explored, both depending on a MgCl2-precipitation step, the preferred one having advantages in speed and yield of the activities. The specific activities of the peptidases in the choroid-plexus membranes were, with the exception of carboxypeptidase M, lower than in renal microvillar membranes: those of aminopeptidase N, peptidyl dipeptidase A ('angiotensin-converting enzyme') and gamma-glutamyltransferase were 3-5-fold lower, those of aminopeptidase A and endopeptidase-24.11 were 12-15 fold lower, and those of dipeptidyl peptidase IV and aminopeptidase W were 50-70-fold lower. Carboxypeptidase M had a similar activity in both membranes. Alkaline phosphatase and (Na+ + K+)-activated ATPase were more active in the choroid-plexus membranes. No activity for microsomal dipeptidase, aminopeptidase P and carboxypeptidase P could be detected. Six of the peptidases and (Na+ + K+)-activated ATPase were also studied by immunoperoxidase histochemistry at light- and electron-microscopic levels. Endopeptidase-24.11 and (Na+ + K+)-activated ATPase were uniquely located on the brush border, and the other two peptidases appeared to be much more abundant on the endothelial lining of microvessels. Dipeptidyl peptidase IV and aminopeptidase W were also detected in microvasculature. Pial membranes associated with the brain and spinal cord also stained positively for endopeptidase-24.11, aminopeptidase N and peptidyl dipeptidase A. The immunohistochemical studies indicated the subcellular fractionation did not discriminate between membranes derived from epithelial cells (i.e. microvilli) and those from endothelial cells. The possible significance of these studies in relation to neuropeptide metabolism and the control of cerebrospinal fluid production is discussed.
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PMID:Membrane peptidases in the pig choroid plexus and on other cell surfaces in contact with the cerebrospinal fluid. 265 79

Alveolar macrophages protect the lungs against noxious agents. Proteases and peptidases are essential for this defense and many metabolic activities. Human alveolar macrophages were evaluated for the presence of six important peptidases. Deamidase, a serine peptidase identical with the lysosomal protective protein and possibly with cathepsin A, had high specific activity in alveolar macrophages and is also present in cultured mouse J774A.1 and human U937 cells, used for the sake of comparison. In fractionated J774A cells, most of the deamidase activity was in the lysosomal fraction and in the final supernatant. Deamidase in human alveolar macrophages, obtained by bronchoalveolar lavage from 23 patients, cleaved dansyl-Phe-Leu-Arg at a rate of 2.26 mumol/h/mg protein and hydrolyzed the chemotactic peptide N-f-Met-Leu-Phe even faster, at a rate of 53.1 mumol/h/mg protein, the highest activity for this enzyme with any of the cells we tested. Rabbit antiserum, elicited with the recombinant partial sequence of the enzyme, immunoprecipitated 77-88% of the macrophage deamidase. In immunocytochemistry, this antiserum localized deamidase within the human macrophages. The enzyme was inhibited by diisopropylfluorophosphate (DFP; 1 mM) and by ebelactone B (10 microM), noncompetitively. The mRNA of deamidase was detected in mouse macrophages by Northern blot; the two protein chains of deamidase were shown in human macrophages by Western blot. In addition, two other serine peptidases were also highly active in macrophages: dipeptidyl peptidase IV (1.38 mumol/h/mg protein) and prolylcarboxypeptidase (0.72 mumol/h/mg protein). The activity of plasma membrane zinc metallopeptidases, neutral endopeptidase 24.11 and carboxypeptidase M, in contrast, was low or absent (angiotensin I converting enzyme; kininase II).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Plasma membrane-bound and lysosomal peptidases in human alveolar macrophages. 762 87

We investigated the release of carboxypeptidase M (CPM), neutral endopeptidase 24.11 (enkephalinase, NEP), and angiotensin I converting enzyme (kininase II, ACE) and their contribution to bradykinin metabolism in the rat lung. The P3, membrane-enriched fraction of the homogenized lung was rich in all three peptidases. The activities of CPM and NEP were high in bronchoalveolar lavage fluid but lower in alveolar macrophages indicating that they originate from other cells present on the alveolar surface. In situ perfusion of rat lung with buffer that contained either deoxycholate or melittin or compound 48/80, produced lung edema. CPM, NEP, and ACE activities were recovered both in edema and perfusate fluid. The level of CPM and NEP was higher in edema fluid whereas, in contrast, more ACE activity was released into the perfusate. To evaluate the effect of peptidase inhibitors on changes in vascular permeability induced by bradykinin in the in situ perfused rat lung we measured the increase in lung weight as an index of increased vascular permeability or edema. Combined inhibition of either ACE plus NEP or ACE plus CPM augmented the effect of a subthreshold dose of bradykinin. Inhibitors of ACE, NEP, or CPM given alone and a combination of NEP plus CPM inhibitors did not enhance the bradykinin effect. Our results indicate that CPM, NEP, and ACE although present on different lung cells, synergistically modulate bradykinin effects. The different ratios of distribution of these enzymes in the perfusate and in edema fluid may not be due only to their presence on different pulmonary cells but also to their different anchoring mechanisms to plasma membranes.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Metabolism of bradykinin by peptidases in the lung. 838 9

Restitution of bronchial artery circulation might alter ischemia- reperfusion injury and improve organ function after lung transplantation. Weight-matched dogs underwent a left lung allotransplantation either with bronchial artery revascularization (BAR; n = 6) or as conventional lung transplantation (LTX; n = 6), to evaluate effects of BAR on lung cell function over a period of 5 h postischemically. Lactate dehydrogenase (LDH) and marker enzymes for pneumocytes type I (carboxypeptidase M [CPM], pneumocytes type II (alkaline phosphatase [AP]), and pulmonary endothelium (angiotensin-converting-enzyme [ACE]) were determined from bronchoalveolar lavage fluid. Donor lungs were preserved with Euro-Collins solution. Total ischemic time was kept at 6 h. CPM and LDH activities were significantly higher in both groups at 2 h and 4 h of reperfusion compared with control dogs (p < 0.01). AP and ACE activities in lavage after 2 h of reperfusion were significantly elevated in animals that underwent LTX (AP: 60 +/- 28 IU/L; ACE: 1.39 +/- 1.13 IU/L) compared with animals with BAR (AP: 33 +/- 29 IU/L; ACE: 0.35 +/- 0.6 IU/L; p < 0.05) and with control animals (AP: 13.58 +/- 11.0 IU/L; ACE: 0.06 +/- 0.14 IU/L; p < 0.01). According to these results, BAR protects pulmonary endothelium and type II pneumocytes in the early phase after lung transplantation and might have consequences for lung tissue in the long term.
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PMID:Bronchial artery revascularization affects graft recovery after lung transplantation. 1179 Jun 58

Trypanosoma cruzi, the protozoan that causes Chagas' heart disease, invades endothelial cells in vitro by activating the B2 kinin receptor (B2R). Here, we demonstrate that mice infected with trypomastigotes develop potent edema after treatment with the angiotensin-converting enzyme (ACE) (or kininase II) inhibitor captopril. Experiments performed with specific kinin receptor (B2R/B1R) antagonists and knockout mice revealed that the early-phase (3-h) edema is mediated by the constitutive B2R, whereas the late-phase (24-h) response depends on stimulation of the up-regulated B1R. Given previous evidence that parasite invasion of cells expressing B2R is potentiated by captopril, we investigated the prerequisites for in vitro infection of Chinese hamster ovary cells overexpressing either B1R or B2R, human umbilical vein endothelial cells activated by lipopolysaccharide, and neonatal rat cardiomyocytes. Our results indicate that captopril potentiates parasite invasion regardless of the kinin (B2/B1) activation pathways, whereas DL-2-mercaptomethyl-3-guanidino-ethylthiopropanoic acid (MGTA), an inhibitor of kininase I (carboxypeptidase M/N), selectively decreases parasite infectivity for B1R-expressing cells. These data suggest that formation of the B1R agonist, i.e., [des-Arg] kinins, critically depends on the processing action of kininase I, here proposed as a potential pathogenesis cofactor. Collectively, our data suggest that fluctuations in the levels of kininases may modulate parasite infectivity and pathological outcome in Chagas' disease.
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PMID:Trypanosoma cruzi induces edematogenic responses in mice and invades cardiomyocytes and endothelial cells in vitro by activating distinct kinin receptor (B1/B2) subtypes. 1242 28

The plasma bradykinin-forming cascade and the complement pathways share many elements, including cross-activation, common control mechanisms, and shared binding proteins. The C1 inhibitor (C1 INH) is not only the inhibitor of activated C1r and C1s, but it is the key control protein of the plasma bradykinin-forming cascade. It inhibits the autoactivation of Factor XII, the ability of Factor XIIa to activate prekallikrein and Factor XI, the activation of high molecular weight kininogen (HK) by kallikrein, and the feedback activation of Factor XII by kallikrein. Thus in the absence of C1 INH (hereditary angioedema or acquired C1 INH deficiency) there is unimpeded formation of bradykinin leading to angioedema. Activated Factor XII (Factor XIIa, 80,000 kDa) is further cleaved by kallikrein or plasmin to yield Factor XII fragment (Factor XIIf, 30,000 kDa) and Factor XIIf can activate the C1r subcomponent of C1, particularly when C1 INH (which inhibits Factor XIIf) is absent. Once bradykinin is formed, it causes vasodilatation and increased vascular permeability by interaction with constitutively expressed B-2 receptors. However degradation of bradykinin by carboxypeptidase N (in plasma) or carboxypeptidase M (on endothelial cells) yields des-arg-9 (Kerbiriou and Griffin, 1979) bradykinin which interacts with B-1 receptors. B-1 receptors are induced in inflammatory states by cytokines such as Interleukin 1 and its interaction with bradykinin may prolong or perpetuate the vascular response until bradykinin is completely inactivated by angiotensin converting enzyme or aminopeptidase P, or neutral endopeptidase. The entire bradykinin-forming cascade is assembled and can be activated along the surface of endothelial cells in zinc dependent reactions involving gC1qR, cytokeratin 1, and the urokinase plasminogen activated receptor (u-PAR). Although Factors XII and HK can be shown to bind to each one of these proteins, they exist in endothelial cells as two bimolecular complexes; gC1qR-cytokeratin 1, which preferentially binds HK, and cytokeratin 1-u-PAR which preferentially binds Factor XII. The gC1qR, which binds the globular heads of C1q is present in excess and can bind either Factor XII or HK however the binding sites for HK and C1q have been shown to reside at opposite ends of gC1qR. Activation of the bradykinin-forming pathway can be initiated at the cell surface by gC1qR-induced autoactivation of Factor XII or direct activation of the prekallikrein-HK complex by endothelial cell-derived heat-shock protein 90 (HSP 90) or prolylcarboxypeptidase with recruitment or Factor XII by the kallikrein produced.
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PMID:The plasma bradykinin-forming pathways and its interrelationships with complement. 2058 91

Phosphorylated kininogen and some of its fragments containing serine phosphorylated bradykinin ([pS(6)]-Bk) were identified in human serum and plasma by a phosphoproteomic approach. We report the kininogenase ability of human tissue and plasma kallikreins and tryptase to generate [pS(6)]-Bk or Lys-[pS(6)]-Bk having as substrate the synthetic human kininogen fluorescent fragment Abz-MISLMKRPPGF[pS(386)]PFRSSRI-NH2. The pharmacological assays of [pS(6)]-Bk showed it as a full B2 bradykinin receptor agonist in smooth muscle, it produces a portal liver hypertensive response in rat and mouse paw edema that lasts longer than Bk. The rat hypotensive response to infusions of Bk is greater than that of [pS(6)]Bk, both if injected through femoral vein or aorta. [pS(6)]-Bk was more resistant than Bk to kininase digestion performed with angiotensin converting enzyme, neprilysin, thimet oligopeptidase, aminopeptidase P and carboxypeptidase M. (1)H-NMR experiments indicated that [pS(6)]-Bk has lower flexibility, with the pS(6)-P(7) bond restricted to the trans conformation, and can explain [pS(6)]-Bk resistance to hydrolysis. In conclusion, [pS(6)]-Bk presenting lower activity than Bk, with longer lasting effects and being slowly released by kininogenases from synthetic Abz-MISLMKRPPGF[pS(386)]PFRSSRI-NH2, suggests that phosphorylation of the kininogens can be an efficient kallikrein-kinin system regulator.
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PMID:Pharmacological Activities and Hydrolysis by Peptidases of [Phospho-Ser(6)]-Bradykinin (pS(6)-BK). 2623 42


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