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)

The relative contribution of plasma carboxypeptidase N (kininase I), angiotensin-converting enzyme (ACE) (kininase II), neutral endopeptidase 24.11 (enkephalinase A) and postproline cleaving enzyme to total kininase activity in rat plasma was determined by measuring bradykinin hydrolysis with and without various concentrations of inhibitors of these enzymes. We used DL-2-mercaptomethyl-3-guanidinoethyl-thiopropanoic acid to inhibit kininase I, enalaprilat for ACE, phosphoramidon for neutral endopeptidase 24.11 and N-benzyloxycarbonyl-Pro-prolinal for postproline cleaving enzyme. Bradykinin was added to rat plasma and incubated at 37 degrees C. Kininase activity was evaluated based on the decrease in bradykinin during incubation. Bradykinin was measured by radioimmunoassay, using an antibody that recognizes its carboxyl group. Of the total plasma kininase activity, carboxypeptidase N was responsible for 11.0 +/- 2.5% (N = 5; P less than .05) and ACE for 46.8 +/- 1.5% (N = 5; P less than .001), whereas the contribution of neutral endopeptidase 24.11 and postproline cleaving enzyme turned out to be negligible. Of the kininase activity in rat plasma, 42% could not be explained by any of these four enzymes. We concluded that ACE is responsible for most of the kininase activity in rat plasma; carboxypeptidase N contributes to a slight degree. The fact that 42% of total plasma kininase activity could not be explained by any of the enzymes tested suggests that there are still other kininases in rat plasma which remain to be discovered.
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PMID:Contributions of various rat plasma peptidases to kinin hydrolysis. 255 17

1. Studies were performed in normal subjects and in rats to assess the effect of angiotensin converting enzyme (ACE) inhibition on the kallikrein-kinin system. As ACE is identical to kininase II, one of the enzymes physiologically involved in bradykinin degradation, bradykinin may be expected to accumulate during ACE inhibition. 2. A competitive antagonist of bradykinin was used to explore in unanaesthetized rats the contribution of circulating bradykinin to blood pressure control under ACE inhibition. 3. No evidence was found for a role of this vasodilating peptide in the blood pressure lowering effect of acute ACE inhibition. 4. The plasma activity of carboxypeptidase N (= kininase I), another pathway of bradykinin degradation, remained intact during a 1 week course of treatment with an ACE inhibitor in normal subjects. This therefore indicates that bradykinin formed during ACE inhibition can still be metabolized.
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PMID:Involvement of the kallikrein-kinin system in the antihypertensive effect of the angiotensin converting enzyme inhibitors. 266 13

To determine the role of endogenous neutral endopeptidase (NEP) (also called enkephalinase, EC 3.4.24.11) in regulating neurotensin-induced airway contraction, we used phosphoramidon, a specific NEP inhibitor, in the guinea pig. In studies in vitro, neurotensin and the COOH-terminal fragment neurotensin-(8-13) contracted strips of bronchial smooth muscle in a concentration-dependent fashion (P less than 0.001). In contrast, the NH2-terminal fragment neurotensin-(1-11) and the COOH-terminal fragment neurotensin-(12-13), the main fragments of neurotensin hydrolysis by NEP, had no effect. Phosphoramidon (10(-5) M) did not change resting tension but shifted the concentration-response curves to neurotensin to lower concentrations (P less than 0.001), whereas inhibitors of kininase II, aminopeptidases, serine proteases, and carboxypeptidase N were without effect. Removing the epithelium increased the contractile response to neurotensin (P less than 0.001), and phosphoramidon further increased the response to neurotensin in these tissues (P less than 0.001). Similar results were obtained in studies in vivo using aerosolized neurotensin and phosphoramidon. These results suggest that endogenous NEP in the airways modulates the effects of neurotensin on airway smooth muscle contraction by inactivating the peptide.
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PMID:Neutral endopeptidase modulates neurotensin-induced airway contraction. 274 98

Kininase I (carboxypeptidase N) and kininase II (angiotensin converting enzyme) were isolated from human plasma by gel filtration on Sephadex G 200, then separated and partially purified by ion exchange chromatography. These two partially purified enzymic preparations allowed us to demonstrate that protamine underwent an extensive degradation only when both kininases acted simultaneously. The effects of CoCl2, an activator, and of several inhibitors, amongst which captopril, suggest that the same enzymatic system is responsible for the in vitro protaminasic activity of diluted unfractionated plasma.
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PMID:[Protaminase activity of plasma. III. Role of conversion enzyme (kininase II) in protaminase activity of plasma]. 285 23

Protamine given to neutralize heparin after extracorporeal circulation can trigger a catastrophic reaction in some patients. While searching for a biochemical basis for this reaction, protamine was tested as an inhibitor of human plasma carboxypeptidase N (CPN) or kininase I, the inactivator of anaphylatoxins and kinins. Human plasma and CPN purified from human plasma, (Mr = 280 K) or its isolated active subunit (Mr = 48 K) were the sources of enzyme. The hydrolysis of furylacryloyl (FA)-Ala-Lys was measured in a UV spectrophotometer and that of bradykinin and the synthetic C-terminal octapeptide of anaphylatoxin C3a (C3a8) by high performance liquid chromatography. Protamine inhibited the hydrolysis of FA-Ala-Lys by CPN, (IC50 = 3.2 X 10(-7) M); added human serum albumin (30 mg/ml) increased the IC50 to 7 X 10(-6) M. When plasma was the source of CPN, the IC50 was 2 X 10(-6) M. Protamine more effectively inhibited the hydrolysis of bradykinin and C3a8. The IC50 for protamine was 5 X 10(-8) M with CPN and bradykinin, 7 X 10(-8) M with CPN and C3a8 and with the 48 K subunit and bradykinin it was 7 X 10(-8) M of protamine. Heparin competes with CPN for protamine, because in high concentration (18 U/ml) it reverses the inhibition by protamine. Protamine did not inhibit angiotensin I converting enzyme (kininase II) or the endopeptidase 24.11 (enkephalinase). Kinetic studies showed the mechanism of protamine inhibition to be partially competitive; about 10-20% of the hydrolysis of bradykinin by CPN was not inhibited by protamine. Thus, by blocking the inactivation of mediators released in shock, protamine inhibition of CPN may be partially responsible for the catastrophic reaction observed to occur in some patients.
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PMID:Protamine inhibits plasma carboxypeptidase N, the inactivator of anaphylatoxins and kinins. 291 61

The retina, choroid, ciliary body, iris and aqueous humor of swine eyes contain enzymes capable of producing (kallikrein) and inactivating (kininase I and II) kinins. The activity of the enzymes varies in different eye structures. Higher activities of kallikrein and kininase II were found in highly vascularized tissues such as retina, choroid and ciliary body. The highest activity of kininase I (carboxypeptidase N) was found in the aqueous humor. The presence of these enzymes in the eye structures suggests a possible role for them in local metabolism of vasoactive peptides.
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PMID:Kallikrein and kininases in ocular tissues. 299 9

Bradykinin (BK) is widely believed to play a role in the pathogenesis of anaphylaxis. To help clarify any such roles, we examined for effects of inhibitors of kininase II (angiotensin converting enzyme, ACE) and "kininase I" (carboxypeptidase N, CPN), on the early course of egg albumin-induced aggregate anaphylaxis in anesthetized guinea pigs. In this model, pulmonary and systemic arterial blood pressure (BP) rise (unless pulmonary fibrillation occurs), lung wgt increases by approximately 60% and pulmonary microvessels are occluded by cell-rich thrombi, all within 5 min of i.v. antigen. The 30 min mortality rate is approximately 2%. ACE inhibitors (BPP9a, Captopril and MK 422; doses up to 140 mumol/kg) do not make anaphylaxis more nor less severe in terms discernible by changes in BP, lung wgt, EKG or intravascular coagulation. In marked contrast, an inhibitor of CPN (2-mercaptomethyl-3-guanidinoethylthiopropionic acid, 2-MGP; 8-16 mumol/kg) increases the 30 min mortality rate to 94% and lung wgt to 180% of control. The animals die in ventricular fibrillation. Given the enormous BK potentiating effects of BPP9a, Captopril and MK 422, it seems likely that little if any BK is formed in the early min of anaphylaxis. 2-MGP does not potentiate BP effects of BK but markedly potentiates effects of C3a anaphylatoxin. Thus, our data support the views that BK is neither a primary nor secondary mediator of aggregate anaphylaxis, and the adverse effects of 2-MGP are best explained in terms of preservation of anaphylatoxins and not in terms of preservation of kinins.
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PMID:Aggregate anaphylaxis and carboxypeptidase N. 302 62

A novel method for the synthesis of histargin and its analogs is described. It includes two kinds of N-alkylation reactions that prevent the formation of side products. The inhibition of enzymes by these compounds was also measured. Some of the compounds strongly inhibited carboxypeptidase B, carboxypeptidase A, carboxypeptidase N (kininase I), and angiotensin converting enzyme.
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PMID:Synthesis of histargin and related compounds and their inhibition of enzymes. 320 75

Although kinins have been reported to affect cerebral vascular tone and permeability, their actions are not potentiated by angiotensin converting enzyme inhibitors. To investigate cerebral vascular kinin metabolism, porcine cerebral microvessels were isolated by differential sieving and centrifugation and characterized by microscopic examination and marker enzyme enrichment. Purified microvessels contained a membrane-bound carboxypeptidase which hydrolyzed the C-terminal Phe-Arg bond of both kallidin and bradykinin. Hydrolysis was optimal at pH 7.0, was activated more than 300% by 0.1 mM CoCl2, and was inhibited by o-phenanthroline and the carboxypeptidase N (EC 3.4.17.3) inhibitor DL-2-mercaptomethyl-3-guanidino-ethylthiopropanoic acid (MERGETPA) (IC50 = 2 microM). Conversely, inhibitors of angiotensin I converting enzyme (captopril), neutral endopeptidase (phosphoramidon), post proline cleaving enzyme (Z-Pro-prolinal), dipeptidyl(amino)peptidase IV (diprotin A) and amino-peptidase M (amastatin) had no effect. When the rates of C-terminal hydrolysis of kallidin by detergent-solubilized cerebral microvasculature were determined over a range of substrate concentrations (16.6 to 250 microM), the Km and Vmax values obtained were 26.0 +/- 3.0 microM and 14.7 +/- 1.3 nmol/min/ml (N = 4) respectively. These data suggest that a cerebral microvascular carboxypeptidase may play a role in vivo in modulating the effects of kinins on cerebral blood flow and permeability and in preventing circulating kinins from crossing the blood-brain barrier.
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PMID:Kallidin and bradykinin metabolism by isolated cerebral microvessels. 339 72

Several enzymes, enzyme inhibitors, receptors and transport structures are situated on the luminal surface of endothelium. Some enzymes and transport systems are continuously active and, in effect, regulate the composition of blood moving downstream. Other components are latent. Their activities are not expressed in the absence of stimulus. Thus, endothelial cells injured by granulocytes or viral infection possess receptors for the Fc segment of IgG and for C3b, whereas normal endothelial cells do not. Both normal and injured endothelial cells express receptors for Clq. To visualize surface enzymes, inhibitors, receptors and transport structures, we have prepared surface replicas suitable for high resolution EM. The surface replication technique, coupled with immunocytochemical procedures, facilitates studies of the topographies of surface enzymes such as angiotensin converting enzyme (ACE) and carboxypeptidase N (CPN). In addition, the replicas provide unique views of the glycocalyx, a cell coating previously believed to be amorphous but now seen to be a highly organized carpet-work under which surface enzymes, receptors, etc are embedded. Given its content of fibronectin, the glycocalyx may be the Clq receptor. Cells treated with antibodies to ACE or CPN show disarrayed glycocalyces and bind Fc and C3b. Latency of the Fc and C3b receptors may be owing to the physical barrier provided by the glycocalyx. Apparently, damage to the glycocalyx creates conditions favoring binding of immune complexes, complement activation and intravascular coagulation with loss of gradients between blood and parenchyma. Whether some non-thrombogenic properties of endothelium require an intact glycocalyx deserves consideration as does the role of the glycocalyx in regulating microvascular permeability.
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PMID:The ultrastructural basis of endothelial cell surface functions. 646 85


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