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)

In recent years, studies of the regulation of the airways have focused to an increasing degree on the roles of neuropeptides. Several peptides have been shown to be present in airways and mediate such diverse responses as ion transport, mucus secretion, bronchospasm or relaxation, edema, cough, changes in vascular permeability, and neutrophil chemotaxis. More recently, studies have described the roles of peptidases, most notably neutral endopeptidase (NEP, also known as enkephalinase, or E.C. 3.4.24.11) and kininase II (also known as angiotensin-converting enzyme, or E.C. 3.4.15.1) in modulating peptide-induced responses. The enzymes cleave a wide variety of peptides, generating metabolites that are inactive in the systems studied to date. Thus inhibitors of NEP potentiate responses to peptides that are cleaved by it. Therefore, NEP plays roles in modulating peptide-induced effects analogous to the role of acetylcholinesterase in modulating cholinergic neurotransmission. In several experimental respiratory diseases, the activity of neutral endopeptidase is decreased, resulting in increased responses to peptides. The therapeutic application of recombinant NEP protects the airways from the adverse actions of stimuli that release inflammatory peptides, and induction of the NEP gene expression by glucocorticoids suggest a possible mechanism for the action of these steroids in treating airway diseases such as asthma, chronic bronchitis, or cystic fibrosis.
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PMID:Roles of neutral endopeptidase in airways. 201 45

The susceptibility to hydrolysis of LHRH and the decapeptide analogue Antide has been compared. The hydrolysis of LHRH by pig kidney brush border membranes is inhibited by phosphoramidon (I50 = 5.6 nM) implicating endopeptidase-24.11 in the initiation of hydrolysis. Under conditions in which LHRH is fully degraded by brush border membranes, Antide was completely resistant to hydrolysis. Similar results were obtained with purified preparations of both endopeptidase-24.11 and angiotensin converting enzyme. These data confirm that the remarkable duration of action of Antide is due principally to its stability to hydrolysis by cell-surface peptidases.
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PMID:Metabolic stability of the LHRH antagonist antide to cell-surface peptidases. 201 20

The effect of peptidase inhibitors on neuropeptide release from peripheral endings of capsaicin-sensitive sensory neurons was studied in cerebral superior sagittal and transverse sinuses of guinea-pig. Capsaicin (1 microM)-evoked release of substance P-like immunoreactivity (SP-LI) was increased in a concentration-dependent manner by thiorphan (0.1-10 microM). Captopril (10 microM) or a mixture of bestatin (10 microM), leupeptin (10 microM) and bacitracin (10 microM) did not affect the capsaicin-evoked SP-LI release. Thiorphan (10 microM) increased also the capsaicin-evoked release of neurokinin A-like immunoreactivity (TK-LI) and calcitonin gene-related peptide-like immunoreactivity (CGRP-LI) by 228% and 172%, respectively, while captopril (10 microM) was without effect. Thiorphan (10 microM), but not captopril (10 microM), enhanced by 239% CGRP-LI release induced by bradykinin (10 microM). In the cerebral venous vessels neutral endopeptidase (EC 3.4.24.11, NEP)-like activity was 58.8 +/- 6.1 pmol/mg protein/min, while angiotensin converting enzyme-like activity was below the detection limit of the assay. A thiorphan-sensitive mechanism, putatively attributable to NEP, plays a major role in the inactivation of peptides released from or acting on capsaicin-sensitive sensory fibres of cerebral venous sinuses of guinea-pig.
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PMID:The effect of thiorphan on release of sensory neuropeptides from guinea-pig cerebral venous sinuses. 206 52

The hydrolysis of the porcine 26-residue brain natriuretic peptide (BNP-26) and its counterpart human 28-residue atrial natriuretic peptide (alpha-hANP) by pig membrane preparations and purified membrane peptidases was studied. When the two peptides were incubated with choroid plexus membranes, the products being analysed by h.p.l.c., alpha-hANP was degraded twice as fast as BNP. The h.p.l.c. profiles of alpha-hANP hydrolysis, in short incubations with choroid plexus membranes, yielded alpha hANP' as the main product, this having been previously shown to be the result of hydrolysis at the Cys7-Phe8 bond. In short incubations this cleavage was inhibited 84% by 1 microM-phosphoramidon, a specific inhibitor of endopeptidase-24.11. BNP-26 was hydrolysed by choroid plexus membranes, kidney microvillar membranes and purified endopeptidase-24.11 in a manner that yielded identical h.p.l.c. profiles. In the presence of phosphoramidon, hydrolysis by the choroid plexus membranes was 94% inhibited. Captopril had no effect and, indeed, no hydrolysis of BNP-26 by peptidyl dipeptidase A (angiotensin-converting enzyme) was observed even after prolonged incubation with the purified enzyme. The stepwise hydrolysis of BNP-26 by endopeptidase-24.11 was investigated by sequencing the peptides produced during incubation. The initial product resulted from hydrolysis at Ser14-Leu15, thereby opening the ring. This product (BNP') was short-lived; further degradation involved hydrolysis at Ile12-Gly13, Arg8-Leu9, Gly17-Leu18, Val22-Leu23, Arg11-Ile12 and Cys4-Phe5. Thus endopeptidase-24.11 is the principal enzyme in renal microvillar and choroid plexus membranes hydrolysing BNP-26 and alpha-hANP.
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PMID:The hydrolysis of brain and atrial natriuretic peptides by porcine choroid plexus is attributable to endopeptidase-24.11. 214 50

1. Bradykinin (BK) instilled directly into the airway lumen caused bronchoconstriction in anaesthetized, mechanically ventilated guinea-pigs in the presence of propranolol (1 mg kg-1 i.v.). The geometric mean dose of BK required to produce 100% increase in airway opening pressure (PD100) was 22.9 nmol (95% c.i. 11.7-44.6 nmol). 2. The dose-response curve for the effect of instilled BK was significantly shifted to the left by the angiotensin converting enzyme (ACE) inhibitor, captopril (5 and 50 nmol instillation, PD100 = 3.0, 95% c.i. 0.98-8.9, and 2.0 nmol, 95% c.i. 0.65-6.2 nmol, respectively). 3. The neutral endopeptidase (NEP) inhibitor, phosphoramidon (5 and 50 nmol instillation) also shifted the dose-response curve for the effect of instilled BK; the PD100 values = 2.2 (95% c.i. 0.40-11.7) and 1.8 nmol (95% c.i. 0.87-3.5 nmol), respectively. 4. After pretreatment with captopril (50 nmol) and phosphoramidon (50 nmol) in combination, the dose-response curve for the effect of instilled BK (PD100 = 1.1 nmol, 95% c.i. 0.37-3.2 nmol) was similar to that obtained in the presence of each inhibitor used alone. 5. The kinase I inhibitor, DL-2-mercaptomethyl-3-guanidinoethylthiopropionic acid (50 nmol instillation) failed to alter the dose-response curve to instilled BK (PD100 = 14.6 nmol, 95% c.i. 6.7-32.0 nmol). 6. These data suggest that both ACE and NEP degrade BK in the airway lumen, but that kininase I is not involved.
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PMID:The effect of peptidase inhibitors on bradykinin-induced bronchoconstriction in guinea-pigs in vivo. 228 70

We have investigated the effect of chronic administration of enalapril on the carboxypeptidases responsible for the formation of angiotensin II from angiotensin I and other peptidases known to recognize angiotensin I as a substrate in the rat. These studies have shown an increase in activity in rate of formation of des-Leu-angiotensin I in both kidney S2 and P2 centrifugal fractions as well as a decrease in the rate of degradation of angiotensin I substrate. Similar increases in the formation of A(1-8) have been observed in kidney using A(1-9) as substrate. These two enzyme activities have been named carboxypeptidase K1 and K2, respectively to reflect their presence in rat kidney. These changes were accompanied by significant decreases in the activity of an amastatin-sensitive aminopeptidase and endopeptidase 24.11 in the kidney P2 fraction. These data suggest that chronic treatment with ACE inhibitors may differentially affect the activity of other enzymes capable of degrading angiotensin causing a substantial re-direction of angiotensin metabolism.
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PMID:Effect of chronic enalapril treatment on enzymes responsible for the catabolism of angiotensin I and formation of angiotensin II. 240 44

Metabolites of substance P, produced by incubation with isolated epithelial cells and with purified brush border and basolateral membrane from pig small intestine, were isolated by high performance liquid chromatography and identified by amino acid analysis. Rapid cleavages between Gln6-Phe7, Phe7-Phe8 and Gly9-Leu10 and oxidation of the methionine residue at position 11 were observed with cells and with both membrane fractions. Formation of substance P3-11' indicative of the action of dipeptidylaminopeptidase IV (EC 3.4.14.5), was observed only at high substrate concentration. Proteolytic degradation was inhibited by phosphoramidon and by EDTA but was insensitive to chloride ion concentration and to captopril. These observations suggest that inactivation of substance P in the epithelial layer of the gut is mediated through endopeptidase-24.11 (EC 3.4.24.11) in the cell-surface membrane and that degradation by angiotensin-converting enzyme (EC 3.4.15.1), although present in high concentration in the mucosa, is unimportant.
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PMID:Proteolytic inactivation of substance P in the epithelial layer of the intestine. 241 32

Hydrolysis of substance P and nine kinds of substance P analogs by angiotensin-converting enzyme highly purified from rat lung was examined by using amino-group fluorometry and high-performance liquid chromatography. The enzyme hydrolyzed substance P and several analogs, notwithstanding that they did not contain free C-terminal residues. The analyses of cleavage products separated by high-performance liquid chromatography indicated that the enzyme hydrolyzed substance P and its analogs mainly at the bond between Phe8-Gly9 and also at another bond, possibly between Gly9-Leu10, to a lesser extent by an endopeptidase action, followed by successive release of dipeptides by a dipeptidyl carboxypeptidase action. The analogs that had D-amino acid residues substituted at the presumed cleavage sites were scarcely hydrolyzed. It was further found that (Pyr6)-fragment (6-11) was hydrolyzed by the enzyme more efficiently than the other fragment-type analogs and was cleaved at a single bond by the endopeptidase activity of the enzyme. Therefore, this fragment was used as a substrate in order to characterized the endopeptidase activity of the enzyme by employing fluorometry. The activity was dependent on chloride ion, and was inhibited by captopril, MK-421, and EDTA. Thus, the endopeptidase activity of the enzyme showed properties similar to those of the dipeptidyl carboxypeptidase activity of the enzyme.
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PMID:Hydrolysis of substance P and its analogs by angiotensin-converting enzyme from rat lung. Characterization of endopeptidase activity of the enzyme. 241 12

The purpose of this investigation was to examine the pathway of substance P (SP) and neurotensin (NT) catabolism in the gastric wall of the rat and identify some of the enzymes involved. Under anaesthesia an infusion catheter and a bundle of dialysis fibres were implanted into the stomach wall of the rat. Experiments commenced on conscious rats 2 days after surgery. In control experiments [3H]-SP(Pro-2,4) or [3H]-NT(Tyr-3,11) were injected into gastric tissues through the catheter and catabolites were collected in the dialysis fibres and separated by high pressure liquid chromatography. In other studies captopril, MK422 (inhibitors of angiotensin converting enzyme) or phosphoramidon (an inhibitor of endopeptidase-24.11, 'enkephalinase') were injected into gastric tissues before the peptide label. SP1-11 was degraded to mainly SP1-2, SP3-4 with some SP1-6, SP1-7 and SP1-8. Catabolism was partially but significantly (5% level) inhibited by MK422 and captopril, but not by phosphoramidon. NT1-13 was degraded to NT1-8, NT9-13, NT1-11 and NT1-12. NT catabolism was partially but significantly (5% level) inhibited by MK422. It is concluded that an enzyme resembling angiotensin converting enzyme is involved in the initial stages of SP and NT catabolism in the rat stomach. The involvement of other peptidases cannot be excluded because inhibition of breakdown was not complete.
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PMID:Catabolism of substance P and neurotensin in the rat stomach wall is susceptible to inhibitors of angiotensin converting enzyme. 242 51

To study the roles of substance P (SP) and endogenous peptidases in regulating mucus secretion from ferret trachea, we measured the SP-induced release of 35SO4-labeled macromolecules after incubating segments of trachea in Ussing chambers in the presence and absence of selected inhibitors of proteolytic enzymes. Our strategy was based on the idea that if endogenous peptidases degrade SP, then inhibitors of these enzymes should potentiate SP-induced secretion. We found that tracheas of ferrets contained SP-like immunoreactivity, and that SP stimulated the release of bound 35SO4 with rapid onset and offset. Eighty-five percent of the total macromolecular radioactivity released was contained in fractions of molecular weights greater than 10(6). The response to SP was concentration-dependent and reproducible. Thiorphan potentiated the secretory response to SP in a concentration-dependent fashion and phosphoramidon potentiated SP-induced secretion, whereas other inhibitors of proteinases and peptidases were without effects. These results suggest that substance P may regulate mucus secretion in ferrets, and that enkephalinase (dipeptidyl carboxypeptidase II, EC 3.4.24.11) in the airway degrades SP in a physiologically significant fashion, and thereby regulates peptide-induced secretion.
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PMID:Enkephalinase inhibitors potentiate substance P-induced secretion of 35SO4-macromolecules from ferret trachea. 243 22


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