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)

Immunohistochemical techniques have been used to study a group of membrane peptidases in the distal segment of the ulnar nerve of piglets 7 and 14 days after surgical section. Five peptidases were studied, all of which have a wide distribution on the surfaces of many cell types and have roles in metabolising neuropeptides. In normal pig nerves, endopeptidase-24.11 is expressed by both myelin- and nonmyelin-forming Schwann cells. Peptidyl dipeptidase A (angiotensin converting enzyme), aminopeptidase-N and dipeptidyl peptidase IV are present in the microvessels, and aminopeptidase-N is also seen in the perineurial connective tissue. Of this group of peptidases, only aminopeptidase-W is a neuronal marker in normal nerve. Macrophages were identified by two antibodies, 74-22-15 and 40D (which recognises Ia). Short-term cultures of macrophages obtained by alveolar lavage were positively stained by both antibodies and about half of the cells also expressed aminopeptidase-N and dipeptidyl peptidase IV. Staining by 40D and 74-22-15 revealed the presence of significant numbers of macrophages in normal nerve, but none of the membrane peptidases colocalized with these cells. Seven days after section of the nerve, the distal segment showed morphological changes typical of Wallerian degeneration. Endopeptidase-24.11 was no longer visible in myelin sheaths, but remained a marker for the surface of Schwann cells (defined also by staining for glial fibrillary acidic protein). The macrophage markers revealed marked changes in the morphology of these cells, often consistent with their phagocytic activity. Two peptidases, aminopeptidase-N and aminopeptidase-W, also appeared at this time to be associated with cells exhibiting the morphology of activated macrophages. This association could be confirmed in many instances by double staining with 74-22-15 and antibodies to the peptidases. Angiotensin converting enzyme retained its single location in microvessels at 7 days after section, but at 14 days a new pattern emerged as it, too, was expressed by macrophages. Dipeptidyl peptidase IV was not shown to be a macrophage marker in the degenerating nerve. Thus Wallerian degeneration leads to remarkable changes in the cellular expression of membrane peptidase; endopeptidase-24.11 reflects the changed morphology of Schwann cells while aminopeptidase-N, aminopeptidase-W and angiotensin converting enzyme become expressed by the actively phagocytosing macrophages.
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PMID:Cellular reorganisation of membrane peptidases in Wallerian degeneration of pig peripheral nerve. 168 7

Using high-performance liquid chromatography with electrochemical detection to measure substrate disappearance and metabolite accumulation following addition of [Leu]enkephalin to samples prepared from chick brain in vitro, the following were found: 1. [Leu]enkephalin hydrolysis by whole forebrain homogenates is almost solely attributable to aminopeptidase MII activity. 2. [Leu]enkephalin hydrolysis by whole forebrain P2 membrane fractions is attributable to both aminopeptidase MII and dipeptidyl carboxypeptidase activity. 3. Differences are apparent in both [Leu]enkephalin disappearance and Tyr-Gly-Gly accumulation in P2 membrane fractions, but not in homogenate fractions, prepared from several regions of the chick brain.
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PMID:Hydrolysis of [Leu]enkephalin by chick brain in vitro. 168 27

Captopril ((2S)-1-(3-mercapto-2-methyl-propionyl)-L-proline) inhibited the bifunctional, Zn(2+)-containing enzyme leukotriene A4 hydrolase/aminopeptidase reversibly and competitively with Ki = 6.0 microM for leukotriene B4 formation and Ki = 60 nM for L-lysine-p-nitroanilide hydrolysis at pH 8. Inhibition was independent of pH between pH 7 and 8, the optimum range for each catalytic activity. Half-maximal inhibition of leukotriene B4 formation by intact erythrocytes and neutrophils required 50 and 88 microM captopril, respectively. In neutrophils and platelets neither 5(S)-hydroxyeicosatetraenoic acid, 12(S)-hydroxyeicosatetraenoic acid, nor leukotriene C4 formation were reduced, indicating selective inhibition of leukotriene A4 hydrolase/aminopeptidase, not 5-lipoxygenase, 12-lipoxygenase, or leukotriene C4 synthase. In whole blood, captopril inhibited leukotriene B4 formation with an accompanying redistribution of substrate toward formation of cysteinyl leukotrienes. The decrease in leukotriene B4 was more substantial than the corresponding increase in cysteinyl leukotrienes suggesting that nonenzymatic hydration predominates over transcellular metabolism of leukotriene A4 by platelets during selective inhibition of leukotriene A4 hydrolase. Enalapril dicarboxylic acid and Glu-Trp-Pro-Arg-ProGln-Ile-Pro-Pro which inhibit angiotensin-converting enzyme: angiotensin I, bradykinin, and N-[3-(2-furyl)acryloyl]Phe-Gly-Gly which are substrates; and chloride ions which activate angiotensin-converting enzyme did not modulate leukotriene A4 hydrolase/aminopeptidase activity. The results indicate that: (i) the sulfhydryl group of captopril is an important determinant for inhibition of leukotriene A4 hydrolase/aminopeptidase, probably by binding to an active site Zn2+; (ii) aminopeptidase and leukotriene A4 hydrolase display differential susceptibility to inhibition; (iii) there is minimal functional similarity between angiotensin-converting enzyme (peptidyl dipeptidase) and leukotriene A4 hydrolase/aminopeptidase; (iv) captopril may be a useful prototype to identify more potent and selective leukotriene A4 hydrolase inhibitors.
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PMID:Inhibition of leukotriene A4 hydrolase/aminopeptidase by captopril. 188 82

Pulmonary vascular relaxant effects of the 28-amino acid atrial natriuretic peptide and atriopeptins I, II and III (21, 23 and 24 amino acid peptides, respectively) were studied in isolated blood vessels and in perfused rat lungs. In isolated tissue studies, intrapulmonary arteries were more responsive to the relaxant effects of atrial peptides than the main pulmonary artery or aorta. In perfused lung preparations, each of the four atrial peptides produced dose-dependent pulmonary vasodilation of PGF2 alpha or hypoxia-induced pulmonary vasoconstriction. Atriopeptin I was the least potent pulmonary vasodilator peptide in all studies. Pretreatment of perfused lungs with various peptidase inhibitors, including the angiotensin converting enzyme inhibitors, captopril and MK-521, the carboxypeptidase inhibitor, 1,10-phenanthroline, and the aminopeptidase inhibitor, bestatin, variably potentiated the pulmonary vasodilator activities of the atrial peptides. The results demonstrate that atrial peptides released from the right heart into the pulmonary circulation can have potent vasorelaxant effects in the pulmonary vascular bed and further suggest that upon passage through the lung atrial peptides may undergo metabolic degradation that alters their pulmonary vasodilator activities.
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PMID:Pulmonary vasorelaxant activity of atrial peptides. 196

Opioid peptides are present in human cerebrospinal fluid (CSF), and their levels are reported to change in some pathologic conditions. However, less is known about their degradation in CSF. In the present study, human CSF was found to contain aminopeptidase activity which hydrolyzed alanyl-, leucyl- and arginyl-naphthylamides in a ratio of 100:28:27. Twelve CSF samples hydrolyzed alanyl-2-naphthylamide and degraded Met5-enkephalin (N-terminal hydrolysis) at rates of 188 +/- 38 and 420 +/- 79 pmol/min/mL respectively. Further, the distribution of alanyl-naphthylamidase activity in individual samples (39-437 pmol/min/mL) was closely correlated with that of Met5-enkephalin degradation (37-833 pmol/min/mL). Both alanyl-naphthylamidase and enkephalin degradation were optimal at pH 7.0 to 7.5 and were inhibited by aminopeptidase inhibitors amastatin (IC50 = 20 nM), bestatin (4-7 microM) and puromycin (30-35 microM). Conversely, degradation was unaffected by inhibitors of neutral endopeptidase (phosphoramidon), carboxypeptidase N (MERGETPA) or angiotensin converting enzyme (captopril). The Km of Met5-enkephalin for the CSF aminopeptidase activity was 201 +/- 19 microM (N = 4). Rates of hydrolysis of the Tyr1-Gly2 bond of larger opioid peptides decreased with increasing peptide length. Pooled, concentrated CSF hydrolyzed Leu5-enkephalin, dynorphin A fragments [1-7], [1-10] and [1-13] and dynorphin A at rates of 2.05 +/- 0.27, 1.27 +/- 0.18, 0.94 +/- 0.06, 0.55 +/- 0.14 and 0.16 +/- 0.03 nmol/min/mL respectively. When analyzed by rocket-immunoelectrophoresis against antisera to aminopeptidase M (EC 3.4.11.2), the concentrated CSF formed an immunoprecipitate which could be stained histochemically for alanyl-naphthylamidase activity. These data are consistent with a significant role for aminopeptidase M activity in the degradation of low molecular weight opioid peptides in human CSF.
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PMID:N-terminal degradation of low molecular weight opioid peptides in human cerebrospinal fluid. 197 24

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

In human cerebrospinal fluid, aminopeptidase, dipeptidyl aminopeptidase, dipeptidyl carboxypeptidase, and carboxypeptidase which were capable of hydrolyzing enkephalins were detected. Among these enzymes, two distinct aminopeptidase, designated C-AP1 and C-AP2, were partially purified. These enzymes were not purified thoroughly, but the characteristics of C-AP2 were similar to those of an aminopeptidase purified from monkey brain. But the inhibitory activity of amastatin on C-AP2 was stronger, and that of substance P was negligible. On the other hand, characteristics of C-Ap1 were extremely differ from those of C-AP2 or an aminopeptidase purified from monkey brain. C-AP1 had an optimum pH more in the acidic range (the highest at pH 6.0) and was not inhibited by any of the protease inhibitor tested including bestatin and amastatin.
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PMID:Partial purification of two distinct enkephalin-degrading aminopeptidases from human cerebrospinal fluid. 240 80

Substance P is a neuropeptide released in vivo from the substantia nigra, the principal substance P nerve terminal region in the rat brain. Its inactivation was investigated in a purified nigral synaptic membrane preparation. The membrane-bound enzyme shares many features with the endopeptidase 24-11 (EC 3.4.24.11): 1) hydrolysis of peptide bonds Gln6-Phe7, Phe7-Phe8 and Gly9-Leu10, 2) sensitivity to the inhibition by phosphoramidon and 3) relative affinity for substance P. Bestatine and captopril inhibit only the hydrolysis of the metabolites. These results suggest that substance P is inactivated in substantia nigra by endopeptidase 24-11 and that a bestatin-sensitive aminopeptidase and angiotensin converting enzyme may play a role in subsequent degradation of the substance P metabolites.
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PMID:Metalloendopeptidase (EC 3.4.24.11) but not angiotensin converting enzyme is involved in the inactivation of substance P by synaptic membranes of the rat substantia nigra. 247 Oct 29

The in vivo metabolism of atrial natriuretic peptide (ANP) has been studied in the rat after i.v. administration of either [106Phe-14C]- or [126Tyr-125I]-ANP(103-126). Plasma samples containing radioactive peptides were separated by reverse-phase high-performance liquid chromatography. The major plasma metabolites were [125I]Tyr and [14C]Phe for the iodinated and 14C-labeled peptides, respectively. Both peptides had ANP(104/5-126) as a metabolite. Administration of labeled peptide by either bolus or infusion produced the same metabolite profile. To determine which enzymes were responsible for generating these initial metabolites, animals were first dosed with various protease inhibitors before the infusion of [14C]ANP(103-126). The amino-peptidase inhibitor bestatin and the angiotensin converting enzyme inhibitor captopril caused 54 and 66% increases in plasma ANP(103-126), respectively, but no other effects. Administration of the endopeptidase 24.11 inhibitor thiorphan led to a 158% increase of ANP(103-126) in plasma and an 11-fold increase in ANP(104/5-126). The latter metabolite could be selectively decreased by pretreatment with bestatin in combination with thiorphan. The results demonstrate that the initial plasma metabolites of ANP(103-126) are due to the activity of endopeptidase 24.11, a bestatin-sensitive aminopeptidase, and a carboxypeptidase. The plasma clearance of the peptide is probably also due to cellular binding and uptake in combination with glomerular filtration as very few plasma metabolites were observed even at very high rates of ANP(103-126) infusion.
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PMID:In vivo metabolism of atrial natriuretic peptide: identification of plasma metabolites and enzymes responsible for their generation. 252 86

The relative importance of three enzymes, amastatin-sensitive aminopeptidase, captopril-sensitive peptidyl dipeptidase A and phosphoramidon-sensitive endopeptidase-24.11, to inactivate two opioid peptides, [Met5]-enkephalin and [Met5]-enkephalin-Arg6, was investigated in three in vitro isolated preparations, guinea-pig ileum, mouse vas deferens and rat vas deferens, by estimating the magnitude of the enhancement of the inhibitory potency of the opioid peptide by each peptidase inhibitor. Results showed that the relative importance of the three enzymes in the inactivation of the opioid peptide, whether it was [Met5]-enkephalin or [Met5]-enkephalin-Arg6, in guinea-pig ileum was significantly different from that in either mouse vas deferens or rat vas deferens. Additionally, the relative importance of the three enzymes in the preparation, whether it was guinea-pig ileum, mouse vas deferens or rat vas deferens, in the inactivation of [Met5]-enkephalin was significantly different from that of [Met5]-enkephalin-Arg6. The significance of the presence of plural inactivating-enzymes for opioid peptides was discussed.
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PMID:Estimation of relative importance of three enzymes in the inactivation of [Met5]-enkephalin and [Met5]-enkephalin-Arg6 in three isolated preparations by employing the inhibitor specific for each enzyme. 282 6


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