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)

Metabolism of enkephalins during transit through the pulmonary circulation may be of significance in regulating systemic levels of these opioids. To determine whether Leu- and Met-enkephalin are metabolized by the pulmonary circulation, [3H]Tyr-Leu-enkephalin (10 microM) or [3H]Tyr-Met-enkephalin (10 microM) were each administered to isolated rat lungs perfused in a recirculating manner with a physiologic salt solution and a recently developed high-performance liquid radiochromatographic analytical method was used to identify and quantitate metabolites in the perfusion medium. Both Leu- and Met-enkephalin were metabolized in a curvilinear, time-dependent manner. The principal metabolites were identified as tyrosine and Tyr-Gly-Gly. Neither Tyr-Gly nor Tyr-Gly-Gly-Phe were detected in significant amounts. After a 20-min perfusion, residual Leu- or Met-enkephalin accounted for 28.4 and 21.5%, respectively, of the radioactivity present in the perfusate. In addition, 97% of the initial radioactivity for both Leu- and Met-enkephalin were found in the perfusion medium, indicating that neither the parent compounds nor metabolites were avidly sequestered in pulmonary tissue. The angiotensin converting enzyme inhibitor, captopril (18 microM) blocked the formation of Tyr-Gly-Gly and attenuated slightly the production of tyrosine. Inhibition of aminopeptidase with bestatin (116 microM) blocked the formation of tyrosine and enhanced production of Tyr-Gly-Gly. Inhibition of enkephalinase with thiorphan (0.3 microM) did not appear to affect Met-enkephalin metabolism. These observations indicate that in isolated, buffer perfused rat lungs Leu- and Met-enkephalin are metabolized during pulmonary transit by at least two enzymes, angiotensin converting enzyme and aminopeptidase.
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PMID:Pulmonary metabolism of exogenous enkephalins in isolated perfused rat lungs. 298 67

High concentrations of neutral metalloendopeptidase (NEP) (enkephalinase) were found in human male genital tract immunohistochemically and by enzyme activity assays, and its distribution was compared with that of angiotensin-converting enzyme (ACE) (kininase II). Whereas the two enzymes colocalize on the luminal aspect of proximal tubular epithelium and are not found elsewhere in the nephron, their distribution in the male genitalia is different. Seminal fluid is rich in NEP and ACE, but after ultracentrifugation ACE remains soluble while NEP sediments. NEP activity is low in testicular homogenate but high in the particulate fraction of epididymides and prostates. ACE, on the other hand, is active in the particulate fraction of testes and in the soluble fraction of epididymides and prostates. Prostatic NEP had a slightly higher molecular weight than the renal NEP, which was reduced by neuraminidase in electroblotting. Testicular and seminal plasma ACE also had a slightly higher molecular weight than the purified renal enzyme (150,000), probably caused by removal of an "anchor" peptide during purification. In the prostate, NEP was found by three different immunohistochemical techniques in luminal epithelial cells and in lumina. The function of NEP in the genital tract may be related to sperm maturation and proacrosin activation.
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PMID:Neutral metalloendopeptidase in human male genital tract. Comparison to angiotensin I-converting enzyme. 298 62

The [R] and [S] enantiomers of the enkephalinase A inhibitor [R,S]-thiorphan have been prepared by asymmetric synthesis. The [S] isomer is principally responsible for the angiotensin converting enzyme inhibitory activity of [R,S]-thiorphan, whereas there were only small differences in the ability of the [R] and [S] isomers to inhibit enkephalinase both in vivo and in vitro. In contrast, the in vivo analgesic activity of [R,S]-thiorphan resided principally in the [R] isomer. These data indicate a surprising dissociation of enkephalinase inhibition from analgesic activity. The fact that the two enantiomers of [R,S]-thiorphan were effective inhibitors of enkephalinase, yet the [R] isomer had substantially greater analgesic activity, indicates that factors other than enkephalinase inhibition may be important for [R, S]-thiorphan's analgesic properties.
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PMID:Enantiomers of [R,S]-thiorphan: dissociation of analgesia from enkephalinase A inhibition. 298

The effectiveness of phosphonamidate peptide analogues as inhibitors of rat kidney or human brain metalloendopeptidase (enkephalinase, E.C. 3.4.24.11) and angiotensin-converting enzyme (ACE, 3.4.14.1) has been explored with a series of enkephalin analogues in which the scissile Gly3-Phe4 amide bond has been replaced with a phosphonamidate moiety. These compounds exhibited good inhibitory potency against enkephalinase with several of the analogues having Ki values in the submicromolar range as contrasted to micromolar or higher toward ACE. Within a series of [(N-acylamino)methyl] phosphonamidates there was a dramatic decrease in inhibitory activity against enkephalinase as the N-acyl moiety was substituted with larger, more hydrophobic acyl groups. Likewise, the inhibitory activity of the [(N-acylamino)methyl] phosphonamidates against ACE was attenuated by larger phenylalkyl acyl functionalities, although not to the same degree as against enkephalinase. However, phosphonamidate pentapeptide analogues of (Leu)enkephalin and (D-Ala2,D-Leu5)enkephalin showed good inhibitory potency against both enzymes. Interestingly, these two (Leu)enkephalin phosphonamidate analogues were completely inactive in the electrically stimulated guinea pig ileum and mouse vas deferens preparations. Conformational factors that may be involved in this inactivity are discussed.
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PMID:Synthesis and biological evaluation of phosphonamidate peptide inhibitors of enkephalinase and angiotensin-converting enzyme. 299 14

Circulating opioids, particularly enkephalins, can act on specific receptors located on the neurovascular sympathetic junction. These peptides are quickly metabolized by enkephalinase and angiotensin converting enzyme (ACE). According to the parallel distribution of enkephalinase with opioid receptors in the rat brain, and its location in the vascular bed, putative differences of enkephalinase and ACE activity between arterial and venous plasma of the same subjects was researched. Venous enkephalinase activity was found to be greater than arterial activity. No arterovenous differences were present in ACE activity. The activities of both enzymes presented a positive correlation between venous and arterial plasma in the same subjects. The arterovenous difference in enkephalinase activity supports a release of the enzyme from microvessels.
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PMID:Enkephalinase and angiotensin converting enzyme activities in human venous and arterial plasma. 302 Apr 71

A preparation of closed membrane vesicles derived from the longitudinal and circular smooth muscle of pig small intestine was enriched eight-fold in the activity of 5'-nucleotidase and six-fold in the activity of peptidyl dipeptidase A relative to the tissue homogenate. The membrane vesicles specifically bound [3H]bradykinin and the concentration of bradykinin required to inhibit 50% binding was 0.76 +/- 0.05 nM. This concentration was not significantly different from the corresponding concentration of lysyl-bradykinin (0.45 +/- 0.13 nM) but was less (P less than 0.05) than the concentration of methionyl-lysyl-bradykinin (1.25 +/- 0.10 nM). The concentration of des-Arg9 bradykinin (7.5 microM) required for 50% inhibition was greater than 10(3) times less than bradykinin indicating the presence of a B2-type receptor. The membrane vesicles also degraded bradykinin and the principal metabolite was identified as bradykinin. Des-Arg1 bradykinin, des-Arg9 bradykinin and bradykinin were also formed in low yield. Cleavage of the Pro7-Phe8 bond was inhibited by phosphoramidon but not by enalapril or captopril indicating that proteolytic inactivation of bradykinin in the muscle layer of the intestine is mediated through endopeptidase 24.11 ("enkephalinase") but not through peptidyl dipeptidase A ("angiotensin-converting enzyme").
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PMID:Specific binding and proteolytic inactivation of bradykinin by membrane vesicles from pig intestinal smooth muscle. 302 39

Ferret tracheal segments were infected with human influenza virus A/Taiwan/86 (H1N1) in vitro. After 4 days, the smooth muscle contractile responses to acetylcholine and to substance P were measured. The response to substance P was markedly accentuated, with a threefold increase in force of contraction at a substance P concentration of 10(-5) M, the highest concentration tested. In contrast, the response to acetylcholine was not affected by viral infection. Histological examination of tissues revealed extensive epithelial desquamation. Activity of enkephalinase (neutral metallo-endopeptidase, EC.3.4.24.11), an enzyme that degrades substance P, was decreased by 50% in infected tissues. Inhibiting enkephalinase activity by pretreating with thiorphan (10(-5) M) increased the response to substance P to the same final level in both infected and control tissues. Inhibiting other substance P-degrading enzymes including kininase II (angiotensin-converting enzyme), serine proteases, and aminopeptidases did not affect the response to substance P. Inhibiting cyclooxygenase and lipoxygenase activity using indomethacin and BW 755c did not affect hyperresponsiveness to substance P. Pretreating tissues with antagonists of alpha-adrenoceptors, beta-adrenoceptors, and H1 histamine receptors (phentolamine 10(-5) M, propranolol 5 X 10(-6) M, and pyrilamine 10(-5) M, respectively) had no effect on substance P-induced contraction. These results demonstrate that infection of ferret airway tissues with influenza virus increases the contractile response of airway smooth muscle to substance P. This effect is caused by decreased enkephalinase activity in infected tissues.
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PMID:Influenza infection causes airway hyperresponsiveness by decreasing enkephalinase. 304 36

Approximately 80% of the hydrolysis of [leu]enkephalin in rat plasma can be attributed to bestatin-sensitive aminopeptidase activity, and an additional 5% is due to angiotensin converting enzyme. Thiorphan-sensitive enkephalinase hydrolysis of [leu]enkephalin could not be detected in plasma. On the other hand, 2-d-ala-l-[leu]enkephalin is metabolized approximately 35% by an unidentified bestatin-sensitive enzyme and approximately 15% by thiorphan-sensitive enkephalinase in rat plasma, while captopril-sensitive angiotensin converting enzyme is without measurable activity against this substrate.
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PMID:Characterization of enkephalin degradation in rat plasma. 312 42

SCH 34826 [(S)-N-[N-[1-[[(2,2-dimethyl-1,3-dioxolan-4yl) methoxy]carbonyl]-2-phenylethyl]-L-phenylalanine]-beta-alanine] was synthesized as a p.o. active prodrug enkephalinase inhibitor. In vivo, it is de-esterified to SCH 32615 (N-[L-(-1-carboxy-2-phenyl)ethyl]-L-phenylalanyl-beta-alanine), the active constituent. In vitro, the Ki for SCH 32615 to block the degradation of Met5-enkephalin by isolated enkephalinase is 19.5 +/- 0.9 nM. In contrast, SCH 32615 did not inhibit aminopeptidase or diaminopeptidase III degradation of Met5-enkephalin up to 10 microM and did not affect angiotensin converting enzyme up to 10 microM. In vivo, p.o. administered SCH 34826 potentiated the analgesic effects of D-Ala2-Met5-enkephalinamide in mice (ED50 = 5.3 mg/kg p.o.) and rats [minimal effective dose (MED) = 1 mg/kg p.o.]; SCH 32615 had no effect up to 30 mg/kg p.o., but was active parenterally (ED50 in mice = 1.4 ng/kg sc). Direct, naloxone-reversible analgesic effects of SCH 34826 were demonstrated in the mouse low temperature hot-plate test (MED = 30 mg/kg p.o.), the mouse acetic acid-induced writhing test (MED = 30 mg/kg p.o.), the rat stress-induced analgesia test (MED = 10 mg/kg p.o.) and the modified rat yeast-paw test (MED = 100 mg/kg p.o.). Using the rat D-Ala2-Met5-enkephalinamide potentiation test the duration of action of SCH 34826 was at least 4 hs. No respiratory or gastrointestinal side effects of any consequence were noted at doses up to 100 times those active in the D-Ala2-Met-5-enkephalinamide potentiation test.
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PMID:Pharmacology of SCH 34826, an orally active enkephalinase inhibitor analgesic. 316 88

We designed phethiol (1-amino-1-benzyl-2-mercaptoethane) as a potent and selective inhibitor of Zn-containing aminopeptidases. This compound inhibited purified aminopeptidase M (EC.3.4.11.2) with a Ki of 5 nM but was at least 1000 times less potent against other metallopeptidases comprising angiotensin-converting enzyme EC 3.4.15.1), enkephalinase (EC 3.4.24.11), thermolysin (EC 3.4.24.4), or dipeptidylaminopeptidases. Phethiol alone significantly but partially protected endogenous (Met5) enkephalin released from depolarized brain slices, total protection being achieved when it was associated with an enkephalinase inhibitor. In order to obtain a parenterally-active inhibitor of cerebral aminopeptidases, the prodrug carbaphetiol, a readily hydrolyzable S-phenylcarbamoyl derivative of phethiol, was designed. Carbaphethiol (i.v.) elicited a rapid rise in mouse striatal level of Tyr-Gly-Gly, a characteristic extracellular metabolite of enkephalins. Carbapethiol alone and, even more, when associated with an enkephalinase inhibitor, exerted a potent naloxone-reversible antinociceptive activity. Carbaphethiol appears as the first parenterally-active inhibitor of cerebral aminopeptidases, potentially useful in neuropeptides degradation studies and as a pain-suppressing agent.
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PMID:Potent inhibition of cerebral aminopeptidases by carbaphethiol, a parenterally active compound. 324 26


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