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 effects of a range of metallopeptidase inhibitors on the activities of the porcine kidney cell surface zinc aminopeptidases, aminopeptidase A (AP-A; EC 3.4.11.2), aminopeptidase N (AP-N; EC 3.4.11.7) and aminopeptidase W (AP-W; EC 3.4.11.16), have been directly compared. Amastatin and probestin were effective against all three aminopeptidases, with the concentration of inhibitor required to cause 50% inhibition (I50) in the low micromolar range (I50 = 1.5-20 microM), except for probestin with AP-N which displayed an I50 of 50 nM. Actinonin failed to inhibit significantly either AP-A or AP-W, and thus can be considered a relatively selective inhibitor (I50 = 2.0 microM) of AP-N. In contrast, bestatin was a relatively poor inhibitor of AP-N (I50 = 89 microM) and failed to inhibit AP-A, but was more potent towards AP-W (I50 = 7.9 microM). Thus, some of the observed chemotherapeutic actions of bestatin may be due to inhibition of cell-surface AP-W. A number of other metallopeptidase inhibitors, including inhibitors of endopeptidase-24.11 (EC 3.4.24.11) and membrane dipeptidase (EC 3.4.13.11), and the carboxylalkyl and phosphoryl inhibitors of angiotensin converting enzyme (EC 3.4.15.1) failed to inhibit significantly AP-A, AP-N or AP-W. However, AP-W was inhibited with I50 values in the micromolar range by the sulphydryl converting enzyme inhibitors rentiapril (I50 = 1.6 microM), zofenoprilat (I50 = 7.0 microM) and YS 980 (I50 = 17.7 microM). Neither AP-A nor AP-N were affected by these sulphydryl compounds. Inhibition of AP-W may account for some of the side effects noted with the clinical use of the sulphydryl converting enzyme inhibitors. The availability of compounds which are totally selective for AP-W over any of the other mammalian cell surface zinc aminopeptidases may aid in identifying endogenous substrates, and thus physiological or pathophysiological role(s) of AP-W.
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PMID:Inhibition of aminopeptidases N, A and W. A re-evaluation of the actions of bestatin and inhibitors of angiotensin converting enzyme. 136 Feb 11

The opdA gene (formerly called optA) of Salmonella typhimurium encodes a metallopeptidase, oligopeptidase A (OpdA), first recognized by its ability to cleave and allow utilization of N-acetyl-L-Ala4 (E. R. Vimr, L. Green, and C. G. Miller, J. Bacteriol. 153:1259-1265, 1983). Derivatives of pBR328 carrying the opdA gene were isolated and shown to express oligopeptidase activity at levels approximately 100-fold higher than that of the wild type. These plasmids complemented all of the phenotypes associated with opdA mutations (failure to use N-acetyl-L-Ala4, defective phage P22 development, and diminished endopeptidase activity). The opdA region of one of these plasmids (pCM127) was defined by insertions of Tn1000 (gamma delta), and these insertions were used as priming sites to determine the nucleotide sequence of a 2,843-bp segment of the insert DNA. This region contained an open reading frame coding for a 680-amino-acid protein, the N terminus of which agreed with that determined for purified OpdA. This open reading frame contained both a sequence motif typical of Zn2+ metalloproteases and a putative sigma 32 promoter. However, no induction was detected upon temperature shift by using a beta-galactosidase operon fusion. The predicted OpdA sequence showed similarity to dipeptidyl carboxypeptidase, the product of the S. typhimurium gene dcp, and to rat metallopeptidase EC 3.4.24.15., which is involved in peptide hormone processing.
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PMID:Cloning and nucleotide sequence of opdA, the gene encoding oligopeptidase A in Salmonella typhimurium. 153 5

The hydrolysis of substance P by membrane peptidases prepared from the rat substantia nigra was studied in the presence of selective inhibitors. Substance P degradation by synaptic and mitochondrial membranes was completely inhibited by 1,10-phenanthroline (1 mM), a non-specific metallopeptidase inhibitor. Captopril and bestatine, selective inhibitors of angiotensin converting enzyme and aminopeptidases respectively, were without effects. However, phosphoramidon (1 microM), a putative 'enkephalinase' inhibitor, selectively inhibited substance P degradation by synaptic membranes. These results suggest that a phosphoramidon-sensitive endopeptidase may be the principal enzyme responsible for substance P degradation in substantia nigra.
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PMID:Degradation of substance P by membrane peptidases in the rat substantia nigra: effect of selective inhibitors. 245 Mar 19

The electric organ of Torpedo marmorata contains a membrane-bound, captopril-sensitive metallopeptidase that resembles mammalian angiotensin converting enzyme (peptidyl dipeptidase A; EC 3.4.15.1). The Torpedo enzyme has now been purified to apparent homogeneity from electric organ by a procedure involving affinity chromatography using the selective inhibitor lisinopril immobilised to Sepharose via a 28-A spacer arm. The purified protein, like the mammalian enzyme, acted as a peptidyl dipeptidase in cleaving dipeptides from the C-terminus of a variety of peptide substrates, including angiotensin I, bradykinin, [Met5]enkephalin, [Leu5]enkephalin, and the model substrate hippuryl (benzoylglycyl; BzGly)-His-Leu. The hydrolysis of BzGly-His-Leu was activated by Cl-. Enzyme activity was inhibited by classical angiotensin converting enzyme inhibitors, including captopril, enalaprilat (MK422), and lisinopril (MK521). Torpedo angiotensin converting enzyme, like its mammalian counterpart, was also able to act as an endopeptidase in hydrolysing the amidated neuropeptide substance P. Hydrolysis of substance P occurred primarily at the Phe8-Gly9 bond with release of the C-terminal tripeptide, Gly-Leu-MetNH2, and this hydrolysis was blocked by selective inhibitors. The Torpedo enzyme was recognised by a polyclonal antibody to pig kidney angiotensin converting enzyme on immunoelectrophoretic (Western) blot analysis. Thus, on the basis of substrate specificity, inhibitor sensitivity, and immunological criteria, the Torpedo enzyme closely resembles mammalian angiotensin converting enzyme. However, the Torpedo enzyme appears somewhat larger (Mr = 190,000) than the pig kidney enzyme (Mr = 180,000) on sodium dodecyl sulphate-polyacrylamide gel electrophoresis. The endogenous peptide substrate(s) for Torpedo electric organ angiotensin converting enzyme and the physiological role of the enzyme in this tissue remain to be evaluated.
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PMID:Purification and characterization of a peptidyl dipeptidase resembling angiotensin converting enzyme from the electric organ of Torpedo marmorata. 302 62

In order to identify which peptidases are involved in the catabolism of neurotensin in the CNS, [3H-Tyr3,11]-neurotensin was superfused over rat hypothalamic slices in the presence and absence of peptidase inhibitors. The degree of degradation of the peptide was determined by reverse phase HPLC separation of 3H-labelled neurotensin from 3H-labelled products. Very little degrading activity was released from the slice into the medium during the superfusion. In the absence of inhibitors, 20 to 50% of 3H-neurotensin was degraded giving mainly 3H-Tyr along with other unidentified 3H-labelled products. Inhibitors of endopeptidase 24.11 (phosphoramidon) and proline endopeptidase (antibody) had no effect on the degradation. Captopril, an inhibitor of angiotensin converting enzyme, had a small inhibitory effect. In contrast, dynorphin(1-13), an inhibitor of a soluble, thiol dependent metallopeptidase which hydrolyses neurotensin at Arg8-Arg9, gave greater than 80% inhibition of 3H-neurotensin degradation in the slice preparation. 1,10-Phenanthroline, an inhibitor of metallopeptidases, was also an effective inhibitor. The dynorphin sequence responsible for the inhibition contains the Arg6-Arg7 bond. Other peptides (bradykinin and angiotensin) which are substrates of the soluble metallopeptidase also inhibited neurotensin breakdown by the slice. This evidence suggests that this thiol dependent metalloendopeptidase is the major neurotensin catabolizing enzyme in hypothalamic slices.
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PMID:Peptidases involved in the catabolism of neurotensin: inhibitor studies using superfused rat hypothalamic slices. 352 99

1. We investigated the role of angiotensin converting enzyme (ACE) in the cardiovascular effects of N-[1-(R,S)-carboxy-3-phenylpropyl]-Ala-Ala-Tyr-p-aminobenzoate (cFP), a peptidase inhibitor selective for metalloendopeptidase (EP) E.C. 3.4.24.15. 2. In conscious rabbits, cFP (5 mg kg-1, i.v.) markedly slowed the degradation of [3H]-bradykinin, potentiated the depressor response to right atrial administration of bradykinin (10-1000 ng kg-1), and inhibited the pressor response to right atrial angiotensin I (10-100 ng kg-1). In each of these respects, the effects of cFP were indistinguishable from those of the ACE inhibitor, captopril (0.5 mg plus 10 mg kg-1h-1 i.v.). Furthermore, the effects of combined administration of cFP and captopril were indistinguishable from those of captopril alone. 3. In experimentally naive anaesthetized rats, cFP administration (9.3 mg kg-1, i.v.) was followed by a moderate but sustained fall in arterial pressure of 13 mmHg. However, in rats pretreated with bradykinin (50 micrograms kg-1) a more pronounced fall of 30 mmHg was observed. Captopril (5 mg kg-1) had similar hypotensive effects to those of cFP, and cFP had no effect when it was administered after captopril. 4. CFP displaced the binding of [125I]-351A (the p-hydroxybenzamidine derivative of lisinopril) from preparations of rat plasma ACE and solubilized lung membrane ACE (KD = 1.2 and 0.14 microM respectively), and inhibited rat plasma ACE activity (KI = 2.4 microM). Addition of phosphoramidon (10 microM), an inhibitor of a range of metalloendopeptidases, including neutral endopeptidase (E.C.3.4.24.11), markedly reduced the potency of cFP in these systems. 5. Taken together these findings suggest that the actions of cFP in vivo are attributable to inhibition of ACE rather than EP 24.15. Given that cFP is a poor inhibitor of ACE in the presence of phosphoramidon in vitro, it is likely that cFP is cleaved by a phosphoramidon-sensitive metallopeptidase in vivo to liberate N-[1-(R,S)-carboxy-3-phenylpropyl]-Ala-Ala, a potent ACE inhibitor.
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PMID:Role of angiotensin converting enzyme in the vascular effects of an endopeptidase 24.15 inhibitor. 762 Jul 8

Inhibition of the metallopeptidase neutral endopeptidase 3.4.24.11 (NEP) protects endogenous natriuretic peptides and potentiates their vasodepressor effects. Inhibition of angiotensin converting enzyme (ACE) attenuates the formation of angiotensin II and enhances the vasodepressor effect of endogenous kinins. A combination of NEP inhibition and ACE inhibition can potentially interact to shift the balance of vasoactive peptides toward vasodilation. This potential interaction was examined in conscious cardiomyopathic hamsters with low cardiac output and compensated heart failure. Neither the selective NEP inhibitor SQ 28,603 nor the selective ACE inhibitor enalaprilat (each at 30 mumol/kg, i.v.) caused significant changes in left ventricular end diastolic pressure or left ventricular systolic pressure when administered separately. However, the combination of these inhibitors, each at that dose, caused significant peak decreases in left ventricular end diastolic pressure and left ventricular systolic pressure of -12 +/- 1 and -18 +/- 4 mm Hg, respectively. In separate cardiomyopathic hamsters, this same combination of treatments resulted in significant decreases in mean arterial pressure (-13%) and total peripheral resistance (-37%) and an increase in cardiac output (36%) as compared with vehicle effects (P < .05). At 90 min after administration of SQ 28,603 alone, plasma atrial natriuretic peptide concentration was double that in the vehicle group. In the group receiving the combination of inhibitors, plasma atrial natriuretic peptide at 90 min was maintained at the high basal levels associated with this model despite the decrease in cardiac filling pressure.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Combined inhibition of neutral endopeptidase and angiotensin converting enzyme in cardiomyopathic hamsters with compensated heart failure. 822 37

Neutral endopeptidase (NEP; also known as neprilysin and enkephalinase; EC 3.4.24.11) is a cell-surface metallopeptidase that is present in many mammalian tissues. It is particularly abundant on the brush-border membranes of the kidney proximal tubule. In this paper, the presence of NEP in purified glomeruli from dog kidney was assessed by measuring phosphoramidon- and thiorphan-sensitive [D-Ala2,Leu5]enkephalin-degrading activity. Using this assay, the Km and kcat. of the glomerular enzyme were found to be identical to those of the tubular enzyme. By Western blotting the apparent M(r) of the glomerular enzyme was found to be 104,000, compared with 94,000 for the tubular enzyme. This might be due to a different glycosylation pattern, since endoglycosidase F treatment of NEP obtained from both tissues yielded deglycosylated enzymes with similar electrophoretic mobilities. The glomerular enzyme also appears to be membrane-bound, since it was retained in the detergent-rich phase after phase separation with Triton X-114. Autoradiography experiments performed with RB104, a new highly selective and potent NEP inhibitor, showed that NEP was expressed in both glomeruli and proximal tubules. The presence in glomeruli of NEP and some other brush-border peptidases (dipeptidyl-dipeptidase IV, aminopeptidase N and angiotensin I-converting enzyme) suggests that cell-surface peptidases might play an important role as regulators of plasma-derived peptides in this part of the nephron.
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PMID:Characterization of neutral endopeptidase 24.11 in dog glomeruli. 848 5

Human heart tissue enzymes cleave angiotensin (Ang) I to release Ang 1-9, Ang II, or Ang 1-7. In atrial homogenate preparations, cathepsin A (deamidase) is responsible for 65% of the liberated Ang 1-9. Ang 1-7 was released (88% to 100%) by a metallopeptidase, as established with peptidase inhibitors. Ang II was liberated to about equal degrees by ACE and chymase-type enzymes. Cathepsin A's presence in heart tissue was also proven because it deamidated enkephalinamide substrate by immunoprecipitation of cathepsin A with antiserum to human recombinant enzyme and by immunohistochemistry. In immunohistochemistry, cathepsin A was detected in myocytes of atrial tissue. The products of Ang I cleavage, Ang 1-9 and Ang 1-7, potentiated the effect of an ACE-resistant bradykinin analog and enhanced kinin effect on the B(2) receptor in Chinese hamster ovary cells transfected to express human ACE and B(2) (CHO/AB), and in human pulmonary arterial endothelial cells. Ang 1-9 and 1-7 augmented arachidonic acid and nitric oxide (NO) release by kinin. Direct assay of NO liberation by bradykinin from endothelial cells was potentiated at 10 nmol/L concentration, 2.4-fold (Ang 1-9) and 2.1-fold (Ang 1-7); in higher concentrations, Ang 1-9 was significantly more active than Ang 1-7. Both peptides had traces of activity in the absence of bradykinin. Ang 1-9 and Ang 1-7 potentiated bradykinin action on the B(2) receptor by raising arachidonic acid and NO release at much lower concentrations than their 50% inhibition concentrations (IC(50)s) with ACE. They probably induce conformational changes in the ACE/B(2) receptor complex via interaction with ACE.
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PMID:Angiotensin 1-9 and 1-7 release in human heart: role of cathepsin A. 1201 79

Some beneficial effects of ACE inhibitors are attributed to potentiation of bradykinin's actions exerted through its B2 receptor. We investigated them on cultured cells transfected or constitutively expressing both ACE and B2 receptor. The potentiation of bradykinin was indirect and attributed to a crosstalk induced between enzyme and receptor via ACE, a heterodimer formation. While looking for endogenous activators, we investigated the split products of angiotensin I (Ang) Ang 1-9 and 1-7, peptides released by enzymes of human atria and ventricle. Ang 1-9 was liberated by a cathepsin A-type enzyme, Ang 1-7 by a different metallopeptidase-protease. Cathepsin A's presence in heart tissue was shown by deamidating enkephalinamide substrate, by immunoprecipitation and by immunohistochemistry. In immunohistochemistry, cathepsin A was detected in myocytes of atrial tissue. Ang 1-9 and Ang 1-7 potentiated the effect of an ACE-resistant bradykinin analogue on the B2 receptor in transfected cells expressing human ACE and B2, and in human endothelial cells. Ang 1-9 and 1-7 augmented arachidonic acid and NO release by bradykinin. NO liberation by bradykinin from endothelial cells was potentiated at 10nmol/L concentration by Ang 1-9 and Ang 1-7; at higher concentrations, Ang 1-9 was significantly more active. Both peptides had little activity in absence of bradykinin or ACE. Ang 1-9 and 1-7 potentiated bradykinin action on its B2 receptor at much lower concentrations than their IC50 values with ACE. They probably induce conformational changes in the ACE/B2 receptor complex via interaction with ACE.
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PMID:Products of angiotensin I hydrolysis by human cardiac enzymes potentiate bradykinin. 1250 55


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