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)

Fast and very slow hydrolyses of des-Arg9-bradykinin and angiotensin II by angiotensin I-converting enzyme were detected by high performance liquid chromatography. The Michaelis constants of the enzyme, Km values, for des-Arg9-bradykinin and bradykinin were found to be 0.24 mM and 4.4 microM, and the maximum velocities, Vmax values (mumol . min-1 . mg protein-1) for these compounds to be 3.24 and 0.34, respectively. The enzyme also hydrolyzed Z-Gly-Pro-Gly-Gly-Pro-Ala to a tripeptide that was identified as dansyl-Gly-Pro-Ala by TLC on polyamide. These observations show that the enzyme hydrolyzes the peptides at the bond before the prolyl residue in the penultimate position.
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PMID:Cleavage of des-Arg9-bradykinin by angiotensin I-converting enzyme from pig kidney cortex. 298 43

The degradation of the enkephalin-containing octapeptide Tyr-Gly-Gly-Phe-Met-Arg-Gly-Leu (YGGFMRGL) was systematically investigated by incubating the peptide with synaptic membranes from rat striatum or with purified peptidases. The degradation products were derivatized with 4-dimethylamino-azobenzene-4'-isothiocyanate and then analyzed by high pressure liquid chromatography and by amino-terminal analysis. The incubation of YGGFMRGL with synaptic membranes yielded YGG, YGGF, YGGFM, and MR in a manner that was linear with respect to time. The corresponding carboxyl-terminal fragments FMRGL, MRGL, and RGL could not be detected, which suggests that the degradation of YGGFMRGL by synaptic membranes occurs by carboxypeptidase activity. The incubation of YGGFMRGL with different purified peptidases produced cleavage patterns unique from that seen with synaptic membranes. Enkephalinase recognized only the Gly-Phe bond to produce YGG and FMRGL. Thermolysin recognized the Gly-Phe bond and the Phe-Met bond to yield YGG, YGGF, FMRGL, and MRGL. Angiotensin-converting enzyme (ACE) produced primarily YGGF, MR, and lesser amounts of YGGFMR and YG. The formation of YGG, YGGF, and YGGFM by synaptic membranes could be stimulated 3-fold by the addition of 30 mM NaCl and inhibited by MK-422, an ACE inhibitor, with an IC50 of 3 nM. These data suggest that ACE, a dipeptidyl carboxypeptidase, is the primary enzyme involved in the degradation of YGGFMRGL in brain. ACE apparently works in concert with another carboxypeptidase in brain to yield YGGFM and YGG since the carboxyl-terminal peptides RGL and FMRGL could not be detected.
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PMID:Proteolytic conversion of [Met]enkephalin-Arg6-Gly7-Leu8 by brain synaptic membranes. Characterization of formed peptides and mechanism of proteolysis. 298 30

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

Angiotensin I converting enzyme (ACE; kininase II; peptidyldipeptide hydrolase, EC 3.4.15.1) cleaves COOH-terminal dipeptides from active peptides containing a free COOH terminus. We investigated the hydrolysis of luteinizing hormone-releasing hormone (LH-RH) by homogeneous human ACE. Although this decapeptide is blocked at both the NH2 and COOH termini, it was metabolized to several peptides, which were separated by HPLC and identified by amino acid analysis. A major product was the NH2-terminal tripeptide, less than Glu-His-Trp, and another was LH-RH-(4-10) heptapeptide, indicating that the Trp-Ser bond is cleaved to release the NH2-terminal tripeptide. ACE also released the COOH-terminal tripeptide, Arg-Pro-Gly-NH2, and then sequentially the dipeptides Gly-Leu and Ser-Try, leaving less than Glu-His-Trp intact. Thus, less than Glu-His-Trp was formed by both NH2- and COOH-terminal hydrolysis. The cleavage of LH-RH was inhibited by specific ACE inhibitors and by antibody to ACE but not by inhibitors of other enzymes, showing that the hydrolysis was indeed due to ACE. In the absence of chloride, the hydrolysis proceeded at only 16% of the maximal rate (in 500 mM NaCl), but in 10 mM NaCl it increased to 64%. In 500 mM NaCl solution, 86% of the hydrolysis was accounted for by the release of the NH2-terminal tripeptide, whereas in 10 mM NaCl, the COOH-terminal and NH2-terminal cleavage occurred about equally. The Km of LH-RH in 500 mM NaCl was 167 microM and the catalytic constant kcat was 210 min-1. When the NH2-terminal pyroglutamic acid was replaced with glutamic acid ([Glu1]LH-RH), ACE liberated almost exclusively the COOH-terminal tripeptide in 10 mM NaCl. Thus, human ACE, although it is named peptidyl dipeptidase or dipeptidyl carboxypeptidase, can cleave a protected peptide at the NH2 or COOH terminus. The enzyme could be involved in the in vivo metabolism of LH-RH and possibly other blocked peptides.
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PMID:Novel activity of human angiotensin I converting enzyme: release of the NH2- and COOH-terminal tripeptides from the luteinizing hormone-releasing hormone. 298 26

Tritium and Carbon 14 analogs of the angiotensin converting enzyme inhibitor ketoACE were synthesized and their oral absorption, metabolism and excretion in rats were investigated. KetoACE, a ketomethylene analog of the tripeptide Bz-Phe-Gly-Pro, was slowly absorbed at a 35% level upon oral administration. It is rapidly eliminated from the blood with a half-life of about 10 minutes. Its excretion is primarily via the bile duct and it is excreted as 80% unchanged drug. The only identified metabolite consisting of 5-10% of the excreted radioactivity was determined to be the reduced ketoACE in which the ketone group was reduced to a hydroxyl.
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PMID:Absorption, metabolism, and excretion studies of carbon 14- and tritium-labeled derivatives of a ketomethylene containing tripeptide. 298 47

We have purified angiotensin-converting enzyme (ACE, EC 3.4.15.1) from rat brain corpus striatum and rat lung. The brain enzyme has Mr 165,000 by sodium dodecyl sulfate gel electrophoresis, whereas the lung enzyme is 175,000. This difference is not an artifact of preparation since mixture of the two tissues prior to purification results in isolation of two proteins with Mr 165,000 and 175,000. Separation of tryptic fragments of 125I-labeled lung and brain ACE by reverse-phase chromatography yields distinct but similar patterns. No differences between the native enzymes are detected in dansyl-tripeptide cleavage specificity, inhibitor profile, immunological properties, sucrose gradient sedimentation, or gel filtration of ACE from the two tissues. However, lung and brain ACE can be differentiated in their ability to cleave amidated peptides. Both lung and brain ACE cleave Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2 (substance P) via two pathways. In one pathway, ACE first releases Gly-Leu-Met-NH2 and then dipeptides sequentially from the carboxyl terminus. The other first produces Leu-Met-NH2, and then releases dipeptides to leave substance P 1-5. Lung ACE favors initial tripeptide release 3:1, while the striatal enzyme acts via the two pathways to a similar extent. Lung and striatal ACE also differ in their ability to degrade other amidated peptides. His-Lys-Thr-Asp-Ser-Phe-Val-Gly-Leu-Met-NH2 (substance K) and bombesin are degraded by striatal but not lung ACE. Physalaemin and luteinizing hormone-releasing hormone are cleaved by both enzymes, while eledoisin, kassinin, thyrotropin-releasing hormone, and substance P 5-11 are not cleaved by either enzyme. Physalaemin is degraded more rapidly by the lung enzyme. The coincidence of an ACE isozyme with substance P and substance K in the descending striatonigral pathway and the unique ability of this isozyme to cleave substance P and substance K suggest that one or both of these peptides is a physiological substrate for striatonigral ACE.
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PMID:A rat brain isozyme of angiotensin-converting enzyme. Unique specificity for amidated peptide substrates. 299 Dec 65

The major site of hydrolysis was the Gly8-Leu9 bond. Angiotensin converting enzyme (peptidyl dipeptidase A, EC 3.4.15.1) from pig kidney hydrolysed substance P releasing the C-terminal tripeptide Gly-Leu-MetNH2 but failed to hydrolyse neurokinin B. Pig brain striatal synaptic membranes hydrolysed neurokinin B producing a similar pattern of products as did endopeptidase-24.11. Substantial inhibition of this activity was achieved with the selective inhibitor phosphoramidon. A combination of phosphoramidon and bestatin abolished the hydrolysis of neurokinin B by synaptic membranes. Thus, a bestatin-sensitive aminopeptidase may play a role in the synaptic metabolism of neurokinin B in addition to endopeptidase-24.11. This aminopeptidase appears to be distinct from aminopeptidase N (EC 3.4.11.2).
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PMID:Neurokinin B is hydrolysed by synaptic membranes and by endopeptidase-24.11 (enkephalinase) but not by angiotensin converting enzyme. 299 26

Zinc is essential to the catalytic activity of angiotensin converting enzyme. The enzyme contains one g-atom of zinc per mole of protein. Chelating agents abolish activity by removing the metal ion to yield the inactive, metal-free apoenzyme. Zinc does not stabilize protein structure since the native and apoenzymes are equally susceptible to heat denaturation. Addition of either Zn2+, Co2+, or Mn2+ to the apoenzyme generates an active metalloenzyme; Fe2+, Ni2+, Cu2+, Cd2+, and Hg2+ fail to restore activity. The activities of the metalloenzymes follow the order Zn greater than Co greater than Mn. The protein binds Zn2+ more firmly than it does Co2+ or Mn2+. Hydrolysis of the chromophoric substrate, furanacryloyl-Phe-Gly-Gly, by the active metalloenzymes is subject to chloride activation; the activation constant is not metal dependent. Metal replacement mainly affects Kcat with very little change in Km, indicating that the role of zinc is to catalyze peptide hydrolysis.
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PMID:The functional role of zinc in angiotensin converting enzyme: implications for the enzyme mechanism. 299 78

We are examining the substrate specificity of atrial dipeptidyl carboxyhydrolase, a membrane-bound metallo enzyme that we isolated from bovine atrial tissue homogenates. This enzyme readily removes the dipeptide, Phe-Arg, from Bz-Gly-Ser-Phe-Arg, a stand-in substrate for atriopeptin II, one of several atrial natriuretic factors. We now report that the atrial enzyme cleaves the C-terminal dipeptide, Phe-Arg, from atriopeptin II to form atriopeptin I. The km (pH 7.5) is 25 microM and the ratio of relative Vmax/km as a measure of substrate specificity indicates that atriopeptin II is a 240-fold better substrate than Bz-Gly-His-Leu. Only Phe-Arg was detected as a hydrolysis product, indicating that sequential cleavage of Asn-Ser from atriopeptin II does not occur, and that atriopeptin I is not a substrate. Bz-Gly-Asn-Ser was as good a substrate for the atrial enzyme as Bz-Gly-His-Leu, but Bz-Cys(bzl)-Asn-Ser was not hydrolyzed. This result suggests that the presence of an intact disulfide bond or an S-alkylated residue in the P1 position of a substrate (as in atriopeptin I) prevents hydrolysis by the atrial enzyme. Comparative studies were made with the angiotensin I converting enzyme. Atriopeptin II was not a substrate. The stand-in substrates for atriopeptin I, Bz-Cys(bzl)-Asn-Ser and Bz-Gly-Asn-Ser were barely hydrolyzed, which by itself suggests that atriopeptin I is not a substrate of the angiotensin converting enzyme. Our results strongly suggest that atriopeptin II is converted to atriopeptin I and that hydrolysis is mediated by the atrial enzyme. The angiotensin I converting enzyme plays no role in processing these peptides. We suggest that the atrial enzyme be named atrial peptide convertase.
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PMID:Conversion of atriopeptin II to atriopeptin I by atrial dipeptidyl carboxy hydrolase. 299 23

The proteolytic degradation of the enkephalin-containing heptapeptide Tyr-Gly-Gly-Phe-Met-Arg-Phe (YGGFMRF) was investigated by incubating the peptide with synaptic membranes from mouse whole brain and characterizing the formed products. The degradation products were derivatized with 4-dimethylaminoazobenzene-4'-isothiocyanate and then analyzed by high pressure liquid chromatography and by amino-terminal analysis. The incubation of YGGFMRF with synaptic membranes yielded YGGFM and RF as the degradation products. The angiotensin-converting enzyme (ACE) inhibitors, MK-422 and captopril, potently inhibited the formation of YGGFM and RF with IC50 values of 8 nM and 95 nM, respectively. The "enkephalinase A" inhibitor, thiorphan, weakly inhibited this dipeptidyl carboxypeptidase activity with an IC50 greater than 1 microM. YGGFMRF, MK-422, captopril, and thiorphan all produced a dose-dependent analgesic response in the mouse hot plate test when administered intracerebroventricularly. However, when subanalgesic doses of inhibitors were co-administered with a subanalgesic dose of YGGFMRF, only the ACE inhibitors, MK-422 and captopril, potentiated the analgesic response of the peptide. These data provide in vitro and in vivo evidence that ACE is the primary enzyme involved in the proteolytic degradation of YGGFMRF in the mouse brain.
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PMID:Angiotensin-converting enzyme inhibitors potentiate the analgesic activity of [Met]-enkephalin-Arg6-Phe7 by inhibiting its degradation in mouse brain. 300 97


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