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)

Enkephalin had been shown to be almost exclusively hydrolyzed by three peptidases in the previous studies. In the present investigation, the relative importance of three enzymes in the inactivation of [Leu5]-enkephalin was examined in three isolated preparations. Results showed that amastatin-sensitive aminopeptidase played the greatest role in both guinea-pig ileum and rat vas deferens while it played the similar role to either phosphoramdidon-sensitive endopeptidase-24.11 or captopril-sensitive peptidyl dipeptidase A in mouse vas deferens.
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PMID:Inactivation of [Leu5]-enkephalin in three isolated preparations: relative importance of aminopeptidase, endopeptidase-24.11 and peptidyl dipeptidase A. 282 76

The formation of AII from a metabolite of AI, des-leu10-angiotensin I [A(1-9)] has been studied in centrifugal fractions of rat lung and kidney using gradient elution HPLC to monitor the formation of peptide products. AII-forming activity was present in kidney S2 (22.3 nmol/mg protein/min) but not in kidney P2 centrifugal fractions. Lung S2 fractions showed relatively weak AII-forming activity (0.34 nmole/mg protein/min) whilst no activity was observed in lung P2. Carboxypeptidase N-like activity measured using both Hipp-Arg and Hipp-Lys as synthetic substrates did not parallel AII-forming activity, since this activity was highest in the P2 fractions of both lung and kidney, as were ACE and aminopeptidase activities. Whilst the major peptide produced in kidney S2 was AII (71%) significant amounts of both AIII (23%) and A(2-9) (6%) were also observed. In lung the amounts of these peptides produced as a percentage of the A(1-9) degrading activity were 2.9%, 2.4% and 21% respectively. The AII-forming activity in kidney S2 was not inhibited by enalaprilat, bestatin, amastatin, phosphoramidon or Pro-Phe but was inhibited (31%) by 1 mM cobalt (II). 1,10-Phenanthroline, iodoacetic acid, EDTA and puromycin significantly enhanced the formation of AII and increased the rate of degradation of the substrate, A(1-9). These results support the concept of a sequential carboxypeptidase pathway operating, particularly in kidney, to produce AII from AI. These results provide further evidence of an alternative metabolic pathway for the formation of AII not involving angiotensin converting enzyme.
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PMID:Formation of angiotensin II and other angiotensin peptides from des-leu 10-angiotensin I in rat lung and kidney. 284 26

The property of solutions of Triton X-114 to separate into detergent-rich and detergent-poor phases at 30 degrees C has been exploited to investigate the identities of the aminopeptidases in synaptic membrane preparations from pig striatum. When titrated with an antiserum to aminopeptidase N (EC 3.4.11.2), synaptic membranes solubilized with Triton X-100 revealed that this enzyme apparently comprises no more than 5% of the activity releasing tyrosine from [Leu]enkephalin. When assayed in the presence of puromycin, this proportion increased to 20%. Three integral membrane proteins were fractionated by phase separation in Triton X-114. Aminopeptidase activity, endopeptidase-24.11 and peptidyl dipeptidase A partitioned predominantly into the detergent-rich phase when kidney microvillar membranes were so treated. However, only 5.5% of synaptic membrane aminopeptidase activity partitioned into this phase, although the other peptidases behaved predictably. About half of the aminopeptidase activity in the detergent-rich phase could now be titrated with the antiserum, showing that aminopeptidase N is an integral membrane protein of this preparation. Three aminopeptidase inhibitors were investigated for their ability to discriminate between the different activities revealed by these experiments. Although amastatin was the most potent (IC50 = 5 X 10(-7) M) it failed to discriminate between pure kidney aminopeptidase N, the total activity of solubilized synaptic membranes and that in the Triton X-114-rich phase. Bestatin was slightly more potent for total activity (IC50 = 6.3 X 10(-6) M) than for the other two forms (IC50 = 1.6 X 10(-5) M). Puromycin was a weak inhibitor, but was more selective. The activity of solubilized membranes was more sensitive (IC50 = 1.6 X 10(-5) M) than that of the pure enzyme or the Triton X-114-rich phase (IC50 = 4 X 10(-4) M). We suggest that the puromycin-sensitive aminopeptidase activity that predominates in crude synaptic membrane preparations may be a cytosolic contaminant or peripheral membrane protein rather than an integral membrane component. Aminopeptidase N may contribute to the extracellular metabolism of enkephalin and other susceptible neuropeptides in the brain.
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PMID:The metabolism of neuropeptides. Phase separation of synaptic membrane preparations with Triton X-114 reveals the presence of aminopeptidase N. 286 52

We have investigated the effect of amastatin, an aminopeptidase inhibitor, and captopril, an angiotensin converting enzyme inhibitor, on the antinociceptive activity induced by intracerebroventricular administration of dermorphin, a heptapeptide. In addition, the potency of dermorphin was compared with that of one of its metabolites, N-terminal tetrapeptide (Tyr-D-Ala-Phe-Gly), by using the tail pressure test. The antinociceptive activity induced by dermorphin was not potentiated by simultaneous administration of amastatin or captopril. However, there was potentiation when dermorphin was combined with both peptidase inhibitors. Moreover, the N-terminal tetrapeptide was 84 times less potent than its parent heptapeptide when administered intracerebroventricularly. The results suggest that the cleavage of Tyr1-D-Ala2 and Gly4-Tyr5 bonds by brain endopeptidase modulates dermorphin-induced antinociceptive activity.
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PMID:Potentiation of dermorphin-induced antinociception by peptidase inhibitors. 287 Nov 64

Since both aminopeptidases and angiotensin I-converting enzyme are reported to degrade circulating enkephalins, we have examined the degradation of low-molecular-weight opioid peptides by a vascular plasma membrane-enriched fraction previously shown to contain both angiotensin I-converting enzyme (EC 3.4.15.1) and aminopeptidase M (EC 3.4.11.2). Except for an enkephalin analog resistant to amino-terminal hydrolysis, [D-Ala2]enkephalin, the purified vascular plasma membrane preferentially degraded low-molecular-weight opioids by hydrolysis of the N-terminal Tyr-1--Gly-2 bond. Enkephalin degradation was optimal at pH 7.0 and was inhibited by the aminopeptidase inhibitors amastatin (I50 = 0.08 microM), bestatin (9.0 microM) and puromycin (80 microM). Maximal rates of hydrolysis, calculated per mg plasma membrane protein, were highest for the shorter peptides (18.3, 15.6 and 16.6 nmol/min per mg for Met5-enkephalin, Leu5-enkephalin and Leu5-enkephalin-Arg6, respectively) and decreased with increasing peptide length (0.7 nmol/min per mg for dynorphin (1-13)). No significant hydrolysis of beta- and gamma-endorphin was detected. Km values decreased significantly with increasing peptide length (Km = 72.9 +/- 2.7, 43.6 +/- 4.7 and 21.4 +/- 0.9 microM for Met5-enkephalin, Leu5-enkephalin-Arg6 and Met5-enkephalin-Arg6-Phe7, respectively). However, no further decreases were seen with even larger sequences, i.e., dynorphin(1-13). Other peptides hydrolyzed by the plasma membrane aminopeptidase (angiotensin III, kallidin and hepta(5-11)-substance P) inhibited enkephalin degradation in a competitive manner. Thus, localization, specificity and kinetic data are consistent with identification of aminopeptidase M as a vascular enzyme with the capacity to differentially metabolize low-molecular-weight opioid peptides within the microenvironment of vascular cell surface receptors. Such differential metabolism may play a role in modulating the vascular effects of peripheral opioids.
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PMID:Degradation of low-molecular-weight opioid peptides by vascular plasma membrane aminopeptidase M. 287 42

Brain contains a membrane-bound form of endopeptidase-24.15, a metalloendopeptidase predominantly associated with the soluble protein fraction of brain homogenates. Subcellular fractionation of the enzyme in rat brain showed that 20-25% of the total activity is associated with membrane fractions including synaptosomes. Solubilization of the enzyme from synaptosomal membranes required the use of detergents or treatment with trypsin. The specific activity of the enzyme in synaptosomal membranes measured with tertiary-butoxycarbonyl-Phe-Ala-Ala-Phe-p-aminobenzoate as substrate was higher than that of endopeptidase-24.11 ("enkephalinase"), a membrane-bound zinc-metalloendopeptidase believed to function in brain neuropeptide metabolism. Purified synaptosomal membranes converted efficiently dynorphin1-8, alpha- and beta-neoendorphin into leucine enkephalin and methionine-enkephalin-Arg6-Gly7-Leu8 into methionine enkephalin in the presence of captopril, bestatin, and N-[1-(R,S)-carboxy-2-phenylethyl]-Phe-p-aminobenzoate, inhibitors of angiotensin converting enzyme (EC 3.4.15.1), aminopeptidase (EC 3.4.11.2), and membrane-bound metalloendopeptidase (EC 3.4.24.11), respectively. The conversion of enkephalin-containing peptides into enkephalins was virtually completely inhibited by N-[1-(R,S)-carboxy-2-phenylethyl]-Ala-Ala-Phe-p-aminobenzoate, a specific active-site-directed inhibitor of endopeptidase-24.15, indicating that this enzyme was responsible for the observed interconversions. The data indicate that synaptosomal membranes contain enzymes that can potentially generate and degrade both leucine- and methionine-enkephalin.
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PMID:Synaptosomal membrane-bound form of endopeptidase-24.15 generates Leu-enkephalin from dynorphin1-8, alpha- and beta-neoendorphin, and Met-enkephalin from Met-enkephalin-Arg6-Gly7-Leu8. 287 74

Based on differences in total metabolite accumulation in the presence or absence of selective peptidase inhibitors, rat plasma is found to have its own unique pattern of enkephalin hydrolysis. Approximately 85-90% of the hydrolysis of [leu]enkephalin is attributed to the combined action of aminopeptidase M and angiotensin converting enzyme, whereas "enkephalinase" and aminopeptidase MII activity against [leu]enkephalin are not detectable. Similarly, 80-90% of the hydrolysis of D-ala2-[L-leu] enkephalin (DALLE) is due to the combined action of aminopeptidase M and angiotensin converting enzyme, whereas aminopeptidase MII and enkephalinase activity against this substrate also could not be detected. This is in contrast to the high susceptibility to hydrolysis by enkephalinase, and the low susceptibility to aminopeptidase activity, for DALLE in brain tissue. Among other alternatives, it is suggested that enkephalin hydrolysis in plasma may appear to be unique because of differences in enzyme conformation and/or the availability of a substance(s) that competes with, or alters the binding of, [leu] enkephalin, DALLE or the inhibitors to the enzymes.
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PMID:Characterization of hydrolysis of [leu]enkephalin and D-ala2-[L-leu]enkephalin in rat plasma. 290 10

The effect of the angiotensin converting enzyme inhibitor 2-[N-[(S)-1-carboxy-3-phenylpropyl]-L-alanyl]-(1S,3S,5S)-2- -azabicyclo(3.3.0)octane-3-carboxylic acid (Hoe 498 diacid) and the aminopeptidase inhibitor bestatin on antinociception induced in rats by intraventricular injections of [Met5]enkephalin-Arg6-Phe7 and [Met5]enkephalin-Arg6-Gly7-Leu8 was investigated. Potentiation and prolongation of the antinociception was observed after pretreatment with bestatin. Further potentiation of the antinociception elicited by the heptapeptide was obtained in rats pretreated with a combination of bestatin and Hoe 498 diacid. In contrast, antinociception elicited by the octapeptide was not potentiated further by pretreatment with the bestatin and Hoe 498 diacid combination.
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PMID:Effect of peptidase inhibitors on [Met5]enkephalin-Arg6-Phe7 and [Met5]enkephalin-Arg6-Gly7-Leu8-induced antinociception. 294 92

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

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


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