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

Two intestinal brush border membrane carboxypeptidases were found to participate in the sequential digestion of proline-containing peptides representing a novel mechanism of hydrolysis from the COOH terminus. NH2-blocked prolyl tripeptides were rapidly hydrolyzed by either brush border membrane angiotensin converting enzyme (ACE, dipeptidyl carboxypeptidase, E.C. 3.4.15.1) or carboxypeptidase P (E.C.3.4.12-) depending on the position of the proline residue. Furthermore, these two enzymes were found to participate in a concerted manner to sequentially degrade larger proline-containing pentapeptides from the COOH terminus. A brush border membrane associated neutral endopeptidase also participated in the hydrolysis of the prolyl pentapeptides. During in vivo intestinal perfusion, the NH2-blocked prolyl peptides were degraded and their constituent amino acids efficiently absorbed by the intestine. Furthermore, hydrolysis and absorption of these peptides could be dramatically suppressed by low concentrations of captopril, a specific inhibitor of ACE. These studies show that prolyl peptides are efficiently and sequentially hydrolyzed from the COOH terminus by the combined action of ACE and carboxypeptidase P, and that these enzymes may play an important role in the digestion and assimilation of proline-containing peptides.
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PMID:Digestion and assimilation of proline-containing peptides by rat intestinal brush border membrane carboxypeptidases. Role of the combined action of angiotensin-converting enzyme and carboxypeptidase P. 283 43

This study provides evidence that: 1) LHRH is degraded by renal brush border hydrolases, followed by reabsorption of oligopeptide metabolites in the proximal kidney tubule. 2) Peptide carriers are present in the luminal membrane of the proximal nephron, which apparently function to reabsorb oligopeptide metabolites resulting from hydrolysis of filtered peptides, including LHRH. 3) Renal brush border hydrolysis of LHRH involves cleavage at multiple sites by endopeptidases like angiotensin I-converting enzyme and endopeptidase 24.11; D-amino acid substituents at these sites may alter the expected cleavage pattern of the analogs. 4) A transcytotic pathway is present in the proximal nephron which is facilitated by endocytosis of cationic macromolecules; such a pathway may function to reabsorb hydrolytically resistant peptides, but the issue of potential toxicity must be clarified.
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PMID:Renal handling of luteinizing hormone releasing hormone: a model for peptide transport and hydrolysis. 283 70

The amino-terminal amino acid sequence and several internal peptide sequences of angiotensin I-converting enzyme (ACE; peptidyl-dipeptidase A, kininase II; EC 3.4.15.1) purified from human kidney were used to design oligonucleotide probes. The nucleotide sequence of ACE mRNA was determined by molecular cloning of the DNA complementary to the human vascular endothelial cell ACE mRNA. The complete amino acid sequence deduced from the cDNA contains 1306 residues, beginning with a signal peptide of 29 amino acids. A highly hydrophobic sequence located near the carboxyl-terminal extremity of the molecule most likely constitutes the anchor to the plasma membrane. The sequence of ACE reveals a high degree of internal homology between two large domains, suggesting that the molecule resulted from a gene duplication. Each of these two domains contains short amino acid sequences identical to those located around critical residues of the active site of other metallopeptidases (thermolysin, neutral endopeptidase, and collagenase) and therefore bears a putative active site. Since earlier experiments suggested that a single Zn atom was bound per molecule of ACE, only one of the two domains should be catalytically active. The results of genomic DNA analysis with the cDNA probe are consistent with the presence of a single gene for ACE in the haploid human genome. Whereas the ACE gene is transcribed as a 4.3-kilobase mRNA in vascular endothelial cells, a 3.0-kilobase transcript was detected in the testis, where a shorter form of ACE is synthesized.
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PMID:Two putative active centers in human angiotensin I-converting enzyme revealed by molecular cloning. 284

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

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

Endopeptidase-24.11 (sometimes referred to as 'enkephalinase') is a key cell-surface enzyme in the metabolism of neuropeptides. A previous immunohistochemical study mapped the enzyme in pig brain and indicated a striosomal ordering of the enzyme within the striatum. This point has now been confirmed by staining adjacent sections for acetylcholinesterase (by histochemistry) and endopeptidase-24.11 (by an immunoperoxidase method). While there were some general similarities in the mapping of these two hydrolases, e.g. in the caudate-putamen, globus pallidus, olfactory tubercle, substantia nigra and striatonigral tract, there were differences in intensity and in the microscopic distribution, e.g. as in striosomes for which acetylcholinesterase was diminished. Two other membrane peptidases, peptidyl dipeptidase A ('angiotensin converting enzyme') and aminopeptidase N, were also mapped by the same immunohistochemical method. Peptidyl dipeptidase A had some similarities with endopeptidase-24.11, e.g. in its concentration within the striatal nuclei, but clear differences were also apparent, in particular the absence of staining of the former in the globus pallidus and olfactory tubercle. Immunostaining for aminopeptidase N, in contrast to the other peptidases, was observed as a diffuse staining throughout the gray matter. At the microscopic level, two important differences were that staining for aminopeptidase N and peptidyl dipeptidase A was very intense throughout the vasculature of the brain and that striatal efferent bundles of unmyelinated fibres staining positively for endopeptidase-24.11 were depleted of the other two peptidases. All three peptidases were identified in the pia mater. Thus, endopeptidase-24.11, unlike peptidyl dipeptidase A and aminopeptidase N, is a marker for a set of striatal efferent fibres in pig brain.
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PMID:Endopeptidase-24.11 is striosomally ordered in pig brain and, in contrast to aminopeptidase N and peptidyl dipeptidase A ('angiotensin converting enzyme'), is a marker for a set of striatal efferent fibres. 290 57

Protamine given to neutralize heparin after extracorporeal circulation can trigger a catastrophic reaction in some patients. While searching for a biochemical basis for this reaction, protamine was tested as an inhibitor of human plasma carboxypeptidase N (CPN) or kininase I, the inactivator of anaphylatoxins and kinins. Human plasma and CPN purified from human plasma, (Mr = 280 K) or its isolated active subunit (Mr = 48 K) were the sources of enzyme. The hydrolysis of furylacryloyl (FA)-Ala-Lys was measured in a UV spectrophotometer and that of bradykinin and the synthetic C-terminal octapeptide of anaphylatoxin C3a (C3a8) by high performance liquid chromatography. Protamine inhibited the hydrolysis of FA-Ala-Lys by CPN, (IC50 = 3.2 X 10(-7) M); added human serum albumin (30 mg/ml) increased the IC50 to 7 X 10(-6) M. When plasma was the source of CPN, the IC50 was 2 X 10(-6) M. Protamine more effectively inhibited the hydrolysis of bradykinin and C3a8. The IC50 for protamine was 5 X 10(-8) M with CPN and bradykinin, 7 X 10(-8) M with CPN and C3a8 and with the 48 K subunit and bradykinin it was 7 X 10(-8) M of protamine. Heparin competes with CPN for protamine, because in high concentration (18 U/ml) it reverses the inhibition by protamine. Protamine did not inhibit angiotensin I converting enzyme (kininase II) or the endopeptidase 24.11 (enkephalinase). Kinetic studies showed the mechanism of protamine inhibition to be partially competitive; about 10-20% of the hydrolysis of bradykinin by CPN was not inhibited by protamine. Thus, by blocking the inactivation of mediators released in shock, protamine inhibition of CPN may be partially responsible for the catastrophic reaction observed to occur in some patients.
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PMID:Protamine inhibits plasma carboxypeptidase N, the inactivator of anaphylatoxins and kinins. 291 61

Chick retina was screened for neuropeptide-metabolizing peptidase activity during development using a kininase bioassay in which hydrolysis of any peptide bond of bradykinin (Arg1-Pro2-Pro3-Gly4-Phe5-Ser6-Pro7-Phe8-Arg9) leads to inactivation, combined with chromatographic bradykinin-product analysis. Bradykinin was degraded at a high rate, 6.1-26.6 mU/mg protein, by retina homogenates of all developmental stages. Kininase activity increased 2.3-fold from the 8th to the 18th embryonic day and 2-fold in the immediate posthatching period relative to the activity level at hatching. Bradykinin-product analysis, 57-113% recovery of the peptide fragments, indicated that kininase activity corresponded mostly to endopeptidase A- and to endopeptidase B-like activities (hydrolysis of Phe5-Ser6 and Pro7-Phe8 peptide bonds, respectively) and to angiotensin I-converting enzyme activity at all developmental stages. The data indicated that the relative amounts of these activities vary during retina differentiation.
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PMID:Screening for neuropeptide-metabolizing peptidases during the differentiation of chick embryo retina. 299 15


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