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)

A mutant strain of Salmonella typhimurium that lacks two proline-specific peptidases (peptidases P and Q) could not complete the degradation of proline peptides formed as intermediates in starvation-induced protein breakdown. The wild-type strain produced free proline as the product of degradation of proline-labeled proteins. The pepP pepQ mutant, however, produced a mixture of small proline peptides. In the absence of peptidase Q only, peptidase P could complete the degradation of most of the proline peptide intermediates formed. In the absence of peptidase P only, about 50% of the proline-labeled, acid-soluble products were proline peptides. These results are consistent with in vitro specificity data indicating that peptidase Q hydrolyzes X-Pro dipeptides only, whereas peptidase P attacks both X-Pro dipeptides and longer peptides with X-Pro at their N-termini. A mutant strain lacking four broad-specificity peptidases (peptidases N, A, B, and D), but containing peptidases P and Q, also produced proline peptides as products of protein breakdown. This observation suggests that broad-specificity peptidases are required to generate the X-Pro substrates of peptidases P and Q. A strain lacking six peptidases (N, A, B, D, P, and Q) was constructed and produced less free proline from protein breakdown than either the pepP pepQ strain or the pepN pepA pepB pepD strain. These observations suggest that the degradation of peptide intermediates involves the sequential removal of N-terminal amino acids and requires both broad-specificity aminopeptidases (peptidases N, A, and B) and the X-Pro-specific aminopeptidase, peptidase P.
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PMID:Degradation of proline peptides in peptidase-deficient strains of Salmonella typhimurium. 633 37

Metal ion-chelating agents inhibited enkephalin degradation by a rat striatal membrane-associated endopeptidase termed 'enkephalinase'. The combination of a hydrophobic dipeptidyl moiety and a transition metal-chelating moiety in the same molecule resulted in very efficient and selective inhibitors of enkephalinase. The mercaptoacetyl dipeptides (2-mercaptoacetyl-Leu-Phe and 2-mercaptoacetyl-Phe-Leu) and the N-phosphorylated dipeptides (phosphoryl-Leu-Phe and phosphoramidon) inhibited enkephalinase with IC50 values of 15, 70, 0.3 and 1 nM respectively, but were much less potent against the aminopeptidase and angiotensin converting enzyme, two other metalloenzymes implicated in the degradation of the enkephalins in brain. The inhibition of enkephalinase, using phosphoryl-Leu-Phe as a selective inhibitor, resulted in a 4 fold increase in the amount of enkephalin recovered following K+ depolarization of rat striatal slices.
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PMID:Protection of enkephalins from enzymatic degradation utilizing selective metal-chelating inhibitors. 635 83

Two proteolytic activities that degrade [Leu5]enkephalin were found in Torpedo californica electric organ. One is a soluble aminopeptidase that degrades enkephalin at the Tyr1-Gly2 peptide bond, and the second is an endopeptidase that degrades enkephalin at the Gly3-Phe4 peptide bond. The aminopeptidase is inhibited by low concentrations of puromycin and bestatin. More than 60% of the endopeptidase is associated with the particulate fraction and is almost completely inhibited by low concentrations of captopril (SQ 14225) or SQ 20881 (potent inhibitors of angiotensin converting enzyme). Thiorphan and phosphoramidon (potent enkephalinase inhibitors) are much less effective. The pattern of cleavage and inhibition of the particulate endopeptidase thus resembles that of angiotensin converting enzyme.
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PMID:Enkephalin degrading enzymes are present in the electric organ of Torpedo californica. 636 28

In superfused anterior pituitary reaggregate cell cultures angiotensin II (AII) stimulated both spontaneous and dopamine-inhibited prolactin (PRL) release from subnanomolar concentrations. Angiotensin I (AI) and angiotensin III (AIII) also stimulated PRL release. The magnitude and rate of response to AI was equal to or only slightly lower than that to AII. However, the angiotensin converting enzyme (ACE) inhibitors captopril and teprotide (1 microM) completely abolished the PRL response to 0.1 nM AI and strongly reduced that to 1 nM AI. The intrinsic activity of AIII was lower than that of AII but could be enhanced by adding 2 microM of the aminopeptidase inhibitor amastatin to the superfusion medium. After withdrawal of AIII, PRL secretion rate rapidly returned to baseline levels, whereas after withdrawal of AI or AII, secretion fell to a level remaining significantly higher than basal release. The present findings indicate that stimulation of PRL release by AI is weak unless it is converted into AII by ACE and that aminopeptidase may be important in determining the magnitude and termination of the PRL response. Furthermore, the active peptides induce a different pattern of response.
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PMID:Stimulation of spontaneous and dopamine-inhibited prolactin release from anterior pituitary reaggregate cell cultures by angiotensin peptides. 637 46

The opioid peptides methionine-enkephalin and leucine-enkephalin appear to exert their biological effects through a receptor mediated mechanism. There appears to be three potential mechanisms for enkephalin degradation which could serve to control enkephalin levels in the vicinity of enkephalin receptors. These are, 1) cleavage of the tyrosyl-glycine bond by aminopeptidases, 2) cleavage of the glycl-glycine bond by a dipeptidyl aminopeptidase, and 3) cleavage of the glycyl-phenylalanine bond by a dipeptidyl carboxypeptidase. In this review the biochemical properties of these potential enkephalinases are described, and the evidence for each acting as an enkephalinase is reviewed.
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PMID:Degradation of enkephalins: the search for an enkephalinase. 675 92

Enkephalins were rapidly degraded by specific enzyme systems in vivo. In cerebrospinal fluid (CSF), however, it has been undefined whether these enzyme systems existed. Our experiments showed enkephalins were hydrolyzed by the enzymatic activity in both CSF of human and monkey. The results by the thin layer chromatography and the high performance liquid chromatography revealed the reaction products of CSF and enkephalin were tyrosine, tyrosyl-glycine and tyrosyl-glycyl-glycine. Therefore, the enzymes in CSF were considered to be an aminopeptidase, a dipeptidyl aminopeptidase and a dipeptidyl carboxypeptidase. Our results suggest that in the assay of enkephalin in CSF, the effects of these enzymes should be considered.
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PMID:Enkephalin degrading enzymes in cerebrospinal fluid. 687 31

Methionine enkephalin release was evoked by depolarization of slices from rat striatum with potassium. In the presence of 0.1 microM thiorphan [(N(R,S)-3-mercapto-2-benzylpropionyl)glycine], a potent inhibitor of enkephalin dipeptidyl carboxypeptidase (enkephalinase), the recovery of the pentapeptide in the incubation medium was increased by about 100 percent. A similar effect was observed with the dipeptide phenylalanylalanine, a selective although less potent enkephalinase inhibitor. Inhibition of other known enkephalin-hydrolyzing enzymes--aminopeptidase by 0.1 mM puromycin or angiotensin-converting enzyme by 1 microM captopril--did not significantly enhance the recovery of released methionine enkephalin. These data indicate that enkephalinase is critically involved in the inactivation of the endogenous opioid peptide released from striatal neurons.
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PMID:Selective protection of methionine enkephalin released from brain slices by enkephalinase inhibition. 701 10

Met-enkephalin-Arg6-Phe7 (E7) is converted to Met-enkephalin by rat striatal membranes; in contrast, Leu-enkephalin (E5) is inactivated by cleavage at the Tyr-Gly (aminopeptidase) and Gly-Phe sites (metalloendopeptidase). Conversion of E7 is inhibited by MK-421, and inactivation of E5 is inhibited by bestatin and Thiorphan. Purified brain angiotensin converting enzyme (EC 3.4.15.1) also converts E7 but a purified metalloendopeptidase acts on both E5 and E7 at the Gly-Phe site. Cleavage of E7-amide by metalloendopeptidase leads to release of Phe-Met-Arg-Phe-amide, a cardioactive neuropeptide. Rat heart, a potential target organ, does not convert E7-amide to release the cardioactive peptide but cleaves the Met5-Arg6 bond to release Met-enkephalin by an enzyme sensitive to MK-421.
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PMID:Metabolism of a heptapeptide opioid by rat brain and cardiac tissue. 715 37

Bradykinin (BK) and its fragments BK(1-8), BK(1-7), and BK(1-5) were incubated with sheep nasal homogenates to investigate the extent of peptide metabolism within the nasal mucosa. The products for both bradykinin and BK(1-8) degradation were found to be BK(1-7) and BK(1-5). BK(1-7) was metabolized to BK(1-5) alone. The patterns of degradation suggest that the Pro7-Phe8 bond of bradykinin was hydrolyzed first, then BK(1-7) was further hydrolyzed to form BK(1-5). The metabolism of bradykinin in rat nasal homogenates and plasma was also investigated. BK(1-5) was the only metabolite measurable in the rat nasal homogenates, likely due to the activity of an endopeptidase. The reduction in the bradykinin degradation rate resulting from the inhibition of angiotensin converting enzyme (ACE) or carboxypeptidase N indicates that these enzymes participate in mucosal bradykinin metabolism to some degree. In comparison, the products of bradykinin hydrolysis in rat plasma were found to be BK(1-8), BK(1-7), and BK(1-5). These results indicate that the enzyme populations or/and activities vary significantly between different species and between different tissues within the same species. Although significant aminopeptidase activities were detected in the sheep nasal homogenates, bradykinin was not affected by their presence, since the N-terminal sequence of bradykinin is not susceptible to hydrolysis by most aminopeptidases.
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PMID:Presystemic bradykinin metabolism in sheep and rat nasal homogenates. 756 26

The nasal secretions are the first barrier that nasally administered drugs encounter. Therefore, the characterization of peptide metabolism in the nasal secretions is essential to predict nasal peptide bioavailability. Metabolism of bradykinin was measured in rat and sheep nasal secretions to estimate the extent of degradation of nasally administered peptide compounds. A single-pass, in situ nasal perfusion technique was employed to collect secretions for the investigation of peptide metabolism in rat nasal secretions. The protein content, mucin concentration, and degree of bradykinin metabolism in perfusate aliquots collected over a 2-h period showed that the early perfusate fractions contained most of the active secretory materials. Evidence of continuous mucus secretion and plasma extravasation was found in the nasal perfusate throughout the entire collection period. Sheep nasal secretions were collected with a cotton pledget inserted into the nasal cavity. Bradykinin and its fragments were degraded by carboxypeptidases and endopeptidases present in both rat and sheep nasal secretions. Hydrolysis of Phe5-Ser6 was the major metabolism pathway of bradykinin in the rat nasal perfusate, whereas in sheep nasal secretions, hydrolysis of the Pro7-Phe8 and Phe8-Arg9 bonds also occurred. Evidence of angiotensin converting enzyme, carboxypeptide N, and aminopeptidase activity was identified in the rat nasal perfusate with specific substrates and inhibitors. The activity of these and other enzymes in the nasal secretions may significantly limit the bioavailability of nasally administered peptide drugs prior to their exposure to the nasal mucosal tissues.
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PMID:Bradykinin metabolism in rat and sheep nasal secretions. 756 32


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