Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.15.1 (ACE)
 18,300 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

When angiotensin fragments, Val-Tyr and Angiotensin III (ANG III), with potent ACE inhibitory activity were intravenously administered to spontaneously hypertensive rat (SHR), a significant reduction of diastolic blood pressure was observed. After incubation of ANG III with SHR plasma, four fragments with ACE inhibitory activity, Val-Tyr (ANG (3-4)) (IC50 = 26.0 microM), Ile-His-Pro-Phe (ANG (5-8)) (11.6 microM), Tyr-Ile-His-Pro-Phe (ANG (4-8)) (457.5 microM), and Val-Tyr-Ile-His-Pro-Phe (ANG (3-8)) (6.55 microM), were confirmed to generate in SHR plasma. Compared the metabolic behavior of ANG II in SHR plasma with that in normotensive Wistar plasma, the initial degradation rate (3.07 nmol/ml/min) in Wistar plasma was about 2-fold higher than that in the SHR one (1.75 nmol/ml/min).
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PMID:Antihypertensive effects of angiotensin fragments in SHR. 754 89

Peptides that display bradykinin-potentiating activity have been obtained from a number of distinct sources, such as snake venoms, fibrinogen, and casein. This paper describes the isolation and sequencing of a novel bradykinin-potentiating peptide, generated by tryptic hydrolysis of the gamma-casein chain. No homology was found to other known vasoactive or vasopotentiating peptides. The octapeptide Tyr-Pro-Val-Gln-Pro-Phe-Thr-Glu, corresponding to the gamma-casein(114-121) sequence, was isolated from the tryptic hydrolysis of gamma-casein and also synthesized by solid-phase peptide synthesis. Both natural and synthetic peptides had the same retention time in HPLC and displayed a selective potentiating activity on isolated guinea-pig ileum for bradykinin and Lys-bradykinin but were not able to potentiate the effects of Met-Lys-bradykinin, Ile-Ser-bradykinin, angiotensin II, acetylcholine, or histamine. Intravenous injections of bradykinin and of bradykinin-potentiating octapeptide produced a persistent hypotension in conscious rats, a pattern that was not obtained when the octapeptide was replaced by captopril. This bradykinin-potentiating octapeptide is a strong competitive inhibitor of endo-oligopeptidase A (EC 3.4.24.15, formerly EC 3.4.22.19), but it has low inhibitory potency towards angiotensin-converting enzyme (EC 3.4.15.1). Thus, our results suggest that other peptidases in addition to angiotensin-converting enzyme, such as endo-oligopeptidase A, may contribute to the reduction of the effective concentration of bradykinin in the circulation.
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PMID:Isolation and characterization of a new bradykinin potentiating octapeptide from gamma-casein. 760 Apr 58

This study reports the antihypertensive effect of orally administered doses of either Calpis sour milk or peptides (Val-Pro-Pro and Ile-Pro-Pro), which are inhibitors to angiotensin I-converting enzyme, isolated from the sour milk using strain SHR spontaneously hypertensive rats. Single oral administration of the sour milk (5 ml/kg of BW), corresponding inhibitory units of the peptides Val-Pro-Pro (.6 mg/kg of BW), or Ile-Pro-Pro (.3 mg/kg of BW) significantly decreased the systolic blood pressure from 6 to 8 h after administration. Blood pressure returned to the initial level at 24 h after administration. Antihypertensive activity of these two tripeptides was dose-dependent up to 5 mg/kg of BW. Conversely, the sour milk (25 ml/kg of BW) and mixed tripeptides (10 mg each of Val-Pro-Pro and Ile-Pro-Pro/kg of BW) did not change the systolic blood pressure of the normotensive strain WKY Wistar-Kyoto rats.
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PMID:Antihypertensive effect of sour milk and peptides isolated from it that are inhibitors to angiotensin I-converting enzyme. 767 15

Six angiotensin I-converting enzyme inhibitory peptides were isolated from a bonito bowels autolysate. Their amino acids were sequenced as Tyr-Arg-Pro-Tyr, Gly-His-Phe, Val-Arg-Pro, Ile-Lys-Pro, Leu-Arg-Pro, and Ile-Arg-Pro. Peptides having corresponding amino acid sequences were synthesized by a solid-phase method and their inhibition of the activity measured. IC50 of these peptides were estimated to be 320, 1100, 2.2, 2.5, 1.0, and 1.8 microM, respectively. The role of carboxyl terminal proline residues on the inhibition is discussed.
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PMID:Angiotensin I-converting enzyme inhibitory peptides derived from bonito bowels autolysate. 776 72

Four angiotensin I-converting enzyme (EC 3.4.15.1) (ACE) inhibitory peptides C105, C107, C111, and C112 were isolated from bonito bowels. C111 was obtained from liver, while the others were from intestine. Their amino acids were sequenced as Ser-Val-Ala-Lys-Leu-Glu-Lys for C105, Ala-Leu-Pro-His-Ala for C107, Gly-Val-Tyr-Pro-His-Lys for C111, and Ile-Arg-Pro-Val-Gln for C112. Their ACE inhibition activities were measured for synthetic peptides. The IC50 of these peptides were estimated to be 82, 79, 1.6, and 1.4 microM, respectively. Carboxyl-terminal amino acid(s) were considered to be essential for their expression of ACE inhibition for C105, C107, and C111, while the amino terminal tripeptide Ile-Arg-Pro of C112 was presumed to inhibit ACE after the removal of a dipeptide from C112 with ACE digestion. Presumed original proteins of these peptides are discussed.
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PMID:Isolation and characterization of angiotensin I-converting enzyme inhibitory peptides derived from bonito bowels. 776 72

The inhibitory activity of angiotensin I-converting enzyme in milk increased during fermentation with the Calpis sour milk starter containing Lactobacillus helveticus and Saccharomyces cerevisiae. Two kinds of peptides inhibitory to angiotensin I-converting enzyme were purified from the sour milk by using four-step HPLC. The amino acid sequences of these inhibitors were identified as Val-Pro-Pro and Ile-Pro-Pro. The concentrations of peptides providing 50% inhibition of angiotensin I-converting enzyme were 9 and 5 microM, respectively. Most of the inhibitory activity in sour milk was attributed to these two peptides.
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PMID:Purification and characterization of angiotensin I-converting enzyme inhibitors from sour milk. 779 May 70

Several neuropeptides, including neurotensin, somatostatin, bradykinin, angiotensin II, substance P, and luteinizing hormone-releasing hormone but not vasopressin and oxytocin, were actively metabolized through proteolytic degradation by cultivated astrocytes obtained from rat cerebral cortex. Because phenanthroline was an effective degradation inhibitor, metalloproteases were responsible for neuropeptide fragmentation. Neurotensin was cleaved by astrocytes at the Pro10-Tyr11 and Arg8-Arg9 bonds, whereas somatostatin was cleaved at the Phe6-Phe7 and Thr10-Phe11 bonds. These cleavage sites have been found previously with endopeptidases 24.16 and 24.15 purified from rat brain. Addition of specific inhibitors of these proteases, the dipeptide Pro-Ile and N-[1-(RS)-carboxy-3-phenylpropyl]-Ala-Ala-Phe-4-aminobenzoate, significantly reduced the generation of the above neuropeptide fragments by astrocytes. The presence of endopeptidases 24.16 and 24.15 in homogenates of astrocytes could also be demonstrated by chromatographic separations of supernatant solubilized cell preparations. Proteolytic activity for neurotensin eluted after both gel and hydroxyapatite chromatography at the same positions as found for purified endopeptidase 24.16 or 24.15. In incubation experiments or in chromatographic separations no phosphoramidon-sensitive endopeptidase 24.11 (enkephalinase) or captopril-sensitive peptidyl dipeptidase A (angiotensin-converting enzyme) could be detected in cultivated astrocytes. Because astrocytes embrace the neuronal synapses where neuropeptides are released, we presume that the endopeptidases 24.16 and 24.15 on astrocytes are strategically located to contribute significantly to the inactivation of neurotensin, somatostatin, and other neuropeptides in the brain.
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PMID:Endopeptidases 24.16 and 24.15 are responsible for the degradation of somatostatin, neurotensin, and other neuropeptides by cultivated rat cortical astrocytes. 790 52

1. Peptides C111 (Gly-Val-Tyr-Pro-His-Lys) and C112 (Ile-Arg-Pro-Val-Gln), extracted from the autolysis product of bonito liver and intestine, have been shown to inhibit angiotensin converting enzyme (ACE) activity in vitro with IC50s of 1.6 microM and 1.4 microM, respectively. We examined the effects of oral administration of these peptides on blood pressure. 2. Oral administration of these peptides (500 mg kg-1 body weight each) inhibited the pressor effect of intravenously administered angiotensin I in Sprague-Dawley rats. 3. In spontaneously hypertensive rats, oral administration of these peptides (100-200 mg kg-1 body weight) showed depressor effects. 4. These results suggest that the peptides, C111 and C112, are orally effective ACE inhibitors with hypotensive effect.
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PMID:Oral administration of peptides derived from bonito bowels decreases blood pressure in spontaneously hypertensive rats by inhibiting angiotensin converting enzyme. 809 90

We present the application of free energy perturbation theory/molecular dynamics to predict the consequence of replacing each of the seven peptide bonds in the potent HIV protease inhibitor JG365: ACE (acetyl)-Ser-Leu-Asn-HEA (hydroxyethylamine analog of Phe-Pro)-Ile-Val-NME (N-methyl) by ethylene or fluoroethylene isosteres. Replacing two of these bonds may well lead to significantly tighter binding; replacing two others is predicted to significantly diminish the binding affinity. Also, for three of the peptide bonds fluoroethylene replacements could lead to increased binding of free energies of the inhibitors. Our results should be considered as predictive since there are, as yet, no experimental results on such peptide replacements as enzyme inhibitors.
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PMID:Peptide mimetics as enzyme inhibitors: use of free energy perturbation calculations to evaluate isosteric replacement for amide bonds in a potent HIV protease inhibitor. 837 26

The bradykinin peptide system is a tissue-based system with potent cardiovascular and renal effects. To investigate the regulation of this system, we developed a highly sensitive amino terminal-directed radioimmunoassay that, with high performance liquid chromatography, enables the measurement of bradykinin-(1-7), bradykinin-(1-8), and bradykinin-(1-9). Together with a carboxy terminal-directed radioimmunoassay, we characterized bradykinin peptides in rat kidney and blood. The predominant bradykinin peptides in kidney were bradykinin-(1-9) (approximately 100 fmol/g wet weight of tissue) and bradykinin-(1-7) (approximately 70 fmol/g), with low levels of bradykinin-(1-8) (approximately 8 fmol/g) and bradykinin-(4-9) (approximately 12 fmol/g) detectable; bradykinin-(2-9) and bradykinin-(3-9) were below the limits of detection. In blood, the levels of bradykinin-(1-9) were very low (approximately 2 fmol/ml), and other bradykinin peptides were below the limits of detection. Ile,Ser-bradykinin and Met,Ile,Ser-bradykinin were below the limits of detection in both kidney and blood, indicating that T-kininogen makes no detectable contribution to renal or circulating bradykinin peptides. Administration of the angiotensin converting enzyme inhibitor perindopril was associated with an approximate twofold increase in renal levels of bradykinin-(1-8) and bradykinin-(1-9) and a decrease in the bradykinin-(1-7)/bradykinin-(1-9) ratio. The amino terminal-directed radioimmunoassay was also applied to heart, aorta, brown adipose tissue, adrenal lung, and brain. For these tissues, bradykinin-(1-7) and bradykinin-(1-9) were of similar abundance (16-340 fmol/g), with lower levels of bradykinin-(1-8). These studies demonstrate that tissue levels of bradykinin peptides are much higher than circulating levels, consistent with their formation at a local tissue site. Of peptides derived from K-kininogen, bradykinin-(1-9) is the predominant bioactive peptide in all tissues, and a major pathway of bradykinin-(1-9) metabolism involves the formation of bradykinin-(1-7). In kidney, angiotensin converting enzyme plays an important role in bradykinin-(1-9) metabolism, and increased bradykinin-(1-9) and bradykinin-(1-8) levels may mediate in part the renal effects of converting enzyme inhibition.
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PMID:Bradykinin peptides in kidney, blood, and other tissues of the rat. 842 78


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