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)

In the search for novel peptides that inhibit the angiotensin I-converting enzyme (ACE), porcine skeletal troponin was hydrolyzed with pepsin, and the products were subjected to various types of chromatography to isolate active peptides. Glu-Lys-Glu-Arg-Glu-Arg-Gln (EKERERQ) and Lys-Arg-Gln-Lys-Tyr-Asp-Ile (KRQKYDI) were identified as active peptides, and their 50% inhibitory concentrations were found to be 552.5 and 26.2 microM, respectively. These are novel ACE inhibitory peptides, and the activity of KRQKYDI was the strongest among previously reported troponin-originated peptides. KRQKYDI was slowly hydrolyzed by treatment with ACE, and kinetic studies indicated that this peptide was a competitive inhibitor of the enzyme. When KRQKYDI was administered orally to spontaneously hypertensive rats (SHR) at a dose of 10 mg/kg, a temporary antihypertensive activity was observed at 3 and 6 h after administration.
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PMID:Porcine skeletal muscle troponin is a good source of peptides with Angiotensin-I converting enzyme inhibitory activity and antihypertensive effects in spontaneously hypertensive rats. 1816 67

Transepithelial transport of the ACE inhibitory peptides Ile-Pro-Pro and Val-Pro-Pro was studied in different models of absorption. Apparent permeability (P(app)) values for absorptive transport across Caco-2 monolayers were 1.0+/-0.9 x 10(-8) (Ile-Pro-Pro) and 0.5+/-0.1 x 10(-8)cms(-1) (Val-Pro-Pro). Ex vivo transport across jejunal segments in the Ussing chamber was 5-times (Ile-Pro-Pro) to 10-times (Val-Pro-Pro) higher with no significant differences (p>0.05) observed between both peptides. The peptidase inhibitor bestatin increased permeability for the absorptive direction for Ile-Pro-Pro by twofold. Neither a transepithelial pH gradient nor increased apical tripeptide concentration nor longitudinal localization of the intestinal segment influenced P(app) in the ex vivo experiments. Val-Pro-Pro transport across Peyer's patches, however, was 4-times higher (P(app)=21.0+/-9.3 x10(-8)cms(-1)) as compared to duodenum (P(app)=4.8+/-1.4 x 10(-8)cms(-1)). In the in situ perfusion experiments P(app) values varied greatly among different animals ranging from 0.5 to 24.0 x10(-8)cms(-1) (Ile-Pro-Pro) and from 1.0 to 15.6 x 10(-8)cms(-1) (Val-Pro-Pro). In summary, Caco-2 and ex vivo absorption models differ considerably regarding their peptide permeability. The in situ model seems to be less appropriate because of the observed large variability in peptide permeability. The results of this study demonstrate that the ACE inhibitory peptides Ile-Pro-Pro and Val-Pro-Pro are absorbed partially undegraded.
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PMID:The angiotensin converting enzyme inhibitory tripeptides Ile-Pro-Pro and Val-Pro-Pro show increasing permeabilities with increasing physiological relevance of absorption models. 1849 81

Egg proteins are an excellent source of bioactive peptides. The purpose of this work was to study the effect of cooking methods on the production of angiotensin converting enzyme (ACE) inhibitory peptides. Boiled or fried eggs (in the forms of whites, yolks, and whole eggs) were digested by gastrointestinal tract proteases at simulated gut conditions. Fried egg digests showed more potent activity than those of boiled egg digests; the fried whole egg digest had an IC(50) value of 0.009 mg protein/mL. This hydrolysate was further purified by cation exchange chromatography and gel filtration chromatography. Seven peptides, Val-Asp-Phe (IC(50): 6.59 microM), Leu-Pro-Phe (10.59 microM), Met-Pro-Phe (17.98 microM), Tyr-Thr-Ala-Gly-Val (23.38 microM), Glu-Arg-Tyr-Pro-Ile (8.76 microM), Ile-Pro-Phe (8.78 microM), and Thr-Thr-Ile (24.94 microM), were identified by liquid chromatography-mass spectrometry (LC-MS/MS), and their IC(50) values were predicted by using our previously reported structure and activity models. The presence of several tripeptides from in vitro simulated gastrointestinal egg digest indicates that these peptides may be absorbed into the body and exert an in vivo antihypertensive activity, although in vivo study is needed to confirm this assumption. Our results showed that in vitro digestion of cooked eggs could generate a number of potent ACE inhibitory peptides which may have implications for cardiovascular disease prevention, including hypertension.
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PMID:Angiotensin I converting enzyme inhibitory peptides from simulated in vitro gastrointestinal digestion of cooked eggs. 1915 60

We have developed a peptide-enriched soy sauce-like seasoning termed Fermented Soybean Seasoning (FSS), by modifying the process of soy sauce brewing. The FSS has a 2.7-fold higher concentration of total peptides than regular soy sauce. The angiotensin I-converting enzyme (ACE) inhibitory activity of FSS (IC(50) = 454 microg/mL) was greater than that of regular soy sauce (IC(50) = 1620 microg/mL). The FSS demonstrated antihypertensive effects both in spontaneously hypertensive rats and in Dahl salt-sensitive rats during continuous feeding. The ACE inhibitory substances were purified from FSS by reversed-phase chromatography. Ala-Trp IC(50) = 10 microM; Gly-Trp IC(50) = 30 microM; Ala-Tyr IC(50) = 48 microM; Ser-Tyr, IC(50) = (67 microM; Gly-Tyr, IC(50) = 97 microM; Ala-Phe, IC(50) = 190 microM; Val-Pro, IC(50) = (480 microM; Ala-Ile, IC(50) = 690 microM; Val-Gly, IC(50) = 1100 microM; and a nicotianamine, IC(50) = 0.26 microM. [corrected] The concentrations of these substances in the FSS were revealed to be higher than that of regular soy sauce through quantitative LC-MS/MS analysis.
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PMID:Antihypertensive effect of peptide-enriched soy sauce-like seasoning and identification of its angiotensin I-converting enzyme inhibitory substances. 1999 57

Pyroglutamyl proline-rich oligopeptides, present in the venom of the pit viper Bothrops jararaca (Bj-PROs), are the first described naturally occurring inhibitors of the angiotensin I-converting enzyme (ACE). The inhibition of ACE by the decapeptide Bj-PRO-10c (<ENWPHPQIPP) and other Bj-PROs was classically used to explain the pharmacological effects of these venom peptides in mammals resulting in a decrease of blood pressure. Recent studies, however, suggest that ACE inhibition alone is not sufficient for explaining the antihypertensive actions exerted by these peptides. In this study, we show that intracerebroventricular injection of Bj-PRO-10c induced a significant reduction of mean arterial pressure (MAP) together with a decrease of heart rate (HR) in spontaneously hypertensive rats, indicating that Bj-PRO-10c may act on the central nervous system. In agreement with its supposed neuronal action, this peptide dose-dependently evoked elevations of intracellular calcium concentration ([Ca(2+)](i)) in primary culture from postnatal rat brain. The N-terminal sequence of the peptide was not essential for induction of calcium fluxes, while any changes of C-terminal Pro or Ile residues affected Bj-PRO-10c's activity. Using calcium imaging by confocal microscopy and fluorescence imaging plate reader analysis, we have characterized Bj-PRO-10c-induced [Ca(2+)](i) transients in rat brain cells as being independent from bradykinin-mediated effects and ACE inhibition. Bj-PRO-10c induced pertussis toxin-sensitive G(i/o)-protein activity mediated through a yet unknown receptor, influx and liberation ofcalcium from intracellular stores, as well as reduction of intracellular cAMP levels. Bj-PRO-10c promoted glutamate and GABA release that may be responsible for its antihypertensive activity and its effect on HR.
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PMID:The central nervous system as target for antihypertensive actions of a proline-rich peptide from Bothrops jararaca venom. 2009 50

The anti-hypertensive peptide Arg-Ile-Tyr, which was isolated based on its inhibitory activity (IC(50)=28microM) for angiotensin I-converting enzyme (ACE) from the subtilisin digest of rapeseed protein, exhibited vasorelaxing activity (EC(50)=5.1microM) in an endothelium-dependent manner in the mesenteric artery of spontaneously hypertensive rats (SHRs). We named the peptide rapakinin. ACE inhibitors are reported to induce nitric oxide (NO)-dependent vasorelaxation by elevating the endogenous bradykinin level; however, the vasorelaxation induced by 10microM of rapakinin was blocked only insignificantly by HOE140 or N(G)-nitro-l-arginine methyl ester (l-NAME), antagonists of bradykinin B(2) receptor and an inhibitor of NO synthase, respectively. On the other hand, the vasorelaxation induced by 10microM rapakinin was significantly blocked by indomethacin and CAY10441, a cyclooxygenase (COX) inhibitor and an antagonist of the IP receptor, respectively. The vasorelaxing activity of rapakinin was also blocked by lorglumide, an antagonist of the cholecystokinin (CCK) CCK(1) receptor, although rapakinin has no affinity for the IP and CCK(1) receptors. The vasorelaxation induced by 10microM iloprost, an IP receptor agonist, was also blocked by lorglumide, suggesting that CCK-CCK(1) receptor system is activated downstream of the PGI(2)-IP receptor system. The anti-hypertensive activity of rapakinin after oral administration in SHRs was also blocked by CAY10441 and lorglumide. These results suggest that the anti-hypertensive activity of rapakinin might be mediated mainly by the PGI(2)-IP receptor, followed by CCK-CCK(1) receptor-dependent vasorelaxation.
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PMID:Rapakinin, an anti-hypertensive peptide derived from rapeseed protein, dilates mesenteric artery of spontaneously hypertensive rats via the prostaglandin IP receptor followed by CCK(1) receptor. 2018 76

Milk-based drinks containing casein-derived tripeptides isoleucine-proline-proline (Ile-Pro-Pro) and valine-proline-proline (Val-Pro-Pro) have been shown to possess antihypertensive and vascular endothelium-protecting properties in hypertensive animal models. Furthermore in clinical intervention trials they reduce blood pressure and arterial stiffness. The exact mechanisms are not known, but inhibition of angiotensin converting enzyme 1 (ACE1) has been suggested mainly to mediate these beneficial effects. The present study investigated the in vitro effects of three tripeptides: Ile-Pro-Pro, Val-Pro-Pro and leqcine-proline-proline (Leu-Pro-Pro) on four renin-angiotensin system enzymes: ACE1, ACE2, chymase, and cathepsin G. Also their effects on arginase I, a critical enzyme in L-arginine-nitric oxide pathway, were studied. It was shown, apparently for the first time, that the inhibitory effects of Ile-Pro-Pro, Val-Pro-Pro and Leu-Pro-Pro on ACE1 at micromolar concentrations are competitive in nature. Therefore the efficacy of inhibition is largely dependent on the amount of substrate present. Inhibition of ACE2 and arginase I was reached only at concentrations three orders of magnitude greater. No inhibition of chymase and cathepsin G was observed by the tripeptides. The findings support the hypothesis that Ile-Pro-Pro, Val-Pro-Pro and Leu-Pro-Pro act favourably on blood pressure mainly by selective inhibition of ACE1.
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PMID:Effects of milk casein-derived tripeptides Ile-Pro-Pro, Val-Pro-Pro, and Leu-Pro-Pro on enzymes processing vasoactive precursors in vitro. 2048 67

An angiotensin I-converting enzyme (ACE) inhibitory peptide Ile-Gln-Pro with an IC(50) value of 5.77 +/- 0.09 microM was purified from the alcalase digests of Spirulina platensis by gel filtration chromatography and two steps of reverse-phase high-performance liquid chromatography (RP-HPLC). The peptide was synthesized and showed resistance to in vitro digestion by gastrointestinal proteases. Kinetics studies indicated that the peptide was a noncompetitive inhibitor and that the K(i) value was 7.61 +/- 0.16 microM. Oral administration of Ile-Gln-Pro at a dosage of 10 mg/kg showed significant decreases of the weighted systolic blood pressure (SBP) and diastolic blood pressure (DBP) in spontaneously hypertensive rats (SHR) at 4, 6, and 8 h after treatment. The results showed that the ACE inhibitory peptide from Spirulina platensis may have potential for use in the prevention and treatment of hypertension.
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PMID:Isolation of an antihypertensive peptide from alcalase digest of Spirulina platensis. 2050 91

The antihypertensive effect of an angiotensin I-converting enzyme (ACE) inhibitory peptide Ile-Gln-Pro (IQP), whose sequence was derived from Spirulina platensis , was investigated in spontaneously hypertensive rats (SHRs) for 1 week. The weighted systolic blood pressure (SBP) and diastolic blood pressure (DBP) of the peptide IQP-treated group were significantly lower than those of the negative control group from the third and fourth days, respectively. Accompanying the blood pressure reduction, a significant regulation of the expression of major components of the renin-angiotensin system (RAS) was found in the treatment group, including downregulation of the mRNA levels of renin, ACE, and the angiotensin II type 1 (AT1) receptor in the kidney, as well as serum angiotensinogen (Ang), ACE, and angiotensin II (Ang II) concentrations. The treatment group also showed upregulation of mRNA expression of the angiotensin II type 2 (AT2) receptor in the kidney. Our findings suggested that IQP might be of potential use in the treatment of hypertension.
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PMID:One-week antihypertensive effect of Ile-Gln-Pro in spontaneously hypertensive rats. 2118 94

The ability of milk protein derived Ile-Pro-Ala (IPA), Phe-Pro (FP) and Gly-Lys-Pro (GKP) peptides to inhibit angiotensin I-converting enzyme (ACE), a protein with an important role in blood-pressure regulation, were verified in vitro and in vivo. This work elucidates the modes and molecular mechanisms of the interaction of IPA, FP and GKP with ACE, including mechanisms that bind the peptides to the cofactor Zn(2+). It was observed that the best docking poses obtained for IPA, FP and GKP were at the ACE catalytic site with very similar modes of interaction, including the interaction with Zn(2+). The interactions, including H-bonds, hydrophobic, hydrophilic, and electrostatic interactions, as well as the interaction with Zn(2+), were responsible for the binding between the bioactive peptides and ACE.
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PMID:The molecular mechanisms of interactions between bioactive peptides and angiotensin-converting enzyme. 2164 May 89


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