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)

Many kinds of bioactive peptides which might prevent lifestyle-related diseases are released from food proteins after enzymatic digestion. Inhibitory peptides for angiotensin I-converting enzyme (ACE) having anti-hypertensive effect have been isolated from enzymatic digests of various food proteins. LKPNM, which was isolated from the thermolysin digest of dried bonito was activated 8-fold by ACE itself and showed a prolonged effect after oral administration. Two vasorelaxing peptides, ovokinin and ovokinin(2-7), showing antihypertensive effect after oral administration were obtained from ovalbumin digests. We found that low molecular weight peptides derived from food proteins lowered serum cholesterol without increasing excretion of cholesterol and bile acids. An immunostimulating peptide isolated from an enzymatic digest of soybean protein prevented alopecia induced by cancer chemotherapy.
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PMID:Bioactive peptides derived from food proteins preventing lifestyle-related diseases. 1121 76

Ab initio molecular orbital methods in combination with DFT calculations were used to study the structural and thermodynamic properties of 17 complexes containing zinc cation and four first-shell ligands as models of active site of metalloenzymes (e.g. angiotensin converting enzyme, thermolysin). The geometry of the complexes was relaxed by complete optimization by ab initio molecular orbital methods at Hertree-Fock level with 3-21G* basis set. Following single point calculation with tight SCF criteria at the B3LYP level with 6-311+G(2d,p) basis set was used to calculate accurate interaction enthalpies. The structure and thermodynamics of optimized complexes are discussed from the point of view of their biological importance.
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PMID:Coordination and thermodynamics of stable Zn(II) complexes in the gas phase. 1274 6

A large number of methods are available for modeling quantitative structure-activity relationships (QSAR). We examine the predictive accuracy of several methods applied to data sets of inhibitors for angiotensin converting enzyme, acetylcholinesterase, benzodiazepine receptor, cyclooxygenase-2, dihydrofolate reductase, glycogen phosphorylase b, thermolysin, and thrombin. Descriptors calculated with CoMFA, CoMSIA, EVA, HQSAR, and traditional 2D and 2.5D descriptors were used for developing models with partial least squares (PLS). In addition, the genetic function approximation algorithm, genetic PLS, and back-propagation neural networks were used for deriving models from 2.5D descriptors (i.e., 2D descriptors and 3D descriptors calculated from CORINA structures and Gasteiger-Marsili charges). Predictive accuracy was assessed using designed test sets. It was found that HQSAR generally performs as well as CoMFA and CoMSIA; other descriptor sets performed less well. When 2.5D descriptors were used, only neural network ensembles were found to be similarly or more predictive than PLS models. In addition, we show that many cross-validation procedures yield similar estimates of the interpolative accuracy of methods. However, the lack of correspondence between cross-validated and test set predictive accuracy for four sets underscores the benefit of using designed test sets.
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PMID:A comparison of methods for modeling quantitative structure-activity relationships. 1548 90

Dcp from Escherichia coli is a 680 residue cytoplasmic peptidase, which shows a strict dipeptidyl carboxypeptidase activity. Although Dcp had been assigned to the angiotensin I-converting enzymes (ACE) due to blockage by typical ACE inhibitors, it is currently grouped into the M3 family of mono zinc peptidases, which also contains the endopeptidases neurolysin and thimet oligopeptidase (TOP). We have cloned, expressed, purified, and crystallized Dcp in the presence of an octapeptide "inhibitor", and have determined its 2.0A crystal structure using MAD methods. The analysis revealed that Dcp consists of two half shell-like subdomains, which enclose an almost closed two-chamber cavity. In this cavity, two dipeptide products presumably generated by Dcp cleavage of the octapeptide bind to the thermolysin-like active site fixed to side-chains, which are provided by both subdomains. In particular, an Arg side-chain backed by a Glu residue, together with two Tyr phenolic groups provide a charged anchor for fixing the C-terminal carboxylate group of the P2' residue of a bound substrate, explaining the strict dipeptidyl carboxypeptidase specificity of Dcp. Tetrapeptidic substrates are fixed only via their main-chain functions from P2 to P2', suggesting a broad residue specificity for Dcp. Both subdomains exhibit very similar chain folds as the equivalent but abducted subdomains of neurolysin and TOP. Therefore, this "product-bound" Dcp structure seems to represent the inhibitor/substrate-bound "closed" form of the M3 peptidases, generated from the free "open" substrate-accessible form by a hinge-bending mechanism. A similar mechanism has recently been demonstrated experimentally for ACE2.
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PMID:Crystal structure of the E. coli dipeptidyl carboxypeptidase Dcp: further indication of a ligand-dependent hinge movement mechanism. 1587 71

In this paper, ACE inhibitory activity in insect protein hydrolyzed by various enzymes (gastrointestinal proteases, alcalase, and thermolysin) is reported for the first time. Four insects of different insect orders were tested: Spodoptera littoralis (Lepidoptera), Bombyx mori (Lepidoptera), Schistocerca gregaria (Orthoptera), and Bombus terrestris (Hymenoptera). ACE inhibitory activity was measured by two different methods: a spectrophotometric method using FAPGG (2-furanacryloyl-phenylalanyl-glycyl-glycine) as substrate, and an HPLC method using dansyltriglycine (DTG) as substrate. Hydrolysis of the insect protein resulted in an increased ACE inhibitory activity. Overall, the highest ACE inhibitory activity was obtained after gastrointestinal digestion. These results suggest a role for insect protein as antihypertensive component in functional foods and nutraceuticals. Furthermore, the ACE inhibitory activity differed according to the method used. As a consequence, there is a need to standardize methodologies to evaluate ACE inhibitory activity.
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PMID:ACE inhibitory activity in enzymatic hydrolysates of insect protein. 1596 98

Dialkylsilanediols have been found to be an effective functional group for the design of active-site-directed protease inhibitors, including aspartic (HIV protease) and metallo (ACE and thermolysin) proteases. The use of silanediols is predicated on its resemblance to the hydrated carbonyl transition-state structure of amide hydrolysis. This concept has been tested by replacing the presumed tetrahedral carbon of a thermolysin substrate with a silanediol group, resulting in an inhibitor with an inhibition constant K(i) = 40 nM. The structure of the silanediol bound to the active site of thermolysin was found to have a conformation very similar to that of a corresponding phosphonamidate inhibitor (K(i) = 10 nM). In both cases, a single oxygen is within bonding distance to the active-site zinc ion, mimicking the presumed tetrahedral transition state. There are binding differences that appear to be related to the presence or absence of protons on the oxygens attached to the silicon or phosphorus. This is the first crystal structure of an organosilane bound to the active site of a protease.
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PMID:Structural analysis of silanediols as transition-state-analogue inhibitors of the benchmark metalloprotease thermolysin. 1634 43

In this study, the antihypertensive activity in spontaneously hypertensive rats of two peptides isolated from beta-lactoglobulin hydrolysates with thermolysin was evaluated. These peptides, with sequences LLF [beta-lg f(103-105)] and LQKW [beta-lg f(58-61)], showed potent in vitro ACE-inhibitory activity. Two hours after administration, both sequences caused a clear and significant decrease in the blood pressure of these rats. The impact of a simulated gastrointestinal digestion on ACE-inhibitory and antihypertensive activities of these peptides was also studied. The results showed that both fragments were susceptible to proteolytic degradation after incubation with pepsin and Corolase PP. In addition, their in vitro ACE-inhibitory activity decreased after the simulated digestion. It is likely that fragment LQK was the active end product of the gastrointestinal digestion of peptide LQKW. The fragment LL, observed after digestion of peptide LLF, probably exert its antihypertensive effect through a mechanism of action different than ACE-inhibition.
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PMID:Effect of simulated gastrointestinal digestion on the antihypertensive properties of synthetic beta-lactoglobulin peptide sequences. 1746 21

Hydrolysis of flaxseed proteins using thermolysin and pronase followed by mixing with activated carbon, centrifugation and filtration yielded a filtrate (peptide mixture) with a Fischer ratio (branched-chain amino acids/aromatic amino acids) of 23.65 and a phenylalanine + tyrosine content of 1.11%. Gel permeation chromatography showed that the flaxseed peptide sample contained mainly low molecular weight peptides (<4 kDa). The high Fischer ratio peptide sample exhibited antioxidant property by scavenging 2,2-diphenyl-1-picrylhydrazyl radical, superoxide radical, hydroxyl radical, and also by protecting linoleic acid from oxidation. In addition, the peptide mixture showed potential antihypertensive properties by inhibiting angiotensin I-converting enzyme in a mixed-type inhibition pattern. Protein hydrolysates with Fischer ratio higher than 20 and phenylalanine + tyrosine content lower than 2% have been used to treat patients with hepatic encephalopathy; thus, this multifunctional flaxseed peptide mixture could be used to formulate food products with multiple human health benefits during liver diseases, oxidative stress and hypertension.
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PMID:Antioxidant and angiotensin converting enzyme-inhibitory properties of a flaxseed protein-derived high Fischer ratio peptide mixture. 2021 6

In this project we report on the angiotensin I-converting enzyme (ACE)-inhibitory activity of a bovine gelatin hydrolysate (Bh2) that was submitted to further hydrolysis by different enzymes. The thermolysin hydrolysate (Bh2t) showed the highest in vitro ACE inhibitory activity, and interestingly a marked in vivo blood pressure-lowering effect was demonstrated in spontaneously hypertensive rats (SHR). In contrast, Bh2 showed no effect in SHR, confirming the need for the extra thermolysin hydrolysis. Hence, an angiotensin I-evoked contractile response in isolated rat aortic rings was inhibited by Bh2t, but not by Bh2, suggesting ACE inhibition as the underlying antihypertensive mechanism for Bh2t. Using mass spectrometry, seven small peptides, AG, AGP, VGP, PY, QY, DY and IY or LY or HO-PY were identified in Bh2t. As these peptides showed ACE inhibitory activity and were more prominent in Bh2t than in Bh2, the current data provide evidence that these contribute to the antihypertensive effect of Bh2t.
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PMID:Angiotensin I-converting enzyme inhibitory activity of gelatin hydrolysates and identification of bioactive peptides. 2117 70

The blood pressure lowering effect of a pea protein hydrolysate (PPH) that contained <3 kDa peptides, isolated by membrane ultrafiltration from the thermolysin digest of pea protein isolate (PPI), was examined using different rat models of hypertension as well as hypertensive human subjects. The PPH showed weak in vitro activities against renin and angiotensin converting enzyme (ACE) with inhibitory activities of 17 and 19%, respectively, at 1 mg/mL test concentration. Oral administration of the PPH to spontaneously hypertensive rats (SHR) at doses of 100 and 200 mg/kg body weight led to a lowering of hourly systolic blood pressure (SBP), with a maximum reduction of 19 mmHg at 4 h. In contrast, orally administered unhydrolyzed PPI had no blood pressure reducing effect in SHR, suggesting that thermolysin hydrolysis may have been responsible for releasing bioactive peptides from the native protein. Oral administration of the PPH to the Han:SPRD-cy rat (a model of chronic kidney disease) over an 8-week period led to 29 and 25 mmHg reductions in SBP and diastolic blood pressure, respectively. The PPH-fed rats had lower plasma levels of angiotensin II, the major vasopressor involved in development of hypertension, but there was no effect on plasma activity or renal mRNA levels of ACE. However, renal expression of renin mRNA levels was reduced by approximately 50% in the PPH-fed rats, suggesting that reduced renin may be responsible for the reduced levels of angiotensin II. In a 3-week randomized double blind placebo-controlled crossover human intervention trial (7 volunteers), significant (p<0.05) reductions (over placebo) in SBP of 5 and 6 mmHg were obtained in the second and third weeks, respectively, for the PPH group. Therefore, thermolysin derived bioactive peptides from PPH reduced blood pressure in hypertensive rats and human subjects, likely via effects on the renal angiotensin system.
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PMID:Blood pressure lowering effect of a pea protein hydrolysate in hypertensive rats and humans. 2185 68


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