Angiotensin Converting Enzyme (ACE)-Peptide Interactions: Inhibition Kinetics, In Silico Molecular Docking and Stability Study of Three Novel Peptides Generated from Palm Kernel Cake Proteins (original) (raw)
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Food chemistry, 2018
The mechanism of action of food-derived angiotensin-I-converting enzyme (ACE) inhibitory peptides has not been completely elucidated. In the present study, ion-exchange chromatography, gel filtration chromatography, reverse phase-high performance liquid chromatography, and liquid chromatography-electrospray ionization-tandem mass (LC-ESI-MS/MS) were employed for purifying and identifying the ACE inhibitory peptides from hazelnut. To understand the mode of action of these peptides, ACE inhibition kinetics, in vitro and in vivo bioavailability assays, active site analysis, and interaction between the inhibitory peptides and ACE were investigated. The results identified novel ACE inhibitory peptides Ala-Val-Lys-Val-Leu (AVKVL), Tyr-Leu-Val-Arg (YLVR), and Thr-Leu-Val-Gly-Arg (TLVGR) with IC50 values of 73.06, 15.42, and 249.3 μM, respectively. All peptides inhibited the ACE activity via a non-competitive mode. The binding free energies of AVKVL, YLVR, and TLVGR for ACE were -3.46, -6.4...
International Journal of Peptide Research and Therapeutics, 2020
Hypertension is declared as the major risk factor of cardiovascular diseases and stroke, and the leading cause of premature deaths. ACE is a zinc dependent dipeptidyl peptidase and plays key role in controlling blood pressure via renin angiotensin system (RAS), and hence serves as the promising target for antihypertension drugs. Many food derived antihypertensive peptides have been identified recently. However, their ACE inhibitory activity, interactions and stability are not fully evaluated. Our work focused on combination of modern bioinformatics techniques for efficient evaluation of potent ACE inhibitory food peptides and understanding of interactions between ACE and inhibitory peptides. We reported novel antihypertensive peptide IQDVPS, LQPGS, VIP from date, salmon and soybean proteins respectively. Food proteins were digested in-silico to release peptides. Molecular docking studies revealed high binding affinities and interactions with ACE active site. MD simulations and Alanine Scanning were carried out to study the stability of these ACE-peptide complexes in cell like environment. The results showed that the suggested peptides competitively inhibit ACE by tightly binding to its active site, meanwhile maintaining the structural stability of the complex. ACE-LQPGS (Salmon) was found to have best binding with least structural fluctuations.
Scientific Reports
The synthetic Angiotensin Converting Enzyme (ACE) inhibitors have side effects and hence demands for natural ACE inhibitors have been rising. The aim of this study is to purify and introduce natural ACE inhibitors extracted from Zizyphus jujuba fruits. Proteins from Zizyphus jujuba were lysed by trypsin, papain and their combination. Acquired peptides were purified and evaluated for ACE inhibitory activity. Peptide fractions with inhibitory activity were sequenced using tandem mass spectrometry. To elucidate the mode of peptide binding to ACE, homology modeling, molecular docking and molecular dynamics simulation were performed. Amino acid sequence of F2 and F4 peptides, which were the most active hydrolysates, were determined to be IER and IGK with the IC50 values of 0.060 and 0.072 mg/ml, respectively. Results obtained by computational analysis revealed that similar to the common ACE competitive inhibitors such as captopril, IER tripeptide binds to the enzyme active site, in vicin...
Affinity Purification of Angiotensin Converting Enzyme Inhibitory Peptides Using Immobilized ACE
Journal of Agricultural and Food Chemistry, 2006
A lung extract rich in angiotensin converting enzyme (ACE) and pure ACE were immobilized by reaction with the activated support 4 BCL glyoxyl-agarose. These immobilized ACE derivatives were used for purification of ACE inhibitory peptides by affinity chromatography. The immobilized lung extract was used to purify inhibitory peptides from sunflower and rapeseed protein hydrolysates that had been obtained by treatment of protein isolates with alcalase. The ACE binding peptides that were retained by the derivatives were specifically released by treatment with the ACE inhibitor captopril and further purified by reverse-phase C 18 HPLC chromatography. Inhibitory peptides with IC 50 50 and 150 times lower than those of the original sunflower and rapeseed hydrolysates, respectively, were obtained. The derivative prepared using pure ACE was used for purification of ACE inhibitory peptides from the same type of sunflower protein hydrolysate. ACE binding peptides were released from the ACE-agarose derivatives by treatment with 1 M NaCl and had an IC 50 a little higher than those obtained using immobilized extract and elution with captopril. Affinity chromatography facilitated the purification of ACE inhibitory peptides and potentially other bioactive peptides present in food proteins.
Journal of Cereal Science, 2014
The present study was carried out to characterize ACE inhibitory peptides which are released from the trypsin hydrolysate of wheat gluten protein. In silico proteolitic digestion of a high molecular weight glutenin subunit was performed. Among the resultant fragments, four peptides were selected for chemical synthesis based on the chemoinformatics studies and docking properties. The ACE inhibitory activity and kinetic parameters of the most important peptides were determined. Molecular docking simulation was also performed to predict the sites on ACE in which these peptides bind and displayed inhibition mechanisms. Two peptide sequences of IPALLKR (P4) and AQQLAAQLPAMCR (P6) showed higher ACE inhibitory activity among peptide collection. The IC 50 values of P6 and P4 were 43 AE 1.3 mM and 68 AE 2.8 mM, respectively. P6 peptide was proved to be a more potent ACE inhibitor than P4 peptide. Lineweaver-Burk plots revealed that P6 and P4 behaved as non-competitive and competitive ACE inhibitors, respectively. The simulations showed that P4 bound to the active site region. Conversely, P6 bound to the N-terminus entrance of substrate tunnel and obstructed the substrate access into the catalytic site. Overall, the results showed that these peptides would be considered as a model for discovering new bio-compatible ACE inhibitors.
Food chemistry, 2015
An alkaline extracted brewers' spent grain protein-enriched isolate (BSG-PI) was hydrolysed using Alcalase, Corolase PP, Flavourzyme and Promod 144MG, yielding Alc hydrolysate (H), CorH, FlavH and ProH, respectively. The degree of hydrolysis (DH) of the protein hydrolysates varied from 4.45% for ProH to 16.4% for CorH. The in vitro ACE inhibitory activity of the BSG-PI increased significantly following 15min incubations with Alcalase, Corolase PP and Flavourzyme. The 5kDa ultrafiltration permeates of FlavH and CorH resulted in lower ACE IC50 values than their respective hydrolysates. The bioactivity of the BSG-PI hydrolysates was retained after simulated gastrointestinal digestion (SGID) while SGID also resulted in the release of ACE inhibitory peptides from the BSG-PI and ProH. UPLC-MS/MS analysis resulted in the identification of 34 peptides. Of 12 synthesised peptides, IVY and ILDL were the most potent, having ACE IC50 values at 80.4±11.9 and 96.4±8.36μM, respectively.
Current Pharmaceutical Design, 2009
The existence of endogenous bioactive protein or peptide with angiotensin-converting enzyme (ACE) inhibitory activity in snakehead fish fillet is promising to be investigated. The purposes of this research were to extract ACE inhibitory endogenous protein or peptide from snakehead fish fillet and to fractionate the active compounds using ultrafiltration. The extraction employed two solvents, i.e. aquadest and 50% ethanol. Fractionation was conducted using ultrafiltration membranes of 10,000; 5,000 and 3,000 Molecular W eight Cut Off (MW CO) to separate the protein or peptide into the sizes of >10 kDa, 5-10 kDa, 3-5 kDa and <3 kDa. The parameters observed were protein and peptide content, ACE inhibitory activity (in vitro) and also protein and peptide profiles. The result revealed that the snakehead fish fillet contained ACE inhibitory endogenous bioactive protein or peptide. The 50% ethanol was more effective in extracting peptide of <10 kDa than the aquadest. Yet, the aquadest was better in extracting higher molecular weight protein of >10 kDa than the 50% ethanol. The fraction of <3 kDa by aquadest had the highest ACE inhibitor activity per g protein (7.85% inhibition of ACE per g protein). Thus, the fraction of <3 kDa aquadest is the most promising option for further research and development of natural anti-hypertension compound. From the result, snakehead fish fillet was potential to be utilized as a functional food as well as functional ingredient to fight hypertension.
Nutrition Research, 2004
Angiotensin I-converting enzyme (ACE) catalyzes the conversion of angiotensin I to vasoconstrictor angiotensin II, and also inactivates the antihypertensive vasodilator bradykinin. Inhibition of ACE mainly results in an overall antihypertensive effect. Peptides derived from food proteins can have ACE inhibiting properties. This article reviews the ACE inhibitory peptides derived from different food proteins. Some of the ACE inhibitory peptides exhibit significant antihypertensive effects. However, the inhibitory potencies of these peptides on ACE activity do not always correlate with their antihypertensive activities. Some peptides with high inhibitory activity on this enzyme in vitro have no blood pressure lowering effects, whereas some peptides with low inhibitory activity on this enzyme in vitro have such effects. The possible mechanisms for this conflicting phenomenon between inhibitory activity and antihypertensive effect, the structure-activity relationships, and the potential use prospect of these peptides in the development of a novel functional food for preventing hypertension as well as therapeutic purposes, are also discussed.
Stone fish is an under-utilized sea cucumber with many health benefits. Hydrolysates with strong ACE-inhibitory effects were generated from stone fish protein under the optimum conditions of hydrolysis using bromelain and fractionated based on hydrophobicity and isoelectric properties of the constituent peptides. Five novel peptide sequences with molecular weight (mw) < 1000 daltons (Da) were identified using LC-MS/MS. The peptides including ALGPQFY (794.44 Da), KVPPKA (638.88 Da), LAPPTM (628.85 Da), EVLIQ (600.77 Da) and EHPVL (593.74 Da) were evaluated for ACE-inhibitory activity and showed IC50 values of 0.012 mM, 0.980 mM, 1.31 mM, 1.44 mM and 1.68 mM, respectively. The ACE-inhibitory effects of the peptides were further verified using molecular docking study. The docking results demonstrated that the peptides exhibit their effect mainly via hydrogen and electrostatic bond interactions with ACE. These findings provide evidence about stone fish as a valuable source of raw mat...
Process Biochemistry, 2011
Chuan Sheih et al. 2009). ACE plays an important physiological role in regulating blood pressure by converting angiotensin I into angiotensin II, a vasoconstrictor, and degrading bradykinin, a vasodilator. ACE inhibitory peptides can decrease blood pressure by inhibiting ACE and, have been isolated from enzymatic digest of various food materials, including casein, sake, sour milk, fish proteins, and plant proteins (Hernández-Ledesma et al. 2011). ACE inhibitory peptides derived from food proteins are usually purified using several chromatographic steps that include size exclusion, ionic exchange, and RP-HPLC chromatography. Affinity chromatography is a powerful purification method for protein and bioactive peptides. It is based on the use of specific ligands to absorb the desired substances on solid supports and to elute them from the support (Megías et al. 2006). Recently, the purification of ACE inhibitory peptides using ACE immobilized and immobilized metal ion affinity chromatography (IMAC) have been reported (Megías et al. 2009; Lan et al. 2015). The aim of our work was to obtain ACE inhibitory peptides from casein hydrolysate. The affinity purification of ACE inhibitory peptides using IMAC with immobilized Ni 2+ is described and a novel ACE inhibitory peptide was isolated by further HPLC purification. Materials and methods Materials Papain (with a declared activity of 500,000 U/g) was kindly provided by Nanning Pangbo Biological Engineering Co., Ltd. (China). ACE from rabbit lung (2.0 units/mg of protein) and hippuryl-l-histidyl-l-leucine (HHL) were purchased from the Sigma Chemical Company (USA). Casein,