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Preparation and Identification of ACE Inhibitory Peptides from the Marine Macroalga Ulva intestinalis
Open accessAbstract
Angiotensin I-converting enzyme (ACE) inhibitory peptides derived from seaweed represent a potential source of new antihypertensive. The aim of this study was to isolate and purify ACE inhibitory peptides (ACEIPs) from the protein hydrolysate of the marine macroalga Ulva intestinalis. U. intestinalis protein was hydrolyzed by five different proteases (trypsin, pepsin, papain, α-chymotrypsin, alcalase) to prepare peptides; compared with other hydrolysates, the trypsin hydrolysates exhibited the highest ACE inhibitory activity. The hydrolysis conditions were further optimized by response surface methodology (RSM), and the optimum conditions were as follows: pH 8.4, temperature 28.5 °C, enzyme/protein ratio (E/S) 4.0%, substrate concentration 15 mg/mL, and enzymolysis time 5.0 h. After fractionation and purification by ultrafiltration, gel exclusion chromatography and reverse-phase high-performance liquid chromatography, two novel purified ACE inhibitors with IC50 values of 219.35 μM (0.183 mg/mL) and 236.85 μM (0.179 mg/mL) were obtained. The molecular mass and amino acid sequence of the ACE inhibitory peptides were identified as Phe-Gly-Met-Pro-Leu-Asp-Arg (FGMPLDR; MW 834.41 Da) and Met-Glu-Leu-Val-Leu-Arg (MELVLR; MW 759.43 Da) by ultra-performance liquid chromatography-tandem mass spectrometry. A molecular docking study revealed that the ACE inhibitory activities of the peptides were mainly attributable to the hydrogen bond and Zn(II) interactions between the peptides and ACE. The results of this study provide a theoretical basis for the high-valued application of U. intestinalis and the development of food-derived ACE inhibitory peptides.
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“Other promising peptides have been identified from Gracilariopsis lemaneiformis, Mazzaella japonica (Rhodophyta), and Ulva intestinalis (Chlorophyta), each contributing to ACE inhibition and cardiovascular health [58–60].”
From Navigating the potential of algal peptides: health effects, market applications, and scientific challenges (2026) · cites this paper as [60]
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Cites
Fish Protein Hydrolysates: Production, Biochemical, and Functional Properties
Kristinsson, H. G., & Rasco, B. A. (2000) · Critical Reviews in Food Science and Nutrition · doi:10.1080/10408690091189266 · Cited by 1,243 · cited 1×
“Different proteases affect the composition and size of the polypeptides produced, which can affect their biological activities [26].”
BackgroundHypotensive Peptides from Milk Proteins
Fitzgerald, R. J., Murray, B. A., & Walsh, D. J. (2004) · Journal of Nutrition · doi:10.1093/jn/134.4.980s · Cited by 725 · cited 1×
“captopril, and lisinopril, are widely used in hypertension treatments, synthetic ACEIs have a series of negative effects, including hypotension, cough, increased potassium levels and, angioedema [5,6].”
BackgroundBioactive Peptides from Muscle Sources: Meat and Fish
Ryan, J. T., Ross, R., Bolton, D., Fitzgerald, G., & Stanton, C. (2011) · Nutrients · doi:10.3390/nu3090765 · Cited by 493 · cited 2×
“According to previous studies, most ACEIPs are small peptides of 2–12 residues and molecular weights less than 3000 Da [33], which may more easily fit in the ACE active site and thus assert inhibitory activity [34].”
BackgroundLópez‐Fandiño, R., Otte, J., & Camp, J. V. (2006) · International Dairy Journal · doi:10.1016/j.idairyj.2006.06.004 · Cited by 389 · cited 1×
“To date, ACEIPs derived from a variety of products such as milk [7], bovine collagen [8], mushrooms [9], rice [10], and marine sources including fish, shellfish, and macroalgae [11,12], have been reported.”
BackgroundWu, J., & Ding, X. (2002) · Food Research International · doi:10.1016/s0963-9969(01)00131-4 · Cited by 344 · cited 1×
“After gastrointestinal digestion, some food-derived ACEIPs do not exhibit (or exhibit fewer than) the expected hypotensive effects [38,39].”
BackgroundHealth benefits of marine foods and ingredients
Larsen, R., Eilertsen, K., & Elvevoll, E. O. (2011) · Biotechnology Advances · doi:10.1016/j.biotechadv.2011.05.017 · Cited by 302 · cited 1×
“According to previous studies, many unique bioactive compounds, including peptides, fats, and carbohydrates, have been isolated from macroalgae [13,14].”
BackgroundSheih, I.-C., Fang, T. J., & Wu, T.-K. (2009) · Food Chemistry · doi:10.1016/j.foodchem.2008.12.019 · Cited by 280 · cited 1×
“Proteases are necessary to release ACEIPs from inactive forms [25].”
BackgroundSuetsuna, K., Maekawa, K., & Chen, J.-R. (2004) · The Journal of Nutritional Biochemistry · doi:10.1016/j.jnutbio.2003.11.004 · Cited by 249 · cited 1×
“5 μM), and Tyr-Asn-Lys-Leu (IC50 = 21 μM) from Undaria pinnatifida [15] and Ile-Tyr (IC50 = 2.”
Wang, J., Hu, J., Cui, J., Bai, X., Du, Y., Miyaguchi, Y., & Lin, B. (2008) · Food Chemistry · doi:10.1016/j.foodchem.2008.03.059 · Cited by 212 · cited 1×
“Hypertension seriously affects human health and is a causative factor of cardiovascular diseases, stroke, and renal diseases, among others [1,2].”
BackgroundWu, Q., Jia, J., Yan, H. H., Du, J., & Gui, Z. (2014) · Peptides · doi:10.1016/j.peptides.2014.07.026 · Cited by 193
Cited by
Sorted by citations
Seaweeds as a Source of Functional Proteins
Thiviya, P., Gamage, A., Gama-Arachchige, N. S., Merah, O., & Madhujith, T. (2022) · Phycology · doi:10.3390/phycology2020012 · Cited by 179
Seaweed Protein Hydrolysates and Bioactive Peptides: Extraction, Purification, and Applications
Echave, J., Fraga‐Corral, M., García-Pérez, P., Popović‐Djordjević, J. B., Avdović, E., Radulović, M. Đ., Xiao, J., Prieto, M. A., & Simal‐Gándara, J. (2021) · Marine Drugs · doi:10.3390/md19090500 · Cited by 154
“5 ◦C FGMPLDR, MELVLR ACE inhibition [84]”
Etemadian, Y., Ghaemi, V., Shaviklo, A. R., Pourashouri, P., Mahoonak, A. S., & Rafipour, F. (2020) · Journal of Cleaner Production · doi:10.1016/j.jclepro.2020.123219 · Cited by 148
Seaweed-Derived Proteins and Peptides: Promising Marine Bioactives
Echave, J., Otero, P., Garcia‐Oliveira, P., Munekata, P. E. S., Pateiro, M., Lorenzo, J. M., Simal‐Gándara, J., & Prieto, M. A. (2022) · Antioxidants · doi:10.3390/antiox11010176 · Cited by 143
“Again, trypsin produced the extract with the highest ACE inhibitory activity, and two peptides were indicated as the most active (FGMPLDR and MELVLR) [53].”
BackgroundInfluentialCermeño, M., Kleekayai, T., Amigo‐Benavent, M., Harnedy‐Rothwell, P. A., & Fitzgerald, R. J. (2020) · Electrophoresis · doi:10.1002/elps.202000153 · Cited by 139
Metadata
- Authors
- Sun, S., Xu, X., Sun, X., Zhang, X., Chen, X., & Xu, N.
- Affiliations
- Ningbo University (CN)
- Vanderbilt University Medical Center (US)
- Corresponding author
- Xu, Nianjun
- Venue
- Marine Drugs
- Publisher
- MDPI AG
- Published
- 2019-03-19
- Volume
- 17
- Issue
- 3
- Pages
- 179
- ISSN
- 1660-3397 (ISSN-L)
- PMC
- PMC6471128
- OpenAlex
- W2922600776
- Cited by
- 140
- References
- 50
- Citations by year
- 2026: 9 · 2025: 21 · 2024: 29 · 2023: 22 · 2022: 27 · 2021: 15 · 2020: 14 · 2019: 3
- FWCI
- 4.88
- Type
- journal article
- Language
- en
- Open access
- gold
- dx.doi.org
- Licence
- Locations
- Marine Drugs (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Discover Archive (Vanderbilt University) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- Natural Science Foundation of Zhejiang Province (LZ17D060001)
- Ningbo International Cooperation Program (2017D10019)
- Ningbo Municipal Bureau of Science and Technology (2016C10034)
- Topics
- Life Sciences › Agricultural and Biological Sciences › Food Science › Protein Hydrolysis and Bioactive Peptides
- Life Sciences › Agricultural and Biological Sciences › Aquatic Science › Seaweed-derived Bioactive Compounds
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Peptidase Inhibition and Analysis
- Keywords
- ACE inhibitory peptides, Ulva intestinalis, seaweed, protein hydrolysates, trypsin hydrolysis, enzymatic hydrolysis optimization, peptide purification, antihypertensive peptides, food-derived bioactive peptides, zinc binding
- MeSH terms
- Angiotensin-Converting Enzyme Inhibitors, Antihypertensive Agents, Drug Stability, Hydrolysis, Hypertension, Peptidyl-Dipeptidase A, Peptide Hydrolases, Peptides, Protein Hydrolysates, Seaweed, Inhibitory Concentration 50, Ulva, Enzyme Assays, Molecular Docking Simulation
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