| | Soybean bioactive peptides: A new horizon in preventing chronic diseasesSoybeans, an excellent source of dietary peptides, have antihypertensive, anticholesterol, and antioxidant activities, and appear to prevent cancer. The processing of soy protein into peptides in the GI tract greatly increases their healthful effects by exposing active groups within the amino acid chain. Lunasin, one of the most promising of these peptides, has been shown in recent studies to be an effective anti-cancer agent. Found in a variety of readily available foods, lunasin is an accessible component to healthy living.
▪Dietary bioactive peptides are short amino acid chains produced by digestion or processing of proteins.
▪Bioactive soy peptides possess antioxidant, antihypertensive and anticancer properties.
▪Soy is an important source of bioactive peptides.
▪Fermented and hydrolyzed soy products, such as yogurt and cheese, are a good source of peptides.
▪Dietary peptides can be absorbed by the body.
▪The unique soy peptide lunasin may be beneficial in cancer prevention.
The bioactive peptides produced by soybeans possess diverse and unique health benefits. These can be effective in the prevention of age-related chronic disorders, such as cardiovascular disease, cancer, obesity, and decreased immune function. Bioactive peptides are released from dietary proteins by either gastrointestinal digestion or by the processing of foods. Evidence also suggests that these peptides can be absorbed by the gastrointestinal system, thus exerting their action on specific target organs. The purpose of this review is to summarize the most recent evidence concerning the possible benefits of soybean peptides, particularly the peptide lunasin, in cancer prevention. Research and clinical trials have demonstrated the biological activities of peptides, but their mechanism of action requires further investigation. It is also important to discover new peptides with health benefits in soy-hydrolyzates and fermented foods. The identification of novel bioactive compounds will contribute towards the development of functional foods that can be used to enhance health and quality of life.
Nutritional importance of soybean  Soybeans, a common source of bioactive peptides, contain about 40% protein and are used in foods, livestock feed, and oil production, and are the source of other healthcare products, such as sterols and vitamin E. The major soy proteins are known as β-conglycinin and glycinin, which account for 65%–80% of total soy proteins. Because soy protein contains all the amino acids that are essential to human nutrition, it is a great substitute for animal protein. The use of soy in human nutrition has increased significantly. There are numerous products on the market which are based on soy or contain soy ingredients. Protein products for food uses include defatted flakes, grits and flour, protein concentrate, protein isolate, and textured protein products. Soybeans can also be used to produce whole bean products (sprout, milk, sauce, tofu, miso, and others). Epidemiological studies suggest that populations consuming high levels of soybean products have both lower incidences of cancer and lower mortality rates for the major cancer types commonly found in the Western hemisphere.1 Thus, as the main components of soybean, soy proteins are receiving increased attention with respect to their health effects. Bowman Birk inhibitor (BBI), a soy protein component, has been shown to suppress carcinogenesis in human prostate cancer cells and has also been the subject of promising clinical trials in cancer patients.2, 3 The low incidence of hypercholesterolemia, heart disease, and cancer in certain Asian populations has also been associated with a high consumption of soy protein.4 By hydrolyzing soy protein isolates, bioactive peptides may be formed that are related to a lower incidence of cancer.5 Dietary bioactive peptides Dietary peptides are protein fragments or short amino acid chains produced by enzymatic digestion in the gut or by the processing of food via fermentation and hydrolysis. Food-derived bioactive peptides from dietary proteins commonly contain 2–9 amino acids.6 However, this range may be extended to 20 or more amino acid units.6 It is known that during gastrointestinal digestion or food processing, these peptides are released from the parent protein and act as regulatory compounds with hormone-like activities.7 Numerous peptides with various bioactive functions have been identified in soy. These include primarily antihypertensive, anticholesterol, antioxidant and cancer prevention peptides, among other newer functions being discovered. In a database named Biopep, more than 1500 different bioactive peptides have been presented.8 Among them, angiotensin converting enzyme (ACE) inhibitors and dipeptidyl peptidase IV inhibitors, which show antihypertensive activity, are the most common. Peptides with other biological activities, such as opioid agonistic and antagonistic, antioxidative, anticancer and immunomodulatory actions have also been identified. Fermentation is considered to be an efficient way to produce bioactive peptides. Bioactive peptides can be released by the microbial activity of fermented food or through enzymes derived from microorganisms.7 Fermented soy milk and cheese have been extensively studied to investigate their potential to form bioactive peptides. Interest in fermented soybean products—such as natto, tempeh, soy sauce, soy paste—has grown in recent years. Table 1 presents soy protein hydrolysates that yield either antioxidant peptides,9 peptides with anticancer properties10 or with hypotensive activity.11 Immunomodulatory peptides derived from tryptic hydrolysates of soybean proteins act to stimulate superoxide anions, which trigger nonspecific immune defense systems.12 Biological activities of soybean peptides Antihypertensive Antihypertensive peptides are the most commonly occurring bioactive peptides in foods. They show their activity by inhibiting angiotensin-converting enzyme. ACE is a nonspecific dipeptidyl carboxypeptidase associated with the regulation of blood pressure by modulating the rennin-angiotensin system. This enzyme converts the decapeptide angiotensin I into the potent vasoconstricting octapeptide angiotensin II, which leads to an increase in blood pressure. Therefore, inhibition of the ACE will result in an antihypertensive effect.13 Several ACE inhibitory bioactive peptides have been found in enzyme hydrolyzates of soy proteins. The peptide fractions given orally to spontaneously hypertensive rats (SHR) at a level of 2.0 g/kg body weight markedly lowered their blood pressure. Antihypertensive peptides were also found in soybean alcalase digest.11 Oral doses of these peptides significantly (P < 0.05) decreased systolic blood pressure of SHR in a dose-dependent manner. However, the peptides had little effect on blood pressure of normotensive rats even at highest dose (1000 mg/kg of body weight/day). Fermented soybean products are a good source of ACE inhibitory bioactive peptides. ACE inhibitory peptides have also been found in many traditional Asian fermented soy foods, such as soybean paste (His-His-Leu),14 soy sauce,15 natto and tempeh.16 Korhonen and Pihlanto7 discuss in their review an antihypertensive peptide from chunggugjang, a traditional fermented Korean soybean product. Hypocholesterolemic The beneficial effects of soybean on cardiovascular diseases were first considered because of its positive impact on blood cholesterol levels. A large body of literature indicates that soy proteins can reduce blood cholesterol concentrations in humans.17 Sagara et al found that dietary intakes of soy protein (at least 20 g) and isoflavones (at least 80 mg) for 5 weeks would be effective in reducing CHD risk among high-risk, middle-aged men.18 Soy protein is known to exert hypocholesterolemic effects when ingested, prompting the Food and Drug Administration to approve a health claim linking foods that are naturally rich in soy protein to a reduction in coronary heart disease.19 Wang et al also showed that soy protein reduces circulating triglycerides and cholesterol in hypercholesterolemic individuals.20 Soy protein can also shift LDL particle distribution to a less atherogenic pattern in an isoflavone independent manner.21 Soy protein (with or without isoflavone) significantly decreased the cholesterol levels in LDL < 25.5 nM by 12.3% (P < 0.001) and increased cholesterol levels in LDL > 26.0 nM by 14.3% (P < 0.05) and therefore shifting LDL particle distribution to a less atherogenic pattern. One hypothesis is that soy proteins might bind with bile acids inhibiting their re-absorption and therefore lowering blood cholesterol level. However, another option could be that soy peptides may lower the endogenous production of cholesterol in the liver and thus decrease serum cholesterol levels. Some researchers have postulated that in humans, soy protein may in some way up-regulate LDL receptors depressed by hypercholesterolemia or by dietary cholesterol administration.22 In most clinical trials, soy proteins have been given to human subjects by oral administration. Thus, these proteins have been subjected to protease digestion in the GI tract, releasing the bioactive peptides, which then may lower cholesterol levels. Based on these observations, it is likely that soy peptides may be responsible, at least in part, for the hypocholesterolemic benefits of soy protein. Soy peptides have been found to bind phospholipids and exert serum cholesterol lowering activity in humans.23 Antioxidant Several amino acids, such as Tyr, Met, His, Lys, and Trp, are generally accepted to be antioxidants. Saito et al constructed two series of tripeptide libraries to explore antioxidative properties of peptides; one was composed of 108 peptides containing either two His or Tyr residues and the other 114 peptides structurally related to Pro-His-His.24 The antioxidative activities of the tripeptide libraries were examined by several methods, including the antioxidative activity against the peroxidation of linoleic acid, the reducing activity, the radical scavenging activity, and the peroxynitrite scavenging activity. Tripeptides containing Trp or Tyr residues at the C-terminus had strong radical scavenging activities, but very weak peroxynitrite scavenging activity. The results explained why protein digests have such a variety of antioxidative properties. They also found that the antioxidative peptides may exert strong synergistic effects with some other antioxidants, such as phenolic compounds. During hydrolysis, the soy protein structure will be altered and more active amino acid R groups will be exposed. Therefore, soybean peptides can have higher antioxidant activity than intact protein.25 After enzyme digestion of β-conglycinin and glycinin, the radical-scavenging activities were increased 3–5 times. Heating did not change the activity of the proteins, indicating that forming peptides was more critical than maintaining protein structure.26 When comparing the antioxidant capacity of 28 structurally related peptides to Leu-Leu-Pro-His-His, isolated from soybean protein digests, Pro-His-His was identified as an active center. It was believed that His-containing peptides can act as metal-ion chelators, active-oxygen quenchers, and hydroxy-radical scavengers, and can contribute to the antioxidant activity of peptides.27 Different hydrolysis conditions (enzyme, temperature, sample preparation) resulted in peptide mixtures with different antioxidant properties. Native and heated soy protein isolate hydrolyzed with different enzymes resulted in different degrees of hydrolysis ranging from 1.7%–20.6% with antioxidant activity ranging from 28% to 65%.28 Liu et al demonstrated that soymilk-kefir possesses significant antimutagenic and antioxidant activity and suggested that fermented soymilk may be considered among the more promising food components in terms of preventing mutagenic and oxidative damage.29 The demonstration that peptides produced during fermentation may play an important role in this biological activity warrants further research. It has also been observed that the radical scavenging ability of soy peptides plays an important role in the suppression of lipid oxidation in a preparation of encapsulated lipids.30 The data available strongly suggest that bioactive peptides from soy protein have a clear anti-oxidant capacity. Anticancer The evidence of an effect of soy peptides on oncogenesis is preliminary;31 however, the newly discovered peptide lunasin has shown promise as an anticancer agent. Other soy peptides with anticancer properties include Kunitz trypsin inhibitor, a peptide that was reported to suppress ovarian cancer cell invasion by blocking urokinase upregulation.32 Another study showed that a soy protein isolate diet may inhibit tumorgenesis by enhancing somatostatin: a known anti-proliferative agent for colon cancer cells.33 It is possible that part of these anticancer activities may be attributed to bioactive peptides derived from soy proteins. In support of this hypothesis, it has been found, both in vitro and in experimental animals, that hydrophobic peptides from soy proteins may have anticancer activity. For example, peptides obtained by thermolase hydrolysis of defatted soy protein, further purified with ethanol and fractionated by gel filtration chromatography, showed an IC50 value of 0.16 mg/mL in vitro cytotoxicity on mouse monocyte macrophage cell line. At 1 mg/mL, this fraction significantly affected cell cycle progression by arresting the cells in G2/M phases. Further purification with C18 HPLC resulted in 1157 Da nonapeptide (X-Met-Leu-Pro-Ser-Tyr-Ser-Pro-Tyr).34 Lunasin: A promising cancer preventive soy peptide Lunasin™, a 43-amino acid peptide naturally present in soy protein, has been found to suppress transformation of mammalian cells induced by carcinogens and viral oncogenes E1A and RAS.35, 36, 37, 38, 39 In the first animal model, lunasin, applied topically, reduces skin tumor formation in mice.37 This novel peptide can be found in amounts ranging from 0.10 to 1.33 g/100 g flour in different soybean varieties and in commonly available soy proteins.34 Interestingly, lunasin has also been found in barley.40 Lunasin is found in the 2S soybean albumin fraction. Structurally, it contains a carboxyl end of nine aspartic acids residues, preceded by a cell adhesion motif (RGD), and a predicted helical region that has structural homology to chromatin binding proteins.35, 36, 37 Lunasin has been shown to inhibit core histone acetylation, by binding to non-acetylated H3 and H4 histones,37 an epigenetic mechanism believed to be responsible for the anti-carcinogenic property of this chromatin-binding peptide. A mechanism is proposed whereby lunasin selectively kills cells being transformed or newly transformed by binding to deacetylated core histones exposed by the transformation event, disrupting the dynamics of histone acetylation-deacetylation and leading to cell death.38 Pilot studies show that lunasin is bioavailable in mice and rats when orally ingested, evidently protected from digestion by naturally occurring protease inhibitors in soy. This opens the way for dietary administration in cancer prevention studies. Conclusion Soy is an important source of bioactive peptides. Several potential bioactive peptides have been identified which include subunits of glycinin and β-conglycinin, as well as in Kunitz and Bowman-Birk inhibitors. The profile of peptides in soy protein demonstrates amino acid sequences with antihypertensive, anticholesterolemic, antioxidant and cancer preventive properties. Antihypertensive activity is the most common effect. A better understanding of how these bioactive peptides work and how they are regulated will be helpful. Understanding whether natural in vivo digestion of food proteins release the same peptide fragments as the ones in vitro experiments also is important. How we can manage to generate the desired bioactive peptides in the GI tract while preventing damage to the desired peptides from digestion constitutes a principal question. Improvements in peptides purification, identification and synthesis techniques are always significant. Large-scale bioactive peptides production is still a challenge. New peptide sequences may also be generated during fermentation. The discovery of the cancer preventive lunasin peptide suggests that soybean and other legumes will play a role in chronic disease prevention. Although there is still much to learn about the effects of lunasin on cancer risk, this area of research holds considerable potential. Future clinical studies will clarify the physiological importance of soy peptides and their role in preventing chronic diseases. References 1.
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a Department of Food Science and Human Nutrition, University of Illinois, Urbana, IL b Department of Nutritional Sciences and Toxicology, University of California, Berkeley, CA  Department of Food Science and Human Nutrition, 228 ERML, 1201 W. Gregory Drive, University of Illinois, Urbana, IL 61801
Department of Nutritional Sciences and Toxicology, 231 Morgan Hall, University of California, Berkeley, CA 94720-3104 PII: S1546-2501(06)00031-4 doi:10.1016/j.sram.2006.08.012 © 2006 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved. | |
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