Skip to main content
Springer Nature Link
Log in

Bioactive peptides encrypted in milk proteins: proteolytic activation and thropho-functional properties

  • Published:
Antonie van Leeuwenhoek Aims and scope Submit manuscript

Abstract

The bioactivities of peptides encrypted in major milk proteins are latent until released and activated by enzymatic proteolysis, e.g. during gastrointestinal digestion or food processing. The proteolytic system of lactic acid bacteria can contribute to the liberation of bioactive peptides. In vitro, the purified cell wall proteinase of Lactococcus lactis was shown to liberate oligopeptides from β- and α-caseins which contain amino acid sequences present in casomorphins, casokinines, and immunopeptides. The further degradation of these peptides by endopeptidases and exopeptidases of lactic acid bacteria could lead to the liberation of bioactive peptides in fermented milk products. However, the sequences of practically all known biologically active peptides can also be cleaved by peptidases from lactic acid bacteria. Activated peptides are potential modulators of various regulatory processes in the body: Opioid peptides are opioid receptor ligands which can modulate ab sorption processes in the intestinal tract, angiotensin-I-converting enzyme (ACE)-inhibitory peptides are hemodynamic regulators and exert an antihypertensive effect, immunomodulating casein peptides stimulate the activities of cells of the immune system, antimicrobial peptides kill sensitive microorganisms, antithrombotic peptides inhibit aggregation of platelets and caseinophosphopeptides may function as carriers for different minerals, especially calcium. Bioactive peptides can interact with target sites at the luminal side of the intestinal tract. Furthermore, they can be absorbed and then reach peripheral organs. Food-derived bioactive peptides are claimed to be health enhancing components which can be used for functional food and pharmaceutical preparations.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Ariyoshi Y (1993) Angiotensin-converting enzyme inhibitors derived from food proteins. Trends Food Sci. Technol. 4: 139-144

    Google Scholar 

  • Bellamy W, Takase M, Yamauchi K, Kawase K, Shimamura S & Tomita M (1992) Identification of the bactericidial domain of lactoferrin. Biochim. Biophys. Acta 1121: 130-136

    Google Scholar 

  • Bellamy W, Wakabayashi H, Takase M, Kawase K, Shimamura S & Tomota M (1993) Role of cell-binding in the antibacterial mechanism of lactoferricin B. J. Appl. Bacteriol. 75: 478-484

    Google Scholar 

  • Bockelmann W (1995) The proteolytic system of starter and nonstarter bacteria: components and their importance for cheese ripening. Int. Dairy J. 5: 977-994

    Google Scholar 

  • Bockelmann W, Fobker M. & Teuber M (1991) Purification and characterization of the X-prolyl-dipeptidyl-aminopeptidase from Lactobacillus delbrueckii subsp. bulgaricus and Lactobacillus acidophilus. Int. Dairy J. 1: 51-66

    Google Scholar 

  • Bouhallab S, Mollé D & Léonil J (1992) Tryptic hydrolysis of case-inomacropeptide in membrane reactor: preparation of bioactive peptides. Biotechnol. Lett. 14: 805-810

    Google Scholar 

  • Brandsch M, Brust P, Neubert K & Ermisch A (1994). β-Casomorphins — chemical signals of intestinal transport systems. In: Brantl V & Teschemacher H (Eds) β-Casomorphins and Related Peptides: Recent Developments (pp 207-219). VCH, Weinheim

    Google Scholar 

  • Brantl V, Teschemacher H, Bläsig J, Henschen A & Lottspeich F (1981) Opioid activities of β-casomorphins. Life Sci. 28: 1903-1909

    Google Scholar 

  • Bruneval P, Hinglais N & Alhenc-Gelas F (1986) Angiotensin I converting enzyme in human intestine and kidney. Ultrastructural immunohistochemical localization. Histochemistry 86: 73-80

    Google Scholar 

  • Chiba H, Tani F & Yoshikawa M (1989) Opioid antagonist peptides derived from κ-casein. J. Dairy Res. 56: 363-366

    Google Scholar 

  • Chiba H & Yoshikawa M (1986) Biologically functional peptides from food proteins: New opioid peptides from milk proteins. In: Feeney RE & Whitaker JR (Eds) Protein Tailoring for Food and Medical Uses (pp 123-153). Marcel Dekker Inc., New York

    Google Scholar 

  • Daniel H, Vohwinkel M & Rehner G (1990a) Effect of casein and β-Casomorphins on gastrointestinal motility in rats. J. Nutr. 120: 252-257

    Google Scholar 

  • Daniel H, Wessendorf A, Vohwinkel M & Brantl V (1990b) Effect of D-Ala2,4Tyr5-β-casomorphin-5-amide on gastrointestinal functions. In: Nyberg F & Brantl V (Eds) β-Casomorphins and Related Peptides (pp 95-104). Fyris-Tryck AB, Uppsala

    Google Scholar 

  • Dionysius DA & Milne JM (1998) Antibacterial peptides of bovine lactoferrin: purification and characterizaton. J. Dairy Sci. 80: 667-674

    Google Scholar 

  • Elitsur Y & Luk GD (1991) β-casomorphin (BCM) and human colonic lamina propria lymphocyte proliferation. Clin. Experiment. Immunol. 85: 493-497

    Google Scholar 

  • Fiat AM & Jollès P (1989) Caseins of various origins and biologically active casein peptides and oligosaccharides: structural and physiological aspects. Mol. Cell. Biochem. 87: 5-30

    Google Scholar 

  • FitzGerald RJ (1998) Potential uses of caseinophosphopeptides. Int. Dairy J. 8: 451-457

    Google Scholar 

  • FitzGerald RJ & Meisel H (1999) Lactokinins: Whey Protein-derived ACE Inhibitory Peptides. Nahrung/Food 431: 165-167

    Google Scholar 

  • Fukudome S-I & Yoshikawa M (1994) Isolation and characterizaton of opioid peptides derived from wheat gluten. In: V. Brantl & H. Teschemacher (Eds) β-Casomorphins and related peptides: recent developments (pp 27-33). VCH, Weinheim

    Google Scholar 

  • Hadden JW (1991) Immunotherapy of human immunodeficiency virus infection. Trends Pharmaceutical Sci. 12: 107-111

    Google Scholar 

  • Hamel U, Kielwein G & Teschemacher H (1985) β-casomorphin immunoreactive materials in cow's milk incubated with various bacterial species. J. Dairy Res. 52: 139-148

    Google Scholar 

  • Hansen M, Sandstöm B, Jensen M & Sörensen SS (1997) Casein phosphopeptides improve zinc and calcium absorption from rice-based but not from whole grain infant cereal. J. Pediatr. Gastroenterol. Nutr. 24: 56-62

    Google Scholar 

  • Johnston CI (1992) Renin-angiotensin system: a dual tissue and hormonal system for cardiovascular control. J. Hypertension 10: S13-S26

    Google Scholar 

  • Jollès P, Lévy-Toledano S, Fiat AM, Soria C, Gillessen D, Thomaidis A, Dunn FW & Caen JB (1986) Analogy between fibrinogen and casein. Eur. J. Biochem. 158: 379-384

    Google Scholar 

  • Juillard V, Laan H, Kunji ERS, Jeronimus-Stratingh CM, Bruins AP & Konings WN (1995) The extracellular PI-type proteinase of Lactococcus lactis hydrolyzes β-casein into more than one hundred different oligopeptides. J. Bacteriol. 177: 3472-3478

    Google Scholar 

  • Kasai T, Honda T & Kiriyama S (1992) Caseinophosphopeptides (CPP) in feces of rats fed casein diet. Biosci. Biotechnol. Biochem. 56: 1150-1151

    Google Scholar 

  • Kayser H & Meisel H (1996) Stimulation of human peripheral blood lymphocytes by bioactive peptides derived from bovine milk proteins. FEES Lett. 383: 18-20

    Google Scholar 

  • Kitts DD & Yuan YV (1992) Caseinophosphopeptides and calcium bioavailability. Trends in Food Sci. & Technol. 3: 31-35

    Google Scholar 

  • Konings WN, Lolkema JS, Bolhuis H, van Veen HW, Poolman B. & Driessen AJM (1997) The role of transport processes in survival of lactic acid bacteria. Antonie van Leeuwenhoek 71: 117-128

    Google Scholar 

  • Kunji ERS, Mierau I, Hagting A, Poolman B & Konings WN (1996) The proteolytic systems of lactic acid bacteria. Antonie van Leeuwenhoek 70: 187-221

    Google Scholar 

  • Lahov E & Regelson W (1996) Antibacterial and immunostimulating casein-derived substances from milk: casesidin isracidin peptides. Fd. Chem. Toxic. 34: 131-145

    Google Scholar 

  • Law J & Haandrikman A (1997) Proteolytic enzymes of lactic acid bacteria. Int. Dairy J. 7: 1-11

    Google Scholar 

  • Loukas S, Varoucha D, Zioudrou C, Streaty RA & Klee WA (1983) Opioid activities and structures of α-casein-dervied exorphins. Biochemistry 22: 4567-4573

    Google Scholar 

  • Maeno M, Yamamoto Y & Takano T (1998) Identification of an antihypertensive peptide from casein hydrolysate produced by a proteinase from Lactobacillus helveticus CP790. J. Dairy Sci. 79: 1316-1321

    Google Scholar 

  • McDonagh D & FitzGerald RJ (1998) Production of caseinophosphopeptides (CPPs) from sodium caseinate using a range of commercial protease preparations. Int. Dairy J. 8: 39-45

    Google Scholar 

  • Meisel H (1986) Chemical characterization and opioid activity of an exorphin isolated from in vivo digests of casein. FEBS Lett. 196: 223-227

    Google Scholar 

  • Meisel H (1993) Casokinins as inhibitors of Angiotensin-Converting-Enzyme. In: Sawatzki G & Renner B (Eds) New Perspectives in Infant Nutrition (pp 153-159). Thieme, Stuttgart, New York

    Google Scholar 

  • Meisel H (1997a) Biochemical properties of bioactive peptides derived from milk proteins: potential nutraceuticals for food and pharmacological applications. Liv. Prod. Sci. 50: 125-138

    Google Scholar 

  • Meisel H (1997b) Biochemical properties of regulatory peptides derived from milk proteins. Biopoly. 43: 119-128

    Google Scholar 

  • Meisel H (1998) Overview on milk protein-derived peptides. Int. Dairy J. 8: 363-373

    Google Scholar 

  • Meisel H & Frister H (1988) Chemical characterization of a case-inophosphopeptide isolated from in vivo digests of a casein diet. Biol. Chem. Hoppe-Seyler 369: 1275-1279

    Google Scholar 

  • Meisel H & Frister H (1989) Chemical characterization of bioactive peptides from in vivo digests of casein. J. Dairy Res. 56: 343-349

    Google Scholar 

  • Meisel H & Schlimme E (1994) Inhibitors of Angiotensin-Converting-Enzyme derived from bovine Casein (Casokinins). In: Brantl V & Teschemacher H (Eds) β-Casomorphins and related peptides: recent developments (pp 27-33). VCH, Weinheim

    Google Scholar 

  • Meisel H & Schlimme E (1996) Bioactive peptides derived from milk proteins: Ingredients for functional foods? Kieler Milchwirtschaftl. Forschungsber. 48: 343-357

    Google Scholar 

  • Meisel H, Goepfert A & Günther S (1997) Occurence of ACE inhibitory peptides in milk products. Milchwissenschaft 52 307-311

    Google Scholar 

  • Mierau I, Kunji ERS, Venema G & Kok J (1997) Casein and peptide degradation in lactic acid bacteria. Biotech. Genetic Engineering Rev. 14: 279-301

    Google Scholar 

  • Migliore-Samour D, Floc'h F & Jollès P. (1989) Biologically active casein peptides implicated in immunomodulation. J. Dairy Res. 56: 357-362

    Google Scholar 

  • Monnet V, Bockelmann W, Gripon JC & Teuber M (1989) Comparison of cell wall proteinases from Lactococcus lactis subsp. cremoris AC1 and Lactococcus lactis subsp. lactis NCDO 763. II. specificity towards bovine b-casein. Appl. Microbiol. Biotechnol. 31: 112-118

    Google Scholar 

  • Monnet V, Chapot-Chartier MP & Gripon JC (1993) Lactococcal peptidases. Lait 73: 97-108

    Google Scholar 

  • Muehlenkamp MR & Warthesen JJ (1996) β-Casomorphins: analysis in cheese and susceptibility to proteolytic enzymes from Lactobacillus lactis ssp. cremoris. J. Dairy Sci. 79: 20-26

    Google Scholar 

  • Mullally MM Meisel H & FitzGerald RJ (1996) Synthetic peptides corresponding to α-lactalbumin and β-lactoglobulin sequences with angiotensin-I-converting enzyme inhibitory activity. Biol. Chem. Hoppe-Seyler 377: 259-260

    Google Scholar 

  • Mullally MM, Meisel H & FitzGerald RJ (1997) Identification of novel angiotensin-I-converting enzyme inhibitory peptide corresponding to a tryptic fragment of β-lactoglobulin. FEBS Lett. 402: 99-101

    Google Scholar 

  • Nakamura Y, Yamamoto N, Sakai K, Okubo A, Yamazaki S & Takano T (1995) Purification and characterization of angiotensin I-converting enzyme inhibitors from a sour milk. J. Dairy Sci. 78: 777-783

    Google Scholar 

  • Ondetti MA & Cushman DW (1982) Enzymes of the renin-angiotensin system and their inhibitors. Ann. Rev. Biochem. 51: 283-308

    Google Scholar 

  • Pelissier JP (1984) Proteolysis of caseins. Sciences des Aliments 4: 1-35

    Google Scholar 

  • Pihlanto-Leppälä A, Rokka T & Korhonen H (1998) Angiotensin I converting enzyme inhibitory peptides from bovine milk proteins. Int. Dairy J. 8: 325-331

    Google Scholar 

  • Poolman B, Kunji, ERS, Hagting A, Juillard V & Konings WN (1995) The proteolytic pathway of Lactococcus lactis. J. Appl. Bacteriol. Symp. Supp. 79: 65S-75S

    Google Scholar 

  • Pritchard GG & Coolbear T (1993) The physiology and biochemistry of the proteolytic system in lactic acid bacteria. FEMS Microbiol. Rev. 12: 179-206

    Google Scholar 

  • Reynolds E (1987) Phosphopeptides. PCT Int. Patent Application WO 87/07615 Al

  • Reid JR, Coolbear T, Pillidge CJ & Pritchard GG (1994) Specificity of hydrolysis of bovine κ-casein by cell envelope-associated proteinases from Lactococcus lactis strains. Appl. Environ. Microbiol. 60: 801-806

    Google Scholar 

  • Reid JR, Moore CH, Midwinter GG & Pritchard GG (1991) Action of cell wall proteinase from Lactococcus lactis subsp. cremoris SK11 on bovine α S1-casein. Appl. Microbiol. Biotechnol. 35: 222-227

    Google Scholar 

  • Sato R, Naguchi T & Naito H (1986) Casein phosphopeptide (CPP) enhance calcium absorption from the ligated segment of rat small intestine. J. Nutri. Sci. Vitaminol. 32: 67-76

    Google Scholar 

  • Schanbacher FL, Talhouk RS & Murray FA (1997) Biology and origin of bioactive peptides in milk. Liv. Prod. Sci. 50: 105-123

    Google Scholar 

  • Shimizu M (1999) Modulation of intestinal functions by food substances. Nahrung/Food 143: 154-158

    Google Scholar 

  • Suetsuna K & Osajima K (1989) Blood pressure reduction and vasodilatory effects in vivo of peptides originating from sardine muscle (in Japan). J. Jp. Soc. Nutr. Food Sci. 42: 47-54

    Google Scholar 

  • Svedberg J, de Haas J, Leimenstoll G, Paul F & Teschemacher H (1985) Demonstration of β-casomorphin immunoreactive materials in in vitro digests of bovine milk and in small intestine contents after bovine milk ingestion in adult humans. Peptides 6: 825-830

    Google Scholar 

  • Teschemacher H & Brantl V (1994) Milk protein derived atypical opioid peptides and related compounds with opioid antagonist activity. In: Brantl V & Teschemacher H (Eds) β-Casomorphins and Related Peptides: Recent Developments (pp 3-17). VCH, Weinheim

    Google Scholar 

  • Teschemacher H, Umbach M, Hamel U, Praetorius K, Ahnert-Hilger G, Brantl V, Lottspeich F & Henschen A (1986) No evidence for the presence of β-casomorphins in human plasma after ingestion of cows' milk or milk products. J. Dairy Res. 53: 135-138

    Google Scholar 

  • Teschemacher H, Koch G & Brantl V (1997) Milk protein-derived opioid receptor ligands. Biopoly. 43: 99-117

    Google Scholar 

  • Tomé D, Dumontier AM, Hautefeuille M & Desjeux JF (1987) Opiate activity and transepithelial passage of intact β-casomorphins in rabbit ileum. Am. J. Physiol. 253: G737-G744

    Google Scholar 

  • Tomita M, Bellamy W, Takase M, Yamauchi K, Wakabayashi H & Kawase K (1991) Potent antibacterial peptides generated by pepsin digestion of bovine lactoferrin. J. Dairy Sci. 74: 4137-4142

    Google Scholar 

  • Tomita M, Takase M, Bellamy W & Shimamura S (1994) A review: the active peptide of lactoferrin. Acta Pediatr. Jpn. 36: 585-591

    Google Scholar 

  • Umbach M, Teschemacher H, Praetorius K, Hirschhäuser R & Bostedt H (1985) Demonstration of a β-casomorphin immunoreactive material in the plasma of newborn calves after milk intake. Regulatory Peptides 12: 223-230

    Google Scholar 

  • Visser S, Slangen J, Exterkate FA & de Veer GJCM (1988) Action of a cell wall proteinase (PI) from streptococcus cremoris HP on bovine β-casein. Appl. Microbiol. Biotechnol. 29: 61-66

    Google Scholar 

  • Yamamoto N (1997) Antihypertensive peptides derived from food proteins. Biopoly. 43: 129-134

    Google Scholar 

  • Yamamoto N, Akino A & Takano T (1994) Antihypertensive effect of the peptides derived from casein by an extracellular proteinase from Lactobacillus helveticus CP790. J. Dairy Sci. 77: 917-922

    Google Scholar 

  • Yoshikawa M, Tani F & Chiba H (1988) Structure-activity relationship of opioid antagonist peptides derived from milk proteins. In: Shiba T (Ed) Peptide Chemistry (pp 473-476). Protein Research Foundation, Osaka

    Google Scholar 

  • Zucht HD, Raida M, Andermann K, Mägert H-J & Forssman WG (1995) Casocidin-I: a casein-α S2 derived peptide exhibits antibacterial activity. FEBS Lett. 372 185-188

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Federal Dairy Research Centre, Switzerland

    Hans Meisel & Wilhelm Bockelmann

  2. Institute for Chemistry and Physics, Germany

    Hans Meisel

  3. Institute for Microbiology, P.O. Box 6069, D-24121, Kiel, Germany

    Wilhelm Bockelmann

Authors
  1. Hans Meisel
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Wilhelm Bockelmann
    View author publications

    You can also search for this author inPubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Meisel, H., Bockelmann, W. Bioactive peptides encrypted in milk proteins: proteolytic activation and thropho-functional properties. Antonie Van Leeuwenhoek 76, 207–215 (1999). https://doi.org/10.1023/A:1002063805780

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1002063805780