Skip to main content

Advertisement

SpringerLink
Log in

Proteolytic Systems in Milk: Perspectives on the Evolutionary Function within the Mammary Gland and the Infant

  • Published:
Journal of Mammary Gland Biology and Neoplasia Aims and scope Submit manuscript

Abstract

Milk contains elements of numerous proteolytic systems (zymogens, active proteases, protease inhibitors and protease activators) produced in part from blood, in part by mammary epithelial cells and in part by immune cell secretion. Researchers have examined milk proteases for decades, as they can cause major defects in milk quality and cheese production. Most previous research has examined these proteases with the aim to eliminate or control their actions. However, our recent peptidomics research demonstrates that these milk proteases produce specific peptides in healthy milk and continue to function within the infant’s gastrointestinal tract. These findings suggest that milk proteases have an evolutionary function in aiding the infant’s digestion or releasing functional peptides. In other words, the mother provides the infant with not only dietary proteins but also the means to digest them. However, proteolysis in the milk is controlled by a balance of protease inhibitors and protease activators so that only a small portion of milk proteins are digested within the mammary gland. This regulation presents a question: If proteolysis is beneficial to the infant, what benefits are gained by preventing complete proteolysis through the presence of protease inhibitors? In addition to summarizing what is known about milk proteolytic systems, we explore possible evolutionary explanations for this proteolytic balance.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Abbreviations

MEC:

Mammary epithelial cell

References

  1. Oftedal OT. The mammary gland and its origin during synapsid evolution. J Mammary Gland Biol Neoplasia. 2002;7(3):225–52.

    Article  PubMed  Google Scholar 

  2. Lefèvre CM, Sharp JA, Nicholas KR. Evolution of lactation: ancient origin and extreme adaptations of the lactation system. Annu Rev Genomics Hum Genet. 2010;11(1):219–38. doi:10.1146/annurev-genom-082509-141806.

    Article  PubMed  CAS  Google Scholar 

  3. Kelly AL, O’Flaherty F, Fox PF. Indigenous proteolytic enzymes in milk: a brief overview of the present state of knowledge. Int Dairy J. 2006;16(6):563–72. doi:10.1016/j.idairyj.2005.10.019.

    Article  CAS  Google Scholar 

  4. Ismail B, Nielsen S. Invited review: plasmin protease in milk: current knowledge and relevance to dairy industry. J Dairy Sci. 2010;93(11):4999–5009.

    Article  CAS  PubMed  Google Scholar 

  5. Barbano D, Rasmussen R, Lynch J. Influence of milk somatic cell count and milk age on cheese yield. J Dairy Sci. 1991;74(2):369–88.

    Article  Google Scholar 

  6. Datta N, Deeth H. Age gelation of UHT milk—a review. Food Bioprod Process. 2001;79(4):197–210.

    Article  Google Scholar 

  7. Farkye N, Landkammer CF. Milk plasmin activity influence on cheddar cheese quality during ripening. J Food Sci. 1992;57(3):622–39.

    Article  CAS  Google Scholar 

  8. Holton TA, Vijaykumar V, Dallas DC, et al. Following the digestion of milk proteins from mother to baby. J Proteome Res. 2014;13(12):5777–83.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  9. Dallas DC, Guerrero A, Khaldi N, et al. A peptidomic analysis of human milk digestion in the infant stomach reveals protein-specific degradation patterns. J Nutr. 2014;144(6):815–20. doi:10.3945/jn.113.185793.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  10. Dallas DC, Underwood MA, Zivkovic AM, German JB. Digestion of protein in premature and term infants. J Nutr Disord Ther. 2012;2(3):112–21.

    Article  PubMed Central  PubMed  Google Scholar 

  11. Palmer DJ, Kelly VC, Smit AM, Kuy S, Knight CG, Cooper GJ. Human colostrum: identification of minor proteins in the aqueous phase by proteomics. Proteomics. 2006;6(7):2208–16.

    Article  CAS  PubMed  Google Scholar 

  12. Borulf S, Lindberg T, Mansson M. Immunoreactive anionic trypsin and anionic elastase in human milk. Acta Paediatr. 1987;76(1):11–5.

    Article  CAS  Google Scholar 

  13. Molinari CE, Casadio YS, Hartmann BT, et al. Proteome mapping of human skim milk proteins in term and preterm milk. J Proteome Res. 2012;11(3):1696–714.

    Article  CAS  PubMed  Google Scholar 

  14. Lemay DG, Ballard OA, Hughes MA, Morrow AL, Horseman ND, Nommsen-Rivers LA. RNA sequencing of the human milk fat layer transcriptome reveals distinct gene expression profiles at three stages of lactation. PLoS One. 2013;8(7):e67531.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  15. Korycha-Dahl M, Dumas BR, Chene N, Martal J. Plasmin activity in milk. J Dairy Sci. 1983;66(4):704–11.

    Article  Google Scholar 

  16. Fox P. Proteinases in dairy technology. Neth Milk Dairy J. 1981;35:233.

    CAS  Google Scholar 

  17. D’Alessandro A, Zolla L, Scaloni A. The bovine milk proteome: cherishing, nourishing and fostering molecular complexity. An interactomics and functional overview. Mol BioSyst. 2011;7(3):579–97.

    Article  PubMed  Google Scholar 

  18. Magboul AA, Larsen LB, McSweeney PL, Kelly AL. Cysteine protease activity in bovine milk. Int Dairy J. 2001;11(11):865–72.

    Article  CAS  Google Scholar 

  19. Heegaard CW, Rasmussen LK, Andreasen PA. The plasminogen activation system in bovine milk: differential localization of tissue-type plasminogen activator and urokinase in milk fractions is caused by binding to casein and urokinase receptor. Biochim Biophys Acta. 1994;1222(1):45–55. doi:10.1016/0167-4889(94)90023-X.

    Article  CAS  PubMed  Google Scholar 

  20. Wickramasinghe S, Rincon G, Islas-Trejo A, Medrano JF. Transcriptional profiling of bovine milk using RNA sequencing. BMC Genomics. 2012;13(1):45–58. doi:10.1186/1471-2164-13-45.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  21. Heegaard CW, Larsen LB, Rasmussen LK, Højberg KE, Petersen TE, Andreasen PA. Plasminogen activation system in human milk. J Pediatr Gastroenterol Nutr. 1997;25(2):159–66.

    Article  CAS  PubMed  Google Scholar 

  22. Lindberg T, Ohlsson K, Westrom B. Protease inhibitors and their relation to protease activity in human milk. Pediatr Res. 1982;16(6):479–83.

    Article  CAS  PubMed  Google Scholar 

  23. Lindberg T. Protease inhibitors in human-milk. Pediatr Res. 1979;13(9):969–72.

    Article  CAS  PubMed  Google Scholar 

  24. McGilligan KM, Thomas DW, Eckhert CD. Alpha-1-antitrypsin concentration in human milk. Pediatr Res. 1987;22(3):268–70.

    Article  CAS  PubMed  Google Scholar 

  25. Dallas D, Guerrero A, Khaldi N, et al. Extensive in vivo human milk peptidomics reveals specific proteolysis yielding protective antimicrobial peptides. J Proteome Res. 2013;12(5):2295–304. doi:10.1021/pr400212z.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  26. Dallas DC, Weinborn V, de Moura Bell JM, et al. Comprehensive peptidomic and glycomic evaluation reveals that sweet whey permeate from colostrum is a source of milk protein-derived peptides and oligosaccharides. Food Res Int. 2014;63(B):203–9. doi:10.1016/j.foodres.2014.03.021.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  27. Guerrero A, Dallas DC, Contreras S, et al. Peptidomic analysis of healthy and subclinically mastitic bovine milk. Int Dairy J. 2014. doi:10.1016/j.idairyj.2014.09.006.

    Google Scholar 

  28. Guerrero A, Dallas DC, Contreras S, et al. Mechanistic peptidomics: factors that dictate the specificity on the formation of endogenous peptides in human milk. Mol Cell Proteomics. 2014;13(12):3343–51. doi:10.1074/mcp.M113.036194.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Dallas DC, Smink CJ, Robinson RC, et al. Endogenous human milk peptide release is greater following preterm birth than term birth. J Nutr. 2015;145(3):425–33.

    Article  CAS  PubMed  Google Scholar 

  30. Khaldi N, Vijayakumar V, Dallas DC, et al. Predicting the important enzyme players in human breast milk digestion. J Agric Food Chem. 2014;62(29):7225–32. doi:10.1021/jf405601e.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  31. Dallas D, Guerrero A, Parker E, et al. Peptidomic profile of milk of Holstein cows at peak lactation. J Agric Food Chem. 2013;62(1):58–65.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  32. Christensen B, Schack L, Kläning E, Sørensen ES. Osteopontin is cleaved at multiple sites close to its integrin-binding motifs in milk and is a novel substrate for plasmin and cathepsin D. J Biol Chem. 2010;285(11):7929–37.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  33. Ferranti P, Traisci MV, Picariello G, et al. Casein proteolysis in human milk: tracing the pattern of casein breakdown and the formation of potential bioactive peptides. J Dairy Res. 2004;71(1):74–87. doi:10.1017/s0022029903006599.

    Article  CAS  PubMed  Google Scholar 

  34. Grufferty MB, Fox PF. Milk alkaline proteinase. J Dairy Res. 1988;55(04):609–30.

    Article  CAS  PubMed  Google Scholar 

  35. Bastian ED, Brown RJ. Plasmin in milk and dairy products: an update. Int Dairy J. 1996;6(5):435–57.

    Article  CAS  Google Scholar 

  36. Okamoto U, Horie N, Nagamatsu Y, Yamamoto J. Plasminogen-activator in human early milk: its partial purification and characterization. Thromb Haemost-Stuttgart. 1981;45(2):121–6.

    CAS  Google Scholar 

  37. Precetti AS, Oria MP, Nielsen SS. Presence in bovine milk of two protease inhibitors of the plasmin system. J Dairy Sci. 1997;80(8):1490–6. doi:10.3168/jds.S0022-0302(97)76077-6.

    Article  CAS  PubMed  Google Scholar 

  38. Uniprot. P34955- A1AT_BOVIN. 2014.

  39. D’Alessandro A, Scaloni A, Zolla L. Human milk proteins: an interactomics and updated functional overview. J Proteome Res. 2010;9(7):3339–73.

    Article  PubMed  CAS  Google Scholar 

  40. Uniprot. Q9N2I2- IPSP_BOVIN. 2014.

  41. Christensen S, Wiegers T, Hermansen J, Sottrup-Jensen L. Plasma-derived protease inhibitors in bovine milk. Int Dairy J. 1995;5(5):439–49. doi:10.1016/0958-6946(95)00020-4.

    Article  CAS  Google Scholar 

  42. Uniprot. Q9TTE1- SPA31_BOVIN. Uniprot, 2014.

  43. Benslimane S, Dognin-Bergeret MJ, Berdague J-L, Gaudemer Y. Variation with season and lactation of plasmin and plasminogen concentrations in Montbeliard cows’ milk. J Dairy Res. 1990;57(04):423–35.

    Article  CAS  Google Scholar 

  44. Politis I. Plasminogen activator system: Implications for mammary cell growth and involution. J Dairy Sci. 1996;79(6):1097–107. doi:10.3168/jds.S0022-0302(96)76463-9.

    Article  CAS  PubMed  Google Scholar 

  45. Eigel W, Hofmann C, Chibber B, Tomich J, Keenan T, Mertz E. Plasmin-mediated proteolysis of casein in bovine milk. Proc Natl Acad Sci. 1979;76(5):2244–8.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  46. Politis I, White JH, Zavizion B, Goldberg JJ, Guo MR, Kindstedt P. Effect of individual caseins on plasminogen activation by bovine urokinase-type and tissue-type plasminogen activators. J Dairy Sci. 1995;78(3):484–90. doi:10.3168/jds.S0022-0302(95)76658-9.

    Article  CAS  PubMed  Google Scholar 

  47. Markus G, Hitt S, Harvey S, Tritsch G. Casein, a powerful enhancer of the rate of plasminogen activation. Fibrinolysis. 1993;7(4):229–36.

    Article  CAS  Google Scholar 

  48. White JH, Zavizion B, O’Hare K, et al. Distribution of plasminogen activator in different fractions of bovine milk. J Dairy Res. 1995;62:115.

    Article  CAS  PubMed  Google Scholar 

  49. Politis I, Voudouri A, Bizelis I, Zervas G. The effect of various vitamin E derivatives on the urokinase-plasminogen activator system of ovine macrophages and neutrophils. Br J Nutr. 2003;89(02):259–65.

    Article  CAS  PubMed  Google Scholar 

  50. Politis I, Zavizion B, Cheli F, Baldi A. Expression of urokinase plasminogen activator receptor in resting and activated bovine neutrophils. J Dairy Res. 2002;69(02):195–204.

    Article  CAS  PubMed  Google Scholar 

  51. Vĕtvicka V, Vagner J, Baudys M, Tang J, Foundling S, Fusek M. Human breast milk contains procathepsin D--detection by specific antibodies. Biochem Mol Biol Int. 1993;30(5):921–8.

    PubMed  Google Scholar 

  52. Bergmann M, Fruton JS. Regarding the general nature of catheptic enzymes. Science. 1936;84(2169):89–90.

    Article  CAS  PubMed  Google Scholar 

  53. Lkhider M, Castino R, Bouguyon E, Isidoro C, Ollivier-Bousquet M. Cathepsin D released by lactating rat mammary epithelial cells is involved in prolactin cleavage under physiological conditions. J Cell Sci. 2004;117(21):5155–64. doi:10.1242/jcs.01396.

    Article  CAS  PubMed  Google Scholar 

  54. Benes P, Vetvicka V, Fusek M. Cathepsin D—many functions of one aspartic protease. Crit Rev Oncol Hematol. 2008;68(1):12–28. doi:10.1016/j.critrevonc.2008.02.008.

    Article  PubMed Central  PubMed  Google Scholar 

  55. Kaminogawa S, Yamauchi K. Acid protease of bovine milk. Agric Biol Chem. 1972;36(13):2351–6.

    Article  CAS  Google Scholar 

  56. Larsen LB, Petersen TE. Identification of five molecular forms of cathepsin D in bovine milk. In: Takahashi K, editor. Aspartic proteinases. Berlin: Springer; 1995. p. 279–83.

    Chapter  Google Scholar 

  57. Larsen LB, Boisen A, Petersen TE. Procathepsin D cannot autoactivate to cathepsin D at acid pH. FEBS Lett. 1993;319(1):54–8.

    Article  CAS  PubMed  Google Scholar 

  58. Wittlin S, Rösel J, Hofmann F, Stover DR. Mechanisms and kinetics of procathepsin D activation. Eur J Biochem. 1999;265(1):384–93.

    Article  CAS  PubMed  Google Scholar 

  59. O’Driscoll B, Rattray F, McSweeney P, Kelly A. Protease activities in raw milk determined using a synthetic heptapeptide substrate. J Food Sci. 1999;64(4):606–11.

    Article  Google Scholar 

  60. Capony F, Rougeot C, Montcourrier P, Cavailles V, Salazar G, Rochefort H. Increased secretion, altered processing, and glycosylation of pro-cathepsin D in human mammary cancer cells. Cancer Res. 1989;49(14):3904–9.

    CAS  PubMed  Google Scholar 

  61. Hasilik A. Theearly andlate processing of lysosomal enzymes: proteolysis and compartmentation. Experientia. 1992;48(2):130–51.

    Article  CAS  PubMed  Google Scholar 

  62. Hurley MJ, Larsen LB, Kelly AL, McSweeney PLH. The milk acid proteinase cathepsin D: a review. Int Dairy J. 2000;10:673–81.

    Article  CAS  Google Scholar 

  63. Considine T, Healy A, Kelly A, McSweeney P. Hydrolysis of bovine caseins by cathepsin B, a cysteine proteinase indigenous to milk. Int Dairy J. 2004;14(2):117–24.

    Article  CAS  Google Scholar 

  64. Kirschke H, Barrett AJ, Rawlings ND. Lysosomal cysteine proteases. Oxford: Oxford University Press; 1998.

    Google Scholar 

  65. Prin-Mathieu C, Le Roux Y, Faure G, Laurent F, Béné M, Moussaoui F. Enzymatic activities of bovine peripheral blood leukocytes and milk polymorphonuclear neutrophils during intramammary inflammation caused by lipopolysaccharide. Clin Diagn Lab Immunol. 2002;9(4):812–7.

    PubMed Central  CAS  PubMed  Google Scholar 

  66. Lewis UJ, Williams DE, Brink NG. Pancreatic elastase: purification, properties, and function. J Biol Chem. 1956;222(2):705–20.

    CAS  PubMed  Google Scholar 

  67. Naughton M, Sanger F. Purification and specificity of pancreatic elastase. Biochem J. 1961;78(1):156–63.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  68. Jochum M, Bittner A. Inter-alpha-trypsin inhibitor of human serum: an inhibitor of polymorphonuclear granulocyte elastase. Hoppe Seylers Z Physiol Chem. 1983;364(12):1709–15.

    Article  CAS  PubMed  Google Scholar 

  69. Travis J, Fritz H. Potential problems in designing elastase inhibitors for therapy. Am Rev Respir Dis. 1991;143(6):1412–5. doi:10.1164/ajrccm/143.6.1412.

    Article  CAS  PubMed  Google Scholar 

  70. Li N, Richoux R, Boutinaud M, Martin P, Gagnaire V. Role of somatic cells on dairy processes and products: a review. Dairy Sci Technol. 2014;94(6):517–38. doi:10.1007/s13594-014-0176-3.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  71. Monti J, Mermoud A-F, Jolles P. Trypsin in human milk. Experientia. 1986;42(1):39–41.

    Article  CAS  PubMed  Google Scholar 

  72. Engel A, Alexander B, Pechet L. Activation of trypsinogen and plasminogen by thrombin preparations. Biochemistry. 1966;5(5):1543–51.

    Article  CAS  PubMed  Google Scholar 

  73. Yamashina I. The action of enterokinase on trypsinogen. Biochim Biophys Acta. 1956;20:433–4.

    Article  CAS  PubMed  Google Scholar 

  74. Hadorn B, Steiner N, Sumida C, Peters T. Intestinal enterokinase: mechanisms of its secretion into the lumen of the small intestine. Lancet. 1971;297(7691):165–6.

    Article  Google Scholar 

  75. Christensen S, Sottrup-Jensen L. Characterization of two serpins from bovine plasma and milk. Biochem J. 1994;303:383–90.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  76. Gettins PGW. Serpin structure, mechanism, and function. Chem Rev. 2002;102(12):4751–804.

    Article  CAS  PubMed  Google Scholar 

  77. Kalsheker N. Alpha 1-antitrypsin: structure, function and molecular biology of the gene. Biosci Rep. 1989;9(2):129–38.

    Article  CAS  PubMed  Google Scholar 

  78. Heyndrickx G. Further investigations on the enzymes in human milk. Pediatrics. 1963;31(6):1019–23.

    CAS  PubMed  Google Scholar 

  79. Wilcox PE. Chymotrypsinogens—chymotrypsins. In: Gertrude E, Perlmann LL, editors. Methods Enzymol. Academic; 1970. p. 64–108.

  80. Uruena C, Telleria JJ, Blanco-Quiros A, Arranz E, Gomez-Carrasco JA. Alpha-1 antichymotrypsin levels are actively increased in normal colostrum. J Pediatr Gastroenterol Nutr. 1998;26(4):376–9.

    Article  CAS  PubMed  Google Scholar 

  81. Beatty K, Bieth J, Travis J. Kinetics of association of serine proteinases with native and oxidized alpha-1-proteinase inhibitor and alpha-1-antichymotrypsin. J Biol Chem. 1980;255(9):3931–4.

    CAS  PubMed  Google Scholar 

  82. Schapira M, Scott CF, Colman RW. Contribution of plasma protease inhibitors to the inactivation of kallikrein in plasma. J Clin Invest. 1982;69(2):462–8.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  83. Zhao L, Morser J, Bajzar L, Nesheim M, Nagashima M. Identification and characterization of two thrombin-activatable fibrinolysis inhibitor isoforms. Thromb Haemost-Stuttgart. 1998;80:949–55.

    CAS  Google Scholar 

  84. Cheung P, Sawicki G, Gross S, Van Aerde J, Radomski M. Differential expression of matrix metalloproteinases and the tissue inhibitor in human milk. Proc West Pharmacol Soc: West Pharmacol Soc 2001;97–8.

  85. Lubetzky R, Mandel D, Mimouni FB, Herman L, Reich R, Reif S. MMP-2 and MMP-9 and their tissue inhibitor in preterm human milk. J Pediatr Gastroenterol Nutr. 2010;51(2):210–2.

    Article  CAS  PubMed  Google Scholar 

  86. Picariello G, Ferranti P, Mamone G, et al. Gel-free shotgun proteomic analysis of human milk. J Chromatogr A. 2012;1227:219–33. doi:10.1016/j.chroma.2012.01.014.

    Article  CAS  PubMed  Google Scholar 

  87. Folley SJ. Biochemical aspects of mammary gland function. Biol Rev. 1949;24(3):316–54. doi:10.1111/j.1469-185X.1949.tb00579.x.

    Article  CAS  PubMed  Google Scholar 

  88. Burgoyne RD, Duncan JS. Secretion of milk proteins. J Mammary Gland Biol Neoplasia. 1998;3(3):275–86. doi:10.1023/a:1018763427108.

    Article  CAS  PubMed  Google Scholar 

  89. Stelwagen K. Mammary gland, milk biosynthesis and secretion | milk protein. In: Fuquay JW, editor. Encyclopedia of Dairy Sciences (Second Edition). San Diego: Academic; 2011. p. 359–66.

    Chapter  Google Scholar 

  90. Mostov KE, Kraehenbuhl JP, Blobel G. Receptor-mediated transcellular transport of immunoglobulin: synthesis of secretory component as multiple and larger transmembrane forms. Proc Natl Acad Sci. 1980;77(12):7257–61.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  91. Seddiki T, Delpal S, Ollivier-Bousquet M. Endocytosis and intracellular transport of transferrin across the lactating rabbit mammary epithelial cell. J Histochem Cytochem. 1992;40(10):1501–10.

    Article  CAS  PubMed  Google Scholar 

  92. Hassiotou F, Geddes DT, Hartmann PE. Cells in human milk: state of the science. J Hum Lact. 2013;29(2):171–82. doi:10.1177/0890334413477242.

    Article  PubMed  Google Scholar 

  93. Manjarin R, Bequette BJ, Wu G, Trottier NL. Linking our understanding of mammary gland metabolism to amino acid nutrition. Amino Acids. 2014;46(11):2447–62. doi:10.1007/s00726-014-1818-8.

    Article  CAS  PubMed  Google Scholar 

  94. Larson BL. Biosynthesis and secretion of milk proteins - review. J Dairy Res. 1979;46(2):161–74.

    Article  CAS  PubMed  Google Scholar 

  95. Lemay DG, Hovey RC, Hartono SR, et al. Sequencing the transcriptome of milk production: milk trumps mammary tissue. BMC Genomics. 2013;14(872):1–17. doi:10.1186/1471-2164-14-872.

    Google Scholar 

  96. Ollivier-Bousquet M. Transferrin and prolactin transcytosis in the lactating mammary epithelial cell. J Mammary Gland Biol Neoplasia. 1998;3(3):303–13.

    Article  CAS  PubMed  Google Scholar 

  97. Field CJ. The immunological components of human milk and their effect on immune development in infants. J Nutr. 2005;135(1):1–4.

    CAS  PubMed  Google Scholar 

  98. Silanikove N, Merin U, Leitner G. Physiological role of indigenous milk enzymes: an overview of an evolving picture. Int Dairy J. 2006;16(6):533–45.

    Article  CAS  Google Scholar 

  99. Somers JS, O’Brien B, Meaney WJ, Kelly AL. Heterogeneity of proteolytic enzyme activities in milk samples of different somatic cell count. J Dairy Res. 2003;70:45–50.

    Article  CAS  PubMed  Google Scholar 

  100. Owen CA, Campbell EJ. The cell biology of leukocyte-mediated proteolysis. J Leukoc Biol. 1999;65(2):137–50.

    CAS  PubMed  Google Scholar 

  101. Heegaard CW, Christensen T, Rasmussen MD, et al. Plasminogen activators in bovine milk during mastitis, an inflammatory disease. Fibrinolysis. 1994;8(1):22–30.

    Article  CAS  Google Scholar 

  102. Politis I, Ng Kwai Hang K, Giroux R. Environmental factors affecting plasmin activity in milk. J Dairy Sci. 1989;72(7):1713–8.

    Article  CAS  PubMed  Google Scholar 

  103. Mason S. Some aspects of gastric function in the newborn. Arch Dis Child. 1962;37(194):387–91.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  104. Neu J. Gastrointestinal maturation and implications for infant feeding. Early Hum Dev. 2007;83(12):767–75.

    Article  CAS  PubMed  Google Scholar 

  105. Britton J, Koldovsky O. Development of luminal protein digestion: implications for biologically active dietary polypeptides. J Pediatr Gastroenterol Nutr. 1989;9(2):144–62.

    Article  CAS  PubMed  Google Scholar 

  106. Hadorn B. Development aspects of intraluminal protein digestion. In: Lebenthal E, editor. Textbook of gastroenterology and nutrition in infancy. New York: Raven; 1981. p. 365–73.

    Google Scholar 

  107. Antonowicz I, Lebenthal E. Developmental pattern of small intestinal enterokinase and disaccharidase activities in the human fetus. Gastroenterology. 1977;72(6):1299.

    CAS  PubMed  Google Scholar 

  108. Lebenthal E, Lee P. Development of functional response in human exocrine pancreas. Pediatrics. 1980;66(4):556–60.

    CAS  PubMed  Google Scholar 

  109. Chowanadisai W, Lonnerdal B. Alpha-1-antitrypsin and antichymotrypsin in human milk: origin, concentrations, and stability. Am J Clin Nutr. 2002;76(4):828–33.

    CAS  PubMed  Google Scholar 

  110. Keller J, Layer P. Human pancreatic exocrine response to nutrients in health and disease. Gut. 2005;54 suppl 6:1–28. doi:10.1136/gut.2005.065946.

    Article  PubMed Central  CAS  Google Scholar 

  111. Kinouchi T, Koyama S, Harada E, Yajima T. Large molecule protein feeding during the suckling period is required for the development of pancreatic digestive functions in rats. Am J Physiol Regul Integr Comp Physiol. 2012;303(12):R1268–76. doi:10.1152/ajpregu.00064.2012.

    Article  CAS  PubMed  Google Scholar 

  112. Davila A-M, Blachier F, Gotteland M, et al. Intestinal luminal nitrogen metabolism: role of the gut microbiota and consequences for the host. Pharmacol Res. 2013;68(1):95–107. doi:10.1016/j.phrs.2012.11.005.

    Article  CAS  PubMed  Google Scholar 

  113. Rist VTS, Weiss E, Eklund M, Mosenthin R. Impact of dietary protein on microbiota composition and activity in the gastrointestinal tract of piglets in relation to gut health: a review. Animal. 2013;7(07):1067–78. doi:10.1017/S1751731113000062.

    Article  CAS  PubMed  Google Scholar 

  114. Macfarlane S, Macfarlane GT. Proteolysis and amino acid fermentation. In: Gibson GR, Macfarlane GT, editors. Human colonic bacteria--role in nutrition, physiology and pathology. CRC Press Inc.; 1995. p. 75–100.

  115. Macfarlane GT, Macfarlane S. Human colonic microbiota: ecology, physiology and metabolic potential of intestinal bacteria. Scand J Gastroenterol Suppl. 1997;32(222):3–9.

    CAS  Google Scholar 

  116. Hughes R, Kurth MJ, McGilligan V, McGlynn H, Rowland I. Effect of colonic bacterial metabolites on Caco-2 cell paracellular permeability in vitro. Nutr Cancer. 2008;60(2):259–66. doi:10.1080/01635580701649644.

    Article  CAS  PubMed  Google Scholar 

  117. McCall IC, Betanzos A, Weber DA, Nava P, Miller GW, Parkos CA. Effects of phenol on barrier function of a human intestinal epithelial cell line correlate with altered tight junction protein localization. Toxicol Appl Pharmacol. 2009;241(1):61–70. doi:10.1016/j.taap.2009.08.002.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  118. Toden S, Bird AR, Topping DL, Conlon MA. Differential effects of dietary whey, casein and soya on colonic DNA damage and large bowel SCFA in rats fed diets low and high in resistant starch. Br J Nutr. 2007;97(3):535–43. doi:10.1017/s0007114507336817.

    Article  CAS  PubMed  Google Scholar 

  119. Windey K, De Preter V, Verbeke K. Relevance of protein fermentation to gut health. Mol Nutr Food Res. 2012;56(1):184–96. doi:10.1002/mnfr.201100542.

    Article  CAS  PubMed  Google Scholar 

  120. Hamer HM, De Preter V, Windey K, Verbeke K. Functional analysis of colonic bacterial metabolism: relevant to health? Am J Physiol Gastrointestinal Liver Physiol. 2012;302(1):G1–9.

    Article  CAS  Google Scholar 

  121. Attene-Ramos MS, Wagner ED, Plewa MJ, Gaskins HR. Evidence that hydrogen sulfide is a genotoxic agent. Mol Cancer Res. 2006;4(1):9–14. doi:10.1158/1541-7786.mcr-05-0126.

    Article  CAS  PubMed  Google Scholar 

  122. Pedersen G, Brynskov J, Saermark T. Phenol toxicity and conjugation in human colonic epithelial cells. Scand J Gastroenterol. 2002;37(1):74–9.

    Article  CAS  PubMed  Google Scholar 

  123. Khalkhali-Ellis Z, Goossens W, Margaryan NV, Hendrix MJC. Cleavage of histone 3 by cathepsin D in the involuting mammary gland. PLoS One. 2014;9(7):1–9.

    Article  CAS  Google Scholar 

  124. Hurley WL, Theil PK. Perspectives on immunoglobulins in colostrum and milk. Nutrients. 2011;3(4):442–74.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  125. Armaforte E, Curran E, Huppertz T, et al. Proteins and proteolysis in pre-term and term human milk and possible implications for infant formulae. Int Dairy J. 2010;20(10):715–23.

    Article  CAS  Google Scholar 

  126. Greenberg R, Groves ML, Dower HJ. Human beta-casein - amino acid sequence and identification of phosphorylation sites. J Biol Chem. 1984;259(8):5132–8.

    CAS  PubMed  Google Scholar 

  127. Nguyen D-AD, Neville MC. Tight junction regulation in the mammary gland. J Mammary Gland Biol Neoplasia. 1998;3(3):233–46.

    Article  CAS  PubMed  Google Scholar 

  128. Anderson G. The effect of prematurity on milk composition and its physiological basis. Fed Proc. 1984;43(9):2438–42.

    CAS  PubMed  Google Scholar 

  129. Borgström B, Lindquist B, Lundh G. Enzyme concentration and absorption of protein and glucose in duodenum of premature infants. Am J Dis Child. 1960;99(3):338–43.

    Google Scholar 

  130. Engberg S, Mansson M, Andersson Y, Jakobsson I, Lindberg T. Trypsin and elastase activity in duodenal juice from preterm infants before and after a meal of human milk. Prenat Neonatal Med. 1999;4(6):466–71.

    CAS  Google Scholar 

  131. Arslanoglu S, Moro GE, Ziegler EE. Optimization of human milk fortification for preterm infants: new concepts and recommendations. J Perinat Med. 2010;38:233–8.

    CAS  PubMed  Google Scholar 

  132. Beck S, Wojdyla D, Say L, et al. The worldwide incidence of preterm birth: a systematic review of maternal mortality and morbidity. Bull World Health Organ. 2010;88(1):31–8.

    Article  PubMed Central  PubMed  Google Scholar 

  133. Mansor R, Mullen W, Albalat A, et al. A peptidomic approach to biomarker discovery for bovine mastitis. J Proteomics. 2013;85:89–98.

    Article  CAS  PubMed  Google Scholar 

  134. Saeman AI, Verdi R, Galton D, Barbano D. Effect of mastitis on proteolytic activity in bovine milk. J Dairy Sci. 1988;71(2):505–12.

    Article  CAS  PubMed  Google Scholar 

  135. Kirschke H, Barrett A, Glaumann H, Ballard F. Lysosomes: their role in protein breakdown. London: Academic; 1987.

    Google Scholar 

  136. Larsen LB, Rasmussen MD, Bjerring M, Nielsen JH. Proteases and protein degradation in milk from cows infected with Streptococcus uberis. Int Dairy J. 2004;14(10):899–907.

    Article  CAS  Google Scholar 

  137. Kaartinen L, Sandholm M. Regulation of plasmin activation in mastitic milk: correlation with inflammatory markers and growth of Streptococcus agalactiae. J Vet Med B Infect Dis Vet Public Health. 1987;34(1–10):42–50.

    Article  CAS  Google Scholar 

  138. Fang W, Sandholm M. Inhibition of the proteinase activity in mastitic milk. J Dairy Res. 1995;62(01):61–8.

    Article  CAS  PubMed  Google Scholar 

  139. Hogan J, Smith KL. Coliform mastitis. Vet Res. 2003;34(5):507–19.

    Article  PubMed  Google Scholar 

  140. Fleminger G, Heftsi R, Uzi M, Nissim S, Gabriel L. Chemical and structural characterization of bacterially-derived casein peptides that impair milk clotting. Int Dairy J. 2011;21(12):914–20.

    Article  CAS  Google Scholar 

  141. Le Roux Y, Laurent F, Moussaoui F. Polymorphonuclear proteolytic activity and milk composition change. Vet Res. 2003;34(5):629–45.

    Article  PubMed  CAS  Google Scholar 

  142. Ning K, Fermin D, Nesvizhskii AI. Comparative analysis of different label-free mass spectrometry based protein abundance estimates and their correlation with RNA-Seq gene expression data. J Proteome Res. 2012;11(4):2261–71.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors thank Cora J. Dillard for editing this manuscript. D.C.D., N.M.M. and J.G. wrote the paper, and D.C.D. had primary responsibility for the final content. All authors read and approved the final manuscript. This project was funded in part by the K99/R00 Pathway to Independence Career Award, Eunice Kennedy Shriver Institute of Child Health & Development of the National Institutes of Health (K99HD079561) (D.C. D.).

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Department of Food Science and Technology, University of California, Davis, One Shields Avenue, Davis, CA, 95616, USA

    David C. Dallas & Junai Gan

  2. Foods for Health Institute, University of California, Davis, One Shields Avenue, Davis, CA, 95616, USA

    David C. Dallas & Junai Gan

  3. Institute of Food and Health, School of Agriculture and Food Science, University College Dublin, Belfield, Dublin, Ireland

    Niamh M. Murray

Authors
  1. David C. Dallas
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Niamh M. Murray
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Junai Gan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to David C. Dallas.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Dallas, D.C., Murray, N.M. & Gan, J. Proteolytic Systems in Milk: Perspectives on the Evolutionary Function within the Mammary Gland and the Infant. J Mammary Gland Biol Neoplasia 20, 133–147 (2015). https://doi.org/10.1007/s10911-015-9334-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10911-015-9334-3

Keywords

Search

Navigation