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Occurrence, structure, biochemical properties and technological characteristics of lactoferrin

Published online by Cambridge University Press:  09 March 2007

Jan M. Steijns*
Affiliation:
DMV International, R&D Center, PO Box 13, 5460 BA Veghel, The Netherlands
A. C. M. van Hooijdonk
Affiliation:
DMV International, R&D Center, PO Box 13, 5460 BA Veghel, The Netherlands
*
*Corresponding author: Dr. Jan Steijns, DMV International, Center of Expertise for Nutrition, PO Box 14, 6700 AA Wageningen, The Netherlands, fax +31 317 475 769, email: [email protected]
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Abstract

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The structure of the iron-binding glycoprotein lactoferrin, present in milk and other exocrine secretions, has been elucidated in great detail, both the three-dimensional protein structure and the attached N-glycans. Structure–function relationships are being established. From these studies a function for lactoferrin in host defence and modulation of iron metabolism emerges. This paper describes in some detail how iron and other cations may be bound by lactoferrins from human or bovine sources and elucidates parts of the molecule that are critical for interactions with cells and biomolecules. Furthermore, the technological aspects, more specifically the heat-sensitivity, of bovine lactoferrin in different matrices are described.

Type
Research Article
Copyright
Copyright © The Nutrition Society 2000

References

Abe, H, Saito, H, Miyakawa, H, Tamura, Y, Shimamura, S, Nagao, E & Tomita, M (1991) Heat stability of bovine lactoferrin at acidic pH. Journal of Dairy Science 74, 6571.CrossRefGoogle Scholar
Arnold, R, Pruitt, KM, Cole, MF, Adamson, JM & McGhee, JR (1979) Salivary antibacterial mechanisms in immunodefiency. In Saliva and Dental Caries, pp. 449462. [Kleinberg, I, Ellison, SA & Mandel, ID, editors]. Washington: Information Retrival IncGoogle Scholar
Baker, EN, Anderson, BF, Baker, HM, Day, CL, Haridas, M, Norris, GE, Rumball, SV, Smith, CA & Thomas, DH (1994) Three-dimensional structure of lactoferrin in various functional states. Advances in Experimental Medicine and Biology 357, 112.CrossRefGoogle ScholarPubMed
Bellamy, W, Takase, M, Yamauchi, K, Wakabayashi, H, Kawase, K & Tomita, M (1992) Identification of the bactericidal domain of lactoferrin. Biochimica et Biophysica Acta 1121, 130136.CrossRefGoogle ScholarPubMed
Bezault, J, Bhimani, R, Wiprovnick, J & Furmanski, P (1994) Human lactoferrin inhibits growth of solid tumors and development of experimental metastases in mice. Cancer Research 54, 23102312.Google ScholarPubMed
Britigan, BE, Serody, JS & Cohen, MS (1994) The role of lactoferrin as an anti-inflammatory molecule. Advances in Experimental Medicine and Biology 357, 143156.CrossRefGoogle ScholarPubMed
Brodie, AH, Ainscough, EW, Baker, EN, Baker, HM, Shongwe, MS & Smith, CA (1994) Synergism and substitution in the lactoferrins. Advances in Experimental Medicine and Biology 357, 3344.CrossRefGoogle ScholarPubMed
Coddeville, B, Strecker, G, Wieruszeski, J-M, Vliegenthart, JFG, van Halbeek, H, Peter-Katalinic, J, Egge, H & Spik, G (1992) Heterogeneity of bovine lactotransferrin glycans. Characterization of α-D-Gal p-(1→3)-β-D-Gal- and α-NeuAc-(2→6)-β-D-GalpNAc-(1→4)-β-D-GlcNAc-substituted N-linked glycans. Carbohydrate Research 236, 145164.CrossRefGoogle ScholarPubMed
Cohen, MS, Mao, J, Rasmussen, GT, Serody, JS & Britigan, BB (1992) Interaction of lactoferrin and lipopolysaccharide (LPS): effects on the antioxidant property of lactoferrin an the ability of LPS to prime human neutrophils for enhanced superoxide formation. Journal of Infectious Diseases 166, 13751378.CrossRefGoogle ScholarPubMed
Dionysius, DA & Milne, JM (1997) Antibacterial peptides of bovine lactoferrin: purification and characterization. Journal of Dairy Science 80, 667674.CrossRefGoogle ScholarPubMed
Elass-Rochard, E, Roseanu, A, Legrand, D, Salmon, V, Motas, C, Montreuil, J & Spik, G (1995) Lactoferrin-lipopolysaccharide interaction: involvement of the 28–34 loop region of human lactoferrin in the high-affinity binding to Escherichia coli 055B5 lipopolysaccharide. Biochemical Journal 312, 839845.CrossRefGoogle ScholarPubMed
Faber, RH, Anderson, BF, Baker, HM, Bland, T, Day, CL, Nicholson, H, Shewry, S, Tweedie, JW & Baker, EN (1997) Altered domain closure and iron binding in lactoferrin mutants Lactoferrin: Interactions and Biological Functions, pp. 2538 , [Hutchens, TW & Lönnerdal, B, editors]. New Jersey: Humana Press.Google Scholar
Hambraeus, L & Lönnerdal, B (1994) The physiological role of lactoferrin. In IDF Bulletin: Indigenous Antimicrobial Agents of Milk: Recent Developments (Uppsala 1993, S.I.9404), pp. 97107.Google Scholar
Haridas, M, Anderson, BF & Baker, EN (1995) Structure of human diferric lactoferrin refined at 2.2 Å resolution. Acta Crystallographia D51, 629646.Google Scholar
Harmsen, MC, Swart, PJ, DeBéthune, M-P, Pauwels, R, De Clercq, E, Hauw, The, T, & Meijer, DKF (1995) Antiviral effects of plasma and milk proteins: lactoferrin shows potent activity against both human immunodeficiency virus and human cytomegalovirus replication in vitro. Journal of Infectious Diseases 172, 380388.CrossRefGoogle ScholarPubMed
Harrington, JP, Stuart, J & Jones, A (1987) Unfolding of iron and copper complexes of human lactoferrin and transferrin. International Journal of Biochemistry 19, 10011008.CrossRefGoogle ScholarPubMed
Hoek, KS, Milne, JM, Grieve, PA, Dionysius, DA & Smith, R (1997) Antibacterial activity of bovine lactoferrin derived peptides. Antimicrobial Agents and Chemotherapy 41, 5459.CrossRefGoogle ScholarPubMed
Hurley, WL, Grieve, RCJ, Magura, CE, Hegarty, HM & Zou, S (1993) Electrophoretic comparisons of lactoferrin from bovine mammary secretions, milk neutrophils, and human milk. Journal of Dairy Science 76, 377387.CrossRefGoogle ScholarPubMed
Hutchens, TW & Lönnerdal, B (1997) Lactoferrin: Interactions and Biological Functions, New Jersey: Humana press.CrossRefGoogle Scholar
Hutchens, TW, Rumball, SV & Lönnerdal, B (1994) Lactoferrin: Structure and Function Advances in Experimental Medicine and Biology, Vol. 357, New York: Plenum.Google Scholar
Inoue, M, Yamada, J, Kitamura, N, Shimazaki, K-I, Andren, A & Yamashita, T (1993) Immunohistochemical localization of lactoferrin in bovine exocrine glands. Tissue and Cell 25, 791797.CrossRefGoogle ScholarPubMed
Kang, JH, Lee, MK, Kim, KL & Hahm, K-S (1996) Structure–biological activity relationships of 11-residue highly basic peptide segments of bovine lactoferrin. International Journal of Peptide and Protein Research 48, 357363.CrossRefGoogle ScholarPubMed
Kawakami, H, Dosako, S & Nakajima, I (1993) Effect of lactoferrin on iron solubility under neutral conditions. Bioscience Biotechnology Biochemistry 57, 13761377.CrossRefGoogle Scholar
Kawakami, H, Hiratsuka, M & Dosako, S (1988) Effects of iron-saturated lactoferrin on iron absorption. Agricultural and Biological Chemistry 52, 903908.Google Scholar
Korhonen, H (1977) Antimicrobial factors in bovine colostrum. Journal of the Scientific Agricultural Society of Finland 49, 434447.Google Scholar
Kussendrager, K (1994) Effects of heat treatment on structure and iron-binding capacity of bovine lactoferrin IDF Bulletin: Indigenous Antimicrobial Agents of Milk: Recent Developments (Uppsala 1993, S.I.9404) 133146.Google Scholar
Legrand, D, Mazurier, J, Colavizza, D, Montreuil, J & Spik, G (1990) Properties of the iron-binding site of the N-terminal lobe of human and bovine lactotransferrins. Biochemical Journal 266, 575581.Google ScholarPubMed
Legrand, D, VanBerkel, PHC, Salmon, V, VanVeen, HA, Slomianny, M-C, Nuijens, JH & Spik, G (1997) The N-terminal Arg2 Arg3 Arg4 of human lactoferrin interact with sulphated molecules but not with the receptor present on Jurkat human lymphoblastic cells. Biochemical Journal 327, 841846.CrossRefGoogle ScholarPubMed
Levay, PF & Viljoen, M (1995) Lactoferrin: a general review. Haematologica 80, 252267.Google ScholarPubMed
Lönnerdal, B & Iyer, S (1995) Lactoferrin: molecular structure and biological function. Annual Review of Nutrition 15, 93110.CrossRefGoogle ScholarPubMed
Luf, W & Rosner, E (1997) Zur Thermostabilität von Lactoferrin in Kuhmilch. Wiener Tieraertzliche Monatsschrift 84, 7073.Google Scholar
Magnusson, JS, Henry, JH, Yip, T-T & Hutchens, TW (1990) Structural homology of human, bovine, and porcine milk lactoferrins: evidence for shared antigenic determinants. Pediatric Research 28, 176181.Google Scholar
Marchetti, M, Longhi, C, Conte, MP, Pisani, S, Valenti, P & Seganti, L (1996) Lactoferrin inhibits herpes simplex virus type 1 adsorption to Vero cells. Antiviral Research 29, 221231.CrossRefGoogle ScholarPubMed
Matsue, M, Matsuyama, J & Kiyosawa, I (1995) Interaction of lactoferrin with ascorbate and the relationship with bleomycin-dependent DNA damage. Bioscience Biotechnology Biochemistry 59, 358362.CrossRefGoogle ScholarPubMed
Matsue, M, Tomita, S, Nyui, S, Matayuma, J & Kiyosawa, I (1994) Suppressive effects of lactoferrin on bleomycin-dependent DNA damage by the iron ion and ascorbate. Bioscience Biotechnology Biochemistry 58, 6771.CrossRefGoogle ScholarPubMed
Mattsby-Baltzer, I, Roseanu, C, Motas, C, Elverfors, J, Engberg, I & Hanson, LA (1996) Lactoferrin or a fragment therof inhibits the endotoxin-induced interleukin-6 response in human monocytic cells. Pediatric Research 40, 257262.CrossRefGoogle ScholarPubMed
Mikogami, T, Marianne, T & Spik, G (1995) Effect of intracellular iron depletion by picolinic acid on expression of the lactoferrin receptor in the human colon carcinoma cell subclone HT29–18-C1. Biochemical Journal 308, 391397.CrossRefGoogle ScholarPubMed
Moore, SA, Anderson, BF, Groom, CR, Haridas, M & Baker, EN (1997) Three-dimensional structure of diferric bovine lactoferrin at 2.8 Å resolution. Journal of Molecular Biology 274, 222236.CrossRefGoogle ScholarPubMed
Naidu, AS (1997) Influence of lactoferrin on host–microbe. In interactions Lactoferrin: Interactions and Biological Functions, pp. 259275, [Hutchens, TW & Lönnerdal, B, editors]. New Jersey: Humana Press.CrossRefGoogle Scholar
Oria, R, Ismael, M, Sanchez, L, Calvo, M & Brock, J (1993) Effect of heat treatment and other milk proteins on the interaction of lactoferrin with monocytes. Journal of Dairy Research 60, 363369.CrossRefGoogle ScholarPubMed
Paulsson, MA, Svensson, U, Kishore, AR & Naidu, AS (1993) Thermal behaviour of bovine lactoferrin in water and its relation to bacterial interaction and antibacterial activity. Journal of Dairy Science 76, 37113720.CrossRefGoogle ScholarPubMed
Pierce, A, Colavizza, D, Benaissa, M, Maes, P, Tartra, A, Montreuil, J & Spik, G (1991) Molecular cloning and sequence analysis of bovine lactoferrin. European Journal of Biochemistry 196, 177184.CrossRefGoogle Scholar
Reiter, B (1985) The biological significance of the non-immunoglobulin protective proteins in milk. Developments in Dairy Chemistry 3, 281336.CrossRefGoogle Scholar
Renner, E, Schaafsma, G & Scott, KJ (1989) Micronutrients in milk. In Micronutrients in Milk and Milk-based Food Products, pp. 170. [Renner, E, editor]. New York: Elsevier Applied Science.Google Scholar
Sanchez, L, Calvo, M & Brock, JH (1992) Biological role of lactoferrin. Archives of Disease in Childhood 67, 657661.CrossRefGoogle ScholarPubMed
Sanchez, L, Peiro, JM, Castillo, H, Perez, MD, Ena, JM & Calvo, M (1992) Kinetic parameters for denaturation of bovine milk lactoferrin. Journal of Food Science 57, 873879.CrossRefGoogle Scholar
Schanbacher, FL, Talhouk, RS & Murray, FA (1997) Biology and origin of bioactive peptides in milk. Livestock Production Science 50, 105123.CrossRefGoogle Scholar
Sekine, K, Watanabe, E, Nakamura, J, Takasuka, N, Kim, DY, Asamoto, M, Krutovskikh, V, Baba-Toriyama, H, Ota, T, Moore, MA, Masuda, M, Sugimoto, H, Nishino, H, Kazikoe, T & Tsuda, H (1997) Inhibition of azoxymethane-initiated colon tumor by bovine lactoferrin adminsitration in F344 rats. Japanese Journal of Cancer Research 88, 523526.CrossRefGoogle Scholar
Shimazaki, K-I, Kawaguchi, A, Sato, T, Ueda, Y, Tomimura, T & Shimamura, S (1993) Analysis of human and bovine milk lactoferrins by rotofor and chromatofocussing. International Journal of Biochemistry 25, 16531658.CrossRefGoogle Scholar
Shimazaki, KI, Tsuda, H, Tomita, M, Kuwata, T & Perraudin, JP (editors)(2000) Lactoferrin: Structure, Function and Applications. Exerpta Medica International Congress Series 1195.Google Scholar
Shimizu, K, Matsuzawa, H, Okada, K, Tazume, S, Dosako, S, Kawasaki, Y, Hashimoto, K & Koga, Y (1996) Lactoferrin-mediated protection of the host from murine cytomegalovirus infection by a T-cell dependent augmentation of natural killer cell activity. Archives of Virology 141, 18751889.CrossRefGoogle ScholarPubMed
Spik, G, Coddeville, B, Mazurier, J, Bourne, Y, Cambillaut, C & Montreuil, J (1994) Primary and three-dimensional structure of lactotransferrin (lactoferrin) glycans. Advances in Experimental Medicine and Biology 357, 2132.CrossRefGoogle ScholarPubMed
Spik, G, Legrand, D, Mazurier, J, Pierce, A & Perraudin, J-P (editors)(1998) Advances in lactoferrin research Advances in Experimental Medicine and Biology Vol. 443,.Google Scholar
Tomita, M, Takse, M, Wakabayashi, H & Bellamy, W (1994) Antimicrobial peptides of lactoferrin. Advances in Experimental Medicine and Biology 357, 209218.CrossRefGoogle ScholarPubMed
VanBerkel, PHC (1998) Structure–function Studies of Human Lactoferrin Thesis, University of Leiden, The Netherlands, pp.95100.Google Scholar
VanBerkel, PHC, Geerts, ME, VanVeen, HA, Kooiman, PM, Pieper, FR, DeBoer, H & Nuijens, JH (1995) Glycosylated and unglycosylated human lactoferrins both bind iron and show identical affinities towards lysozyme and bacterial lipopolysaccharide, but differ in their susceptibilities towards tryptic proteolysis. Biochemical Journal 312, 107114.CrossRefGoogle Scholar
VanBerkel, PHC, Geerts, M, VanVeen, HA, Mericskay, M, DeBoer, H & Nuijens, JH (1997) N-terminal stretch Arg2 Arg3, Arg4 and Arg5 of human lactoferrin is essential for binding to heparin, bacterial lipopolysaccharide, human lysozyme and DNA. Biochemical Journal 328, 141151.Google Scholar
Ward, PP, Zhou, X & Conneely, OM (1996) Cooperative interactions between the amino- and carboxyl-terminal lobes contribute to the unique iron-binding stability of lactoferrin. Journal of Biological Chemistry 22, 1279012794.CrossRefGoogle Scholar
Yi, M, Kaneko, S, Yu, DY & Murakami, S (1997) Hepatitis C virus envelope proteins bind lactoferrin. Journal of Virology 71, 59976002.CrossRefGoogle ScholarPubMed
Yoo, Y-C, Watanane, S, Watanabe, R, Hata, K, Shimazaki, K-I & Azuma, I (1997) Bovine lactoferrin and lactoferricin, a peptide derived from bovine lactoferrin, inhibit tumor metastasis in mice. Japanese Journal of Cancer Research 88, 184190.CrossRefGoogle ScholarPubMed
Zimecki, M, Mazurier, J, Machnicki, M, Wieczorek, Z, Montreuil, J & Spik, G (1991) Immunostimulatory activity of lactoferrin and maturation of CD4-, CD8-murine thymocytes. Immunology Letters 30, 119123.CrossRefGoogle ScholarPubMed