The transferrin family of non-heme iron binding glycoproteins are believed to play a central role in iron metabolism and have been implicated in iron transport, cellular iron delivery and control of the level of free iron in external secretions. Lactoferrin (LF) is a member of this family that is widely localized in external fluids including milk and mucosal secretions, in addition to being a prominent component of the secondary granules of neutrophils. Although structurally related to transferrin, LF appears to have a broader functional role mediated by both iron dependent and iron independent mechanisms. In this review, we will focus on our current understanding on the role of LF in regulating iron homeostasis and its role in host protection against microbial infection at the mucosal surface. In addition, recent insights obtained from analyzing the phenotypic consequences of LF ablation in lactoferrin knockout mice (LFKO), which challenge the long held dogma that LF is required for intestinal iron absorption in the neonate, are summarized.

Lactoferrin is a member of the transferrin family of iron-binding proteins. Several functions have been ascribed to lactoferrin, including regulation of iron homeostasis, antibacterial properties, and regulation of myelopoiesis. However, the structural features of lactoferrin that are required for most of these functions are unknown.Previously, we reported the development of an efficient fungal expression system to produce recombinant human lactoferrin. The availability of this production system demonstrated the feasibility of producing mutant lactoferrins to address the structure/function relationship of the protein. In the present study, we used a site-directed mutagenesis approach to address the contribution of the bilobal structure of lactoferrin to its unique iron-binding stability. Like transferrin, lactoferrin consists of two repeated iron-binding lobes that bind one iron atom each. However, unlike transferrin, lactoferrin retains iron over a broad pH range, a key property that contributes to the unique iron-binding functions of the protein. Using mutants that selectively ablate the iron-binding function in either lobe, we demonstrate differential iron-binding stability of the aminoand carboxyl-terminal iron-binding lobes of lactoferrin. Further, we show that the unique iron-binding stability of the protein is imparted primarily by the carboxylterminal domain which functions cooperatively to stabilize iron-binding to the amino-terminal domain of lactoferrin.Lactoferrin is a member of the transferrin family of nonheme iron-binding glycoproteins (1) which includes transferrin, the major iron-transport protein in blood (2), ovotransferrin, an avian egg white protein (3), and melanotransferrin, a membrane bound form of this family found in human melanocytes (4). Lactoferrin has a broad distribution, present in both external secretions that bathe the body surfaces (5-9) and also in the secondary granules of polymorphonuclear neutrophils where it can be released into the bloodstream upon neutrophil activation (10). The functions proposed for this protein include iron binding and delivery to the small intestine (11-17), antimicrobial activity against a wide range of Gram-negative and Grampositive bacteria (18 -22), cellular growth promotion (23, 24), regulation of myelopoiesis (25-27), and immunomodulatory properties (28 -30).Lactoferrin shares a high degree of structural homology with other members of the transferrin family. All of these proteins are monomeric glycoproteins with a molecular mass of ϳ80 kDa (1, 31). The three-dimensional structure of lactoferrin (32) and transferrin (33) have been precisely defined by x-ray crystallographic analysis. The proteins are folded into two globular lobes corresponding to the amino-and carboxyl-terminal halves of the protein. This bilobal structure, with ϳ40% conservation between the NH 2 -and COOH-terminal halves, is thought to have evolved by intragenic duplication from a common ancestral gene (34). Each of these lobes can reversibly bind iron with high affinity and w...

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We report the activity of recombinant human lactoferrin against Helicobacter pylori. Lactoferrin exerted a time-and dose-dependent action against 8 of the 13 clinical isolates of H. pylori tested in vitro. These results highlight a potential therapeutic use for lactoferrin against H. pylori infection.