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PubMed2000

Transferrins: iron release from lactoferrin.

Iron loss in vitro by the iron scavenger bovine lactoferrin was investigated in acidic media in the presence of three different monoanions (NO(3)(-), Cl(-) and Br(-)) and one dianion (SO(4)(2-)). Holo and monoferric C-site lactoferrins lose iron in acidic media (pH< or =3.5) by a four-step mechanism. The first two steps describe modifications in the conformation affecting the whole protein, which occur also with apolactoferrin. These two processes are independent of iron load and are followed by a third step consisting of the gain of two protons. This third step is kinetically controlled by the interaction with two Cl(-), Br(-) and NO(3)(-) or one SO(4)(2-). In the fourth step, iron loss is under the kinetic control of a slow gain of two protons; third-order rate-constants k(2), 4.3(+/-0.2)x10(3), 3.4(+/-0.5)x10(3), 3.3(+/-0.5)x10(3) and 1.5(+/-0.5)x10(3) M(-2) s(-1) when the protein is in interaction with SO(4)(2-), NO(3)(-), Cl(-) or Br(-), respectively. This step is accompanied by the loss of the interaction with the anions; equilibrium constant K(2), 20+/-5 mM, 1.0(+/-0.2)x10(-1), 1.5(+/-0.5)x10(-1) and 1.0(+/-0.3)x10(-1) M(2), for SO(4)(-), NO(3)(-), Cl(-) and Br(-), respectively. This mechanism is very different from that determined in mildly acidic media at low ionic strength (micro<0.5) for the iron transport proteins, serum transferrin and ovotransferrin, with which no prior change in conformation or interaction with anions is required. These differences may result from the fact that in the transport proteins, the interdomain hydrogen bonds that consolidate the closed conformation of the iron-binding cleft occur between amino acid side-chain residues that can protonate in mildly acidic media. With bovine lactoferrin, most of the interdomain hydrogen bonds involved in the C-site and one of those involved in the N-site occur between amino acid side-chain residues that cannot protonate. The breaking of the interdomain H-bond upon protonation can trigger the opening of the iron cleft, facilitating iron loss in serum transferrin and ovotransferrin. This situation is, however, different in lactoferrin, where iron loss requires a prior change in conformation. This can explain why lactoferrin does not lose its iron load in acidic media and why it is not involved in iron transport in acidic endosomes.

Animals↗

PubMed2001

Production of recombinant bovine lactoferrin N-lobe in insect cells and its antimicrobial activity.

Lactoferrin is a multifunctional, iron-binding glycoprotein found in physiological fluids of mammals. In the present study, a gene encoding the N-terminal half (N-lobe) of bovine lactoferrin was cloned and expressed in cultured insect cells using a baculovirus expression system. One mutation was found in the lactoferrin N-lobe gene, but it resulted in no amino acid substitution. The recombinant lactoferrin N-lobe was secreted into the culture medium and partially purified by means of an immobilized heparin column. The recombinant lactoferrin N-lobe secreted was not glycosylated, but it possessed antimicrobial activity toward Escherichia coli O111. The recombinant product synthesized and accumulated in the host cells exhibited greater electrophoretic mobility on SDS-PAGE than the secreted product and showed no potency to inhibit the growth of bacteria. It is thought that the product accumulated intracellularly lacks antimicrobial ability due to its degradation in the host cells or due to disruption of the active conformation.

Animals↗

PubMed1994

Three-dimensional structure of lactoferrin in various functional states.

The three-dimensional structures of various forms of lactoferrin, determined by high resolution crystallographic studies, have been compared in order to determine the relationship between structure and biological function. These comparisons include human apo and diferric lactoferrins, metal and anion substituted lactoferrins, the N-terminal half molecule of human lactoferrin, and bovine diferric lactoferrin. The structures themselves define the nature and location of the iron binding sites and allow anti-bacterial and putative receptor-binding regions to be mapped on to the molecular surface. The structural comparisons show that small internal adjustments can allow the accommodation of different metals and anions without altering the overall molecular structure, whereas large-scale conformational changes are associated with metal binding and release, and smaller, but significant, movements accompany species variations. The results also focus on differences in flexibility between the two lobes, and on the importance of interactions in the inter-lobe region in modulating iron release from the N-lobe and in possibly enabling binding at one site to be signalled to the other.

Animals↗

PubMed1983

67Ga-transferrin and 67Ga-lactoferrin binding to tumor cells: specific versus nonspecific glycoprotein-cell interaction.

In order to evaluate the mechanisms which facilitate the transfer of 67Ga from transferrin in plasma to intracellular binding sites, lactoferrin, a glycoprotein with high affinity for 67Ga, was used as a probe to study the effect of protein binding on gallium uptake by tumor cells. The in vivo effect of transferrin and lactoferrin on the biodistribution of 67Ga was studied in nude mice bearing human malignant mesothelioma. Tumor uptake of 67Ga was reduced 30% by transferrin and 57% by lactoferrin compared with 67Ga-citrate alone. Liver uptake of 67Ga, however, was significantly increased by binding to lactoferrin. The in vitro binding of 67Ga to tumor cells (Burkitt's lymphoma) was apparently promoted by the addition of transferrin or lactoferrin to the incubation medium, but this glycoprotein enhancement of gallium uptake by the cells was dependent on the albumin level, decreasing in absolute uptake as the albumin concentration was increased, suggesting nonspecific binding of glycoproteins to cells. Because of the significant amount of nonspecific binding of 67Ga-labeled glycoprotein complexes in cell culture experiments, in vitro experiments should be used with caution in developing a hypothesis on the mechanisms of cellular uptake of radiogallium. In vivo experiments suggest different mechanisms for cellular uptake of 67Ga in neoplastic tissue and in liver.

Adult↗

PubMed1981

Lactoferrin in human prostate tissue.

Lactoferrin levels have been determined by radialimmunodiffusion in homogenates of both human benign prostatic hypertrophy obtained at open surgery from patients, some of whom had been treated with oestrogens or antiandrogens, and also in prostatic adenocarcinoma tissue removed by transurethral resection. Results show that in untreated benign prostatic hyperplasia there is a statistically lower lactoferrin level in the median compared with the lateral lobes. In patients with benign prostatic hypertrophy treated before prostatectomy with oestrogens or antiandrogens the lactoferrin concentration is decreased. In neoplastic tissue removed by open surgery, the lactoferrin level is very low. Homogenates of tissue resected from prostatic cancer patients show similarly low levels. The concentration of lactoferrin in human prostate is hormone dependent. The role of the protein is considered to be bacteriostatic.

Adenocarcinoma↗

PubMed1995

Lactoferrin inhibits herpes simplex virus type-1 (HSV-1) infection to mouse cornea.

Lactoferrin inhibits bacterial growth in the conjunctival sac. However, its antiviral function particularly in ocular tissue has not been reported in the literature. We studied whether lactoferrin inhibits infection of herpes simplex virus type-1 (HSV-1) in vitro using Vero cell monolayer. We also tested the inhibitory effect of lactoferrin on HSV-1 infection in the mouse cornea. Lactoferrin prevented HSV-1 plaque formation. Administration of topical 1% lactoferrin prior to the virus inoculation suppressed infection on ocular tissue, however it did not inhibit propagation of the virus.

Acyclovir↗

PubMed1988

Lactoferrin secretion in alcoholic pancreatic disease.

Lactoferrin, a nonenzyme protein normally secreted in small amounts in pancreatic juice, has been reported by several investigators to be secreted in large amounts in chronic pancreatitis. Whether this increased secretion first occurs at an early or late stage of alcoholic pancreatic disease is unknown. In this study we measured lactoferrin and enzyme outputs in duodenal juice from 10 healthy subjects and three groups of alcoholic subjects: asymptomatic chronic alcoholics without evidence, clinically or biochemically, of pancreatitis (10), those recovered from acute pancreatitis (8), and those with established chronic pancreatitis (8). A multilumen, marker-perfused duodenal catheter was used to aspirate basal pancreatic secretions at the ligament of Treitz. The mean ( +/-SE) lactoferrin concentration in duodenal juice for the four groups of subjects was: healthy, 0.7 +/- 0.1 micrograms/ml; asymptomatic alcoholics, 5.5 +/- 1.5 micrograms/ml; alcoholics who had recovered from acute pancreatitis, 7.4 +/- 0.8 micrograms/ml; and alcoholics with chronic pancreatitis 7.1 +/- 1.9 micrograms/ml. The three groups of alcoholics each had a greater lactoferrin concentration than the normals (P less than 0.005). The output of lactoferrin in the four groups paralleled the concentration in that the three groups of alcoholics had a significantly greater output: healthy subjects, 3.4 +/- 0.5 micrograms/kg/hr; asymptomatic alcoholics, 25.7 +/- 7.4 micrograms/kg/hr; alcoholics recovered from acute pancreatitis, 80.1 +/- 27 micrograms/kg/hr; and alcoholics with chronic pancreatitis, 90.9 +/- 32 micrograms/kg/hr. The output of chymotrypsin and trypsin in the four groups of subjects revealed increased secretory rates in the asymptomatic alcoholics and the alcoholics recovered from acute pancreatitis.(ABSTRACT TRUNCATED AT 250 WORDS)

Alcoholism↗

PubMed1989

Immunohistochemical demonstration of lysozyme and lactoferrin in salivary pleomorphic adenomas.

Immunohistochemical identification of lysozyme and lactoferrin was made in salivary pleomorphic adenomas (147 cases) and the staining patterns were evaluated with respect to the histological features and histogenesis. In normal salivary glands, the intercalated duct cells gave positive staining for lysozyme in major glands, and serous acinar cells, demilune cells, and interlobular duct cells were positive in minor glands. Lactoferrin staining was irregularly positive in serous cells and ductal epithelium. In pleomorphic adenomas, the reaction for lysozyme was positive in 14% (21/147) of the cases, and was confined to luminal cells of tubulo-ductal structures. Lactoferrin in pleomorphic adenomas was distributed in luminal tumor cells (51%; 75/147), in outer tumor cells (3%; 4/147), and in both luminal and outer tumor cells (5%; 7/147) in tubulo-ductal structures; it was also detected in plasmacytoid myoepithelial cells (5%, 8/147). However, modified myoepithelial cells and other types of neoplastic myoepithelial participants were negative for lactoferrin staining. The occurrence of both lysozyme and lactoferrin in salivary pleomorphic adenomas suggests their participation in the local defense mechanism in the tumor.

Adenoma↗

PubMed1997

Antirotaviral activity of milk proteins: lactoferrin prevents rotavirus infection in the enterocyte-like cell line HT-29.

Different milk proteins were analyzed for their inhibitory effect on either rotavirus-mediated agglutination of human erythrocytes or rotavirus infection of the human enterocyte-like cell line HT-29. Proteins investigated were alpha-lactalbumin, beta-lactoglobulin, apo-lactoferrin, and Fe(3+)-lactoferrin, and their antiviral action was compared with the activity of mucin, a milk glycoprotein known to affect rotavirus infection. Results obtained demonstrated that beta-lactoglobulin, apo- and Fe(3+)-lactoferrin are able to inhibit the replication of rotavirus in a dose-dependent manner, apo-lactoferrin being the most active. It was shown that apo-lactoferrin hinders virus attachment to cell receptors since it is able to bind the viral particles and to prevent both rotavirus haemagglutination and viral binding to susceptible cells. Moreover, this protein markedly inhibited rotavirus antigen synthesis and yield in HT-29 cells when added during the viral adsorption step or when it was present in the first hours of infection, suggesting that this protein interferes with the early phases of rotavirus infection.

Animals↗

PubMed2007

A structural comparison of human serum transferrin and human lactoferrin.

The transferrins are a family of proteins that bind free iron in the blood and bodily fluids. Serum transferrins function to deliver iron to cells via a receptor-mediated endocytotic process as well as to remove toxic free iron from the blood and to provide an anti-bacterial, low-iron environment. Lactoferrins (found in bodily secretions such as milk) are only known to have an anti-bacterial function, via their ability to tightly bind free iron even at low pH, and have no known transport function. Though these proteins keep the level of free iron low, pathogenic bacteria are able to thrive by obtaining iron from their host via expression of outer membrane proteins that can bind to and remove iron from host proteins, including both serum transferrin and lactoferrin. Furthermore, even though human serum transferrin and lactoferrin are quite similar in sequence and structure, and coordinate iron in the same manner, they differ in their affinities for iron as well as their receptor binding properties: the human transferrin receptor only binds serum transferrin, and two distinct bacterial transport systems are used to capture iron from serum transferrin and lactoferrin. Comparison of the recently solved crystal structure of iron-free human serum transferrin to that of human lactoferrin provides insight into these differences.

Amino Acid Sequence↗

PubMed1987

The purification of lactoferrin from human whey by batch extraction.

The isolation of lactoferrin from human whey has been accomplished using a rapid two-step procedure. The lactoferrin is directly adsorbed to cellulose phosphate by batch extraction and eluted by a stepped salt and pH gradient. The major impurity, a low-molecular-weight fraction, is quickly removed by gel filtration. The recovered lactoferrin has a purity of about 96%. The yield of lactoferrin averaged 80%. This method of lactoferrin purification greatly reduces the labor and time required, and the procedure is easily scaled to any volume of starting material.

Chromatography, Gel↗

PubMed1976

Isolation and characterization of murine lactoferrin.

Lactoferrin, a non-heme, iron-binding glycoprotein, was isolated from mouse milk. The purification procedure involved an initial centrifugation to remove much of the casein and to separate the fat from the whey, followed by ammonium sulfate precipitation and chromatography on carboxymethyl-Sephadex. The lactoferrin preparation obtained was highly purified as judged by polyacrylamide gel electrophoresis under both non-denaturing and denaturing conditions, and the presence of lysine as the only NH2-terminal amino acid. Polyacrylamide gel electrophoresis in the presence of sodium dodecyl sulfate indicated a single component having a molecular weight of 78 000 +/- 2800. Sedimentation equilibrium ultracentrifugation studies suggested that in addition to monomers of molecular weight 75 000 +/- 1000, other oligomeric forms of the protein were also present. Amino acid and amino sugar analyses revealed that there were 5 methionine, 10 histidine, 10 tryptophan and 5 glucosamine residues per mol of protein. Isoelectric focusing of lactoferrin in a polyacrylamide gel stabilized pH gradient indicated a single component having an isoelectric point of about 9; however, depending on the preparation examined, a range of 8.7-9.6 was noted. A single precipitin line was observed with rabbit anti-mouse lactoferrin when examined by immunodiffusion and immunoelectrophoresis. No immunological cross-reaction was observed between mouse lactoferrin and mouse transferrin.

Amino Acids↗

PubMed1991

Lactoferrin activates plasma membrane oxidase and Na+/H+ antiport activity.

Lactoferrin is a growth stimulant. The basis for this effect is not clear since it is not thought to be involved in iron uptake through endocytosis. Ferric lactoferrin supports external ferrous chelate formation by K562 and HeLa cells, and ferric lactoferrin stimulates the reduction of external ferric iron by cells. Ferric lactoferrin also stimulates NADH oxidase activity in isolated rat liver plasma membranes and stimulates amiloride sensitive proton release from K562 cells. The evidence that ferric lactoferrin can participate in oxidoreduction reactions at the plasma membrane leading to activation of Na+/H+ exchange provides an alternative explanation for the proliferative effect.

Amiloride↗

PubMed1983

A non competitive enzyme immunoassay of human lactoferrin in biological fluids.

A sandwich enzyme immunoassay was developed for human lactoferrin using polystyrene balls coated with specific IgG fraction as the first antibody and peroxidase labelled IgG fraction as the second antibody. The detection limit was 1 microgram/l. A good parallelism was observed with the curves obtained from standard lactoferrin (purified from mammary gland), plasma lactoferrin (mainly derived from granulocytes), and pancreatic lactoferrin demonstrating that the assay may be used to measure the level of the protein in different biological materials. The simplicity and the sensitivity of this assay may permit the follow-up of patients with chronic calcifying pancreatitis (in which an increase of pancreatic lactoferrin has already been demonstrated) and a study of the protein in various circumstances leading to a better understanding of its biological role.

Adult↗

PubMed1984

Serum-levels of lactoferrin, lysozyme and myeloperoxidase in normal, infection-prone and leukemic children.

Serum levels of lactoferrin, lysozyme and myeloperoxidase have been established in 31 healthy children. On average, serum lactoferrin was 330 micrograms/1, serum lysozyme 1638 micrograms/1 and serum myeloperoxidase 174 micrograms/1. Serum myeloperoxidase was, on average, significantly higher in children than in adults (p = 0.01), whereas serum lactoferrin and serum lysozyme were equal to those of adults. In a group of infection-prone children (n = 31), both serum lactoferrin and serum myeloperoxidase, but not the serum lysozyme levels, were significantly lower (p less than 0.001 and p = 0.002, respectively) than those of the reference children in spite of normal intracellular contents and even somewhat higher peripheral blood polymorphonuclear counts. Based on the assumption that serum lactoferrin and serum myeloperoxidase reflect turnover and activity of neutrophil granulocytes, the findings could suggest reduction in these respects and could be one contributing factor to the high infection propensity of these children. Serum levels of the three proteins have also been measured in 10 children with suspected or various forms of manifest leukemia. It is suggested that the levels reflect turnover and stage of maturation of the myeloid and monocytic cells and could, therefore, aid in the understanding and diagnosis of these diseases.

Adolescent↗

PubMed1984

The effect of zinc on [59Fe]lactoferrin binding to blood neutrophilic leucocytes and colostral cells.

Zn2+ inhibits the binding of [59Fe]lactoferrin to neutrophilic leucocytes. The inhibiting effect is proportional to zinc concentration in the range 10-330 mumol/l. Zn2+ inhibits the [59Fe]lactoferrin binding to the colostral cells in the same degree as PMN. The inhibiting effect of Zn2+ on [59Fe]lactoferrin binding to neutrophilic leucocytes is equal to those of non-labelled lactoferrin and transferrin. Fe2+ and Cu2+ does not have such effect on binding of [59Fe]lactoferrin to the PMN leucocytes.

Cell Membrane↗

PubMed1987

The effect of lactoferrin on complement mediated modulation of immune complex size.

Earlier we showed that human lactoferrin is capable of inhibiting the complement-mediated lysis of antibody-coated erythrocytes due to an inhibition of the formation of the classical C3 convertase. In this report the effect of lactoferrin on complement mediated modulation of immune complex size was studied. Lactoferrin was shown to inhibit the complement-dependent solubilization of immune precipitates with kinetics resembling that seen by others using C2 deficient serum. Lactoferrin, however, did not affect the complement-dependent inhibition of immune precipitation. These findings confirm our earlier observations that lactoferrin has no effect on the activation of the very early complement components (C1 and C4), but inhibits C3 deposition on immune complexes which is a crucial mechanism in immune precipitate solubilization.

Animals↗

PubMed1989

Purification and characterization of bovine lactoferrin from secretions of the involuting mammary gland: identification of multiple molecular weight forms.

1. Lactoferrin was isolated from bovine mammary secretions collected during the nonlactating period. 2. A method utilizing heparin-agarose affinity chromatography was more efficient for purifying lactoferrin than a method including gel filtration, ion exchange chromatography and a second gel filtration. 3. Analysis by sodium dodecyl sulfate-polyacrylamide gel electrophoresis demonstrated that the purified lactoferrin was composed of two protein bands of apparent mol. wt. of 83,000 and 87,000. 4. Digestion with endoglycosidase H resolved the lactoferrin into two lower mol. wt. bands of 78,000 and 81,000. 5. The biochemical differences between the forms of lactoferrin are not exclusively due to differences in endoglycosidase H-sensitive oligosaccharide composition.

Amino Acid Sequence↗