Animal models for the study of innate immunity: protozoan infections in fish
G. F. Wiegertjes, G. Flik in Host-Parasite Interactions, 2004
In plasma, iron is transported by transferrin, with high affinity for ferric iron, a 80-kDa glycoprotein consisting of two globular domains, both containing a high-affinity binding site for a single iron molecule. These binding sites are highly conserved through evolution (Ford, 2001). Transferrin exists as a mixture of iron-free (apo), single-iron (monomeric) and two-iron (diferric) forms. Although the relative percentage of each form depends on the concentration of iron and transferrin in plasma, under normal conditions most of the iron molecules are bound to transferrin. Most cells (so not only macrophages) acquire iron from transferrin first by binding of transferrin to transferrin receptors. Following binding, the complex consisting of iron, transferrin and transferrin receptor is internalized via a classic receptor-mediated endocytic pathway. Iron is released from transferrin within acidic endosomal compartments and then transported across the endosomal membrane into the cytoplasm by the iron transporter, NRAMP2, or solute carrier family 11 member 2 (Slclla2). Apotransferrin and the transferrin receptor both return to the cell surface, where they dissociate at neutral pH.
Iron Metabolism: Iron Transport and Cellular Uptake Mechanisms
Bo Lönnerdal in Iron Metabolism in Infants, 2020
The iron donating behavior of the transferrin molecule has also been clarified.156,158,214–220 The two monoferric forms of transferrin have identical iron donating capacities,158,215 both in animals and in humans.216–218 The rate of iron donation and pattern of tissue distribution in vivo are identical. Iron release from transferrin to erythroid cells from either mono- or diferric transferrin is an “all or none” phenomenon leaving only apotransferrin.216,221 While receptors cycle transferrin into the cell regardless of its iron content, there is a competitive advantage of diferric over monoferric transferrin.156,220 Apotransferrin is not competitive. These iron-related differences in affinity between transferrin and receptor may well relate to the shape changes of the molecule during iron loading.36,91,209 The higher affinity of the diferric molecule was responsible for the original effects described by Fletcher and Huehns.222
Radiotracers for Nonimaging Studies
Garimella V. S. Rayudu, Lelio G. Colombetti in Radiotracers for Medical Applications, 2019
Soon after the absorption of iron, it is transported in the blood by a metal-binding protein with physical characteristics of β1-globulin, known as transferrin (sometimes called siderophilin). The importance of transferrin and its functions in the regulation of iron metabolism has been reviewed by Katz.156 Approximately one third of the plasma transferrin is saturated with iron under normal conditions. A transferrin molecule could hold one or two atoms of iron with a very high stability constant (it may, however, dissociate easily at acid pH). The synthesis of transferrin occurs predominantly in the liver. Studies with radioiodinated human transferrin have shown a turnover half-life of 8 to 11 days, similar to other serum proteins. However, the normal half-clearance time of the iron bound to transferrin is only 80 to 90 min. A major portion of this iron is delivered to the bone marrow where it is taken up by the eryth-roid precursors. Subsequently, the iron reappears in the circulating red blood cells being incorporated into the hemoglobin. Following a definite life span, the red cells are catabolized in the reticuloendothelial system, releasing bilirubin and iron which rapidly binds to the transferrin for recycling. Radioactive iron has helped tremendously in the understanding of iron kinetics (ferrokinetics). Finch and co-workers157 have offered an excellent review on ferrokinetics in man.
The aging brain: impact of heavy metal neurotoxicity
Published in Critical Reviews in Toxicology, 2020
Omamuyovwi M. Ijomone, Chibuzor W. Ifenatuoha, Oritoke M. Aluko, Olayemi K. Ijomone, Michael Aschner
Iron (Fe) is an important metal found in an ample amount in the brain. It plays essential roles in many physiologic processes of the brain, which include; the synthesis of the neuronal myelin sheath, synthesis and optimal functionality of neurotransmitters, and the generation of ATP (Ashraf et al. 2018). It serves as a cofactor for many enzymes and it is also involved in the modulation of neuronal plasticity and synaptic activity (Wang et al. 2012; Braidy et al. 2017). Thus, the homeostasis of Fe is critical for a plethora of metabolic functions. The homeostatic balance of iron is controlled by the ferritin family (Fe-storage proteins). The ferritin family is made of three subfamilies, which include the canonical ferritin (FTN), the heme-containing bacterioferritin (BFR), and the starved cells’ DNA-binding proteins (DPS). The two subunits of the FTN, H-chain, and L-chain, are responsible for the oxidation of Fe2+ to Fe3+, and the formation of Fe core minerals, respectively (Arosio et al. 2017). Ideally, the BBB prevents the free passage of the iron-regulating proteins including ferritin, transferrin, ceruloplasmin and so on from the blood stream to the CNS. The circulating diferric-transferrin binds to the cerebrovascular endothelial cells of the BBB and the resulting complexes crosses over into the intercellular compartment. Following the dissolution of these complexes, apotransferrin is recycled to the blood where iron, probably via ferrotin, is transported out across the abluminal membrane into the interstitial space (Schipper 2012).
Modulations of ferroptosis in lung cancer therapy
Published in Expert Opinion on Therapeutic Targets, 2022
Robert Walters, Shaker A. Mousa
Lastly, lactoferrin is a naturally occurring non-heme iron-binding protein and member of the transferrin family commonly found in mammalian secretions, such as milk, seminal fluid, intestinal secretions, tears, sweat, saliva, nasal secretions, as well as secretory granules of neutrophils [79,80]. As a transferrin, its role is to transport iron in the blood serum. The use of iron-saturated lactoferrin (Holo-Lactoferrin) has been shown to significantly increase total iron content, initiate ROS generation, increase lipid peroxidation, leading to enhancement of ferroptosis [81]. Lactoferrin has also shown anticancer effects in NSCLC. In a randomized control trial, talactoferrin, an oral recombinant lactoferrin produced by fungus Aspergillus Niger var. awamori, significantly increased overall survival by 65% compared to placebo in advanced NSCLC patients [82]. Thus, lactoferrin has effects on both ferroptosis induction and anticancer effects, allowing for potential synergistic manipulation to enhance its utility in lung cancer patients.
Self-assembled non-covalent protein-drug nanoparticles: an emerging delivery platform for anti-cancer drugs
Published in Expert Opinion on Drug Delivery, 2020
Islam A. Hassanin, Ahmed O. Elzoghby
Transferrin (Tf), an 80 kDa glycoprotein with iron-binding properties, is composed structurally of two lobes (N and C lobes) [56]. Transferrin can act as an effective protein nanocarrier for hydrophobic drugs. The interaction between estradiol and holo-transferrin (HTf) was investigated and it was found that estradiol was placed via hydrophobic interactions between α-helix and β-sheet of the N-terminal of HTf. In addition, hydrogen bonding was formed with Ala 670. The self-assembly process of the protein was induced by the addition of estradiol, due to the induction of the hydrophobic groups, which resulted in the formation of protein micelles [57]. In another example, it was found that the hydrophobic forces were the major forces governing the interactions between alprazolam and apo-human serum transferrin (apo-hTf). The protein exhibited an unfolded structure, probably due to changes in the protein microenvironment brought by changes in temperature. Then the unfolded protein structure exhibited an interaction with alprazolam. Alprazolam incorporated itself in the hydrophobic cavity of the protein, forming an inclusion complex, which was accompanied with fluorescence quenching of apo-hTf on increasing of the drug concentration [58].
Related Knowledge Centers
- Hemolymph
- Iron
- Ph
- Glycoprotein
- Liver
- Blood Plasma
- Gene
- Binding Constant
- Transferrin Receptor
- Cell