Transferrins iron complexes

Schade reviewed (114) the earlier studies on the role of serum transferrin in iron transport. Various early investigators had observed that the blood serum transferrin rapidly bound iron administered either through the gastrointestinal tract or by intravenous injection. There was a rapid turnover of iron in the blood serum and the degree of saturation of the transferrin was related to the amount of iron administered. In no instances, however, was the blood serum transferrin ever saturated with iron. Jandl et al. (71) have shown that both ovotransferrin and serum transferrin can transport plasma iron into red cells and that the transport is dependent on the concentration of transferrin. Iron taken up by the blood cells could not be eluted by subsequent incubation with iron-free transferrin solutions. More recently Morgan and Laurel (99) reported that iron uptake in reticulocytes is independent of the transferrin concentration. The iron complex of serum transferrin has a higher affinity for immature red cells than does the iron-free protein (72). Both bind specifically to immature red cells and the attachment permits the cells to remove the iron. Once the iron is removed, however, the iron-free transferrin can be replaced by an iron-transferrin complex. 

Davis, B., P. Saltman, and S. Benson The stability constants of the iron-transferrin complex. Biochem. Biophys. Res. Commun. 8, 56 (1962). 

Transferrin is mainly synthesized in the hepatocytes. There are about 20 known variants. Iron is transported by transferrin (approx. 30% of transferrin is saturated with iron). With the help of a membrane receptor, the iron-transferrin complex is taken up and released in the liver cell, where it is immediately bound (because of its toxicity) to ferritin. The liver cells take up iron predominantly from transferrin, to a lesser degree also from haptoglobin, haemopexin, lactoferrin and circulating ferrin. Transferrin, which is mainly formed in the hepatocytes, may also bind and transport, in decreasing order, chromium, copper, manganese, cobalt, cadmium, zinc and nickel. The half-life of transferrin is 1 - 2 hours, which is very short in view of its total blood concentration of 3-4 mg. Approximately 0.4 g ferritin iron is stored in the liver. In the case of transferrin deficiency, its bacteriostatic and fungistatic effects are also reduced. Transferrin without iron saturation is known as apo-transferrin. (31, 66, 67)... 

FIGURE 10.25 Utilization of transferrin and its receptor for delivering iron into the cell. The iron/transferrin complex circulates throughout the bloodstream. Eventually, the iron/transferrin complex binds to the transferrin receptor, a membrane-bound protein (Step 1). Part of the plasma membrane pinches off, creating an endocytotic vesicle, which resides in the cytoplasm (Step 2). The interior of the vesicles becomes acidified (Step 3), and the iron atoms leave the vesicle (Step 4). MobUferrin is a cytosolic protein that is thought to bind the released iron atoms, and to shuttle them to newly synthesized iron metalloproteins (Conrad et al, 1996). Finally, the transferrin receptor is inserted back into the plasma membrane (Steps 5 and 6). 

The cell membranes of the developing RBC precursors in bone marrow are very rich in transferrin receptors, to which the iron-transferrin complex binds before it is internalized... 

The role of melanotransferrin has been recently elucidated by Kennard et al. [207] who demonstrated that this membrane bound iron binding protein is involved in the transferrin-independent uptake of iron in mammals but from iron-citrate and not from iron-transferrin complexes. This alternative iron uptake pathway may not function in the normal recirculation of iron within the body but might play a role during iron overload. On the other hand, rapidly proliferative tumor cells like melanocytes could use the alternative pathway to increase iron uptake. This independent system could also participate in the absorption of iron by intestinal cells that have no transferrin receptor on their lumenal surfaces [208], but express a transferrin-like GPI-linked iron-binding protein at the apical surface of fetal intestinal epithelial cells [209]. 

R. Soda and M. Tavassoli. Transendothelial transport (transcytosis) of iron-transferrin complex in bone and marrow. J. Ultrastruct. Res. 88 18-25 (1984). 

Early experiments showed that a transferrin-polycation complex transported bacterial DNA into cells [12]. Ions are taken up by cells as an iron-transferrin complex by receptor-mediated endocytosis. Protamine or poly-lysine ligated by disulfide bonds to transferring and mixed with a lu-ciferase-encoding plasmid may bind the DNA because of the cationic properties of the complex [12]. Subsequently, avian ery-throblasts and human K-562 cells were incubated with the transferrin-polycation peptide-DNA complex, and the complexes were recognized and transported into the cells by receptor-mediated endocytosis and taken up into endosome-Hke intracellular vesicles [12]. Treatment with chloroquine (an agent that affects the endosomal pH) enhanced the uptake considerably. In contrast to other transfection methods, the transfection of cells with transferrin-mediated endocytosis did not cause significant cell death, because of the physiologi-... 

Internal exchange of iron is accomplished by the plasma protein transferrin. This 76 kDa /Ij-glycoprotein has 2 binding sites for ferric iron. Iron is delivered from transferrin to intracellular sites by means of specific transferrin receptors in the plasma membrane. The iron-transferrin complex binds to the receptor, and the ternary complex is taken up by receptor-mediated endocytosis. Iron subsequently dissociates in the acidic, intracellular vesicular compartment (the endosomes), and the receptor returns the apotransferrin to the cell surface, where it is released into the extracellular environment. Cells regulate their expression of transferrin receptors and intracellular ferritin in response to the iron supply. Apoferritin synthesis is regulated post-transcriptionally by 2 cytoplasmic binding proteins (IRP-1 and lRP-2) and an iron-regulating element on its mRNA (IRE). 

Regulation of transcription by iron. A cell s ability to acquire and store iron is a carefully controlled process. Iron obtained from the diet is absorbed in the intestine and released into the circulation, where it is bound by transferrin, the iron transport protein in plasma. When a cell requires iron, the plasma iron-transferrin complex binds to the transferrin receptor in the cell membrane and is internalized into the cell. Once the iron is freed from transferrin, it then binds to ferritin, which is the cellular storage protein for iron. Ferritin has the capacity to store up to 4,000 molecules of iron per ferritin molecule. Both transcriptional and translational controls work to maintain intracellular levels of iron (see Figs. 16.23 and 16.24). When iron levels are low, the iron response element binding protein (IRE-BP) binds to specific looped structures on both the ferritin and transferrin receptor mRNAs. This binding event stabilizes the transferrin receptor mRNA so that it can be translated and the number of transferrin receptors in the cell membrane increased. Consequently, cells will take up more iron, even when plasma transferrin/iron levels are low. The binding of IRE-BP to the ferritin mRNA, however, blocks translation of the mRNA. With low levels of intracellular iron, there is little iron to store and less need for intracellular ferritin. Thus, the IRE-BP can stabilize one mRNA, and block translation from a different mRNA. 

Coated vesicle bearing complex of receptor and iron-transferrin... 

Fe(III) displacement of Al(III), Ga(III), or In(III) from their respective complexes with these tripodal ligands, have been determined. The M(III)-by-Fe(III) displacement processes are controlled by the ease of dissociation of Al(III), Ga(III), or In(III) Fe(III) may in turn be displaced from these complexes by edta (removal from the two non-equivalent sites gives rise to an appropriate kinetic pattern) (343). Kinetics and mechanism of a catalytic chloride ion effect on the dissociation of model siderophore-hydroxamate iron(III) complexes chloride and, to lesser extents, bromide and nitrate, catalyze ligand dissociation through transient coordination of the added anion to the iron (344). A catechol derivative of desferrioxamine has been found to remove iron from transferrin about 100 times faster than desferrioxamine itself it forms a significantly more stable product with Fe3+ (345). 

Many of the investigations into endosomal pathways have concentrated on receptor-mediated endocytosis, as in the iron-transferrin-receptor complex, and it is not clear how the systems vary depending on whether or not the pathway is clathrin-dependent or clathrin-independent [54],... 

The haem molecule would be incomplete without iron so this must be delivered to the progenitor red cells. Iron is toxic so it is carried in the plasma bound to a specific protein named transferrin (Tf). Uptake of iron is via a Tf receptor, of which there are approximately 300 000 per cell. The whole iron/Tf complex is taken into the cell by endocytosis where the iron is released and made available for incorporation into the porphyrin ring by ferrochelatase. 

Iron(III) citrate, " " or iron(III) ammonium citrate, is the usual vehicle for administering supplementary iron to an iron-deficient patient, for inducing iron-overload in rats or other creatures prior to testing the efficacy of iron chelators, or for introducing the isotope Fe for metabolic tracer studies. Stability constants for the aqueous iron(III)-citrate system have been established. " The 2 1 complex is claimed to be the dominant species in iron(III)/citrate/DMF systems. " There has been a very qualitative study of the incorporation of iron into transferrin from iron citrate. " Iron(III) citrate reacts relatively slowly with the aluminum(III)-transferrin complex to give the thermodynamically strongly favored combination of iron(III)-transferrin with aluminum(lll) citrate. " The mechanism of iron uptake from citrate complexes in cells has been briefly discussed. An octa-iron citrate complex appears in Section 5.4.5.4.3 below. 

Iron-gluconate complexes are sufficiently stable not to cause iron toxicity (in contrast to Fe aq, Fe aq, and complexes of low stability) and are safe and effective in hemodialysis. " There is information on iron transfer between gluconate and transferrin. Dithionite releases Fe + from gluconate. ... 

Pharmacology Iron dextran, a hematinic agent, is a complex of ferric hydroxide and dextran for IM or IV use. The iron dextran complex is dissociated by the reticuloendothelial system, and the ferric iron is transported by transferrin and... 

The X-ray absorption spectra of a series of 28 model Fem complexes and those of ovatransferrin, protocatechuate 3,4-dioxygenase and catechol 1,2-dioxygenase have been analyzed, and appear to give information on the coordination number of the protein-bound iron. Thus the transferrin complexes appear to be six- or seven-coordinate, while the dioxygenase complexes could be five-or six-coordinate.816... 

Fiala (45) and Fiala and Burk (46) early postulated, by analogy from the visible absorption spectra of iron transferrin and the iron complex of aspergillic acid, that iron was bound in transferrins through a hydroxamic acid-CC>2 complex. This formulation is shown in Fig. 15. Fraenkel-Conrat (48), however, could find no evidence for hydroxylamido groups in chicken ovotransferrin. He also prepared and studied the properties of several hydroxylamido proteins by the chemical introduction of the hydroxylamido groups, and found that their properties were quite different from those of the transferrins. 

Comparisons of the iron and copper complexes of the transferrins (128, 129) showed that the iron transferrin had a negative Cotton effect at the absorption maximum of the iron complex while the copper complex showed no such relationship. They concluded that the copper did not form an asymmetric center in the metal complexes, whereas the iron did form an asymmetric center. 

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