Ferric transferrin Plasma membrane

The determination of the structure of the iron transporter, ferric-binding, protein (hFBP)t from Haemophilus influenzae (Bruns et ah, 1997) at 0.16 nm resolution shows that it is a member of the transferrin superfamily, which includes both the transferrins and a number of periplasmic binding proteins (PBP). The PBPs transport a wide variety of nutrients, including sugars, amino acids and ions, across the periplasm from the outer to the inner (plasma) membrane in bacteria (see Chapter 3). Iron binding by transferrins (see below) requires concomitant binding of a carbonate anion, which is located at the N-terminus of a helix. This corresponds to the site at which the anions are specifically bound in the bacterial periplasmic sulfate- and... 

Iron ion The protein transferrin binds ferric ions and transports them in the semm aronnd the body. The ions are taken np by cells via a transferrin receptor which is present in the plasma membrane. The receptor binds transferrin and the complex enters the cell where transferrin releases... 

Figure 6. Scheme to represent known aspects of the plasma membrane NADH oxidase and its association with proton release. The oxidase is activated when hormones or ferric transferrin bind receptors. Oxidase may activate tyrosine kinase which can activate MAP kinases to result in phosphorylation of the exchanger leading to Na+/H+ exchange. Oxidation of quinol in the membrane can also release protons to the outside equal to the number of electrons transferred. External ferricyanide can activate electron flow by accepting electrons at the quinone. G proteins (GTP binding proteins) such as ras-activate electron transport and proton release in some way and may be a link to kinase activation (McCormick, 1993). Semiquinone formation in the membrane could lead to superoxide and peroxide formation by one electron reduction of oxygen. 

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). 

In the bloodstream, ferric iron binds tightly to circulating plasma transferrin (TF) to form diferric transferrin (FeTF). Absorption of iron into erythrocytes depends on basolateral membrane receptor-mediated endocytosis of FeTF by transferrin receptor 1 (TfR 1). FeTF binds to TfR 1 on the surface of erythroid precursors. These complexes invaginate in pits on the cell surface to form endosomes. Proton pumps within the endosomes lower pH to promote the release of iron into the cytoplasm from transferrin. Once the cycle is completed,TF and TfR 1 are recycled back to the cell surface. TF and TfR 1 play similar roles in iron absorption at the basolateral membrane of crypt enterocytes (Parkilla et al., 2001 Pietrangelo, 2002). 

There is some evidence that ceruloplasmin is involved in iron metabolism. It has been suggested that ceruloplasmin and ferritin in plasma work together to reduce the levels of free ferrous ions in plasma. Here, the ceruloplasmin catalyzes the oxidation of Fe (ferrous) to (ferric), the form of the metal that binds to ferritin. Ceruloplasmin acts as an oxidant in this process. This proposed function may reduce damage to membrane lipids possibly inflicted by the small amount of Fe in the circulation. It is thought that ceruloplasmin may be used in the mobilization of iron from intracellular stores. Here, the protein may facilitate the transfer of iron from ferritin to transferrin [Frieden and Hsieh, 1976), A relationship between copper and irtm is suggested by the fact that copper-deficient rats may develop iron deficiency anemia, as revealed by measurements of hemoglobin and hematocrit (Johnson and Dufault, 19S9 Cohen et a ., 1985), Ceruloplasmin may also function in a unique iron transport mechanism, as mentioned in the Iron section. 

The accumulation of iron is dependent on its transport into the cell. Askwith and Kaplan (Chapter 4) discuss iron transport mechanisms in eukaryotic cells, developing models based on studies carried out in the yeast, Saccharomyces cerevisiae. These cells possess both siderophore-dependent and elemental iron transport systems. The latter system relies on cell surface ferrireductases to convert extracellular ferric chelates to ferrous iron, which can be transported through either a high or low affinity iron transport system. Studies on a high affinity ferrous iron transporter (FET3) revealed that the multicopper oxidase will oxidize ferrous to ferric iron, which is then mobilized across the membrane by a ferric transmembrane permease (Ftrlp). This is a highly specific transport system in yeast it only transports iron. In humans, the copper enzyme, ceruloplasmin, is responsible for the radical-free oxidase activity. This plasma protein oxidizes the ferrous iron that is excreted from cells into the transferrin-usable ferric form. 

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