Iron protein from transferrin, physiologic

A biological example of E° is the reduction of Fe(III) in the protein transferrin, which was introduced in Figure 7-4. This protein has two Fe(III)-binding sites, one in each half of the molecule designated C and N for the carboxyl and amino terminals of the peptide chain. Transferrin carries Fe(III) through the blood to cells that require iron. Membranes of these cells have a receptor that binds Fe(III)-transferrin and takes it into a compartment called an endosome into which H is pumped to lower the pH to —5.8. Iron is released from transferrin in the endosome and continues into the cell as Fe(II) attached to an intracellular metal-transport protein. The entire cycle of transferrin uptake, metal removal, and transferrin release back to the bloodstream takes 1-2 min. The time required for Fe(III) to dissociate from transferrin at pH 5.8 is —6 min, which is too long to account for release in the endosome. The reduction potential of Fe(IH)-transferrin at pH 5.8 is E° = —0.52 V, which is too low for physiologic reductants to reach. 

The specific reactions involved in the physiologic release of iron from transferrin have not been elucidated. An enzymatic mechanism has been postulated (55), but without direct evidence. Recently, Ponka and Neuwirt have found that cyclic AMP may be involved, possibly by activating a protein kinase (89). If so, it may be worthwhile to consider whether the specifically bound carbonate itself is the site of a phosphorylation reaction, perhaps entailing its removal as carbamyl phos-... 

Figure 50-4. Absorption of iron. is converted to Fe + by ferric reductase, and Fe " is transported into the enterocyte by the apicai membrane iron transporter DMTl. Fieme is transported into the enterocyte by a separate heme transporter (HT), and heme oxidase (FiO) reieases Fe from the heme. Some of the intraceiiuiar Fe + is converted to Fe + and bound by ferritin. The remainder binds to the basoiaterai Fe + transporter (FP) and is transported into the biood-stream, aided by hephaestin (FiP). in piasma, Fe + is bound to the iron transport protein transferrin (TF). (Reproduced, with permission, from Ganong WF Review of Medical Physiology, 21 st ed. McGraw-Hill, 2003.)...

Transferrin is a single-chain glycoprotein that binds 2 g-atoms of ferric iron per mole of protein. The iron is chelated via tyrosyl and histidyl residues, and the complex is extremely stable at physiologic pH. The function of transferrin is to transport iron throughout the human organism, especially to the immature red cells, which cannot effectively acquire iron for the biosynthesis of hemoglobin unless it is presented to them in combination with transferrin. Specific transferrin receptors are present on the surface of such immature red cells as well as in all other tissues. Receptor-mediated endocytosis (see Chapter 9) is believed to be the main means of transferrin-bound iron entry into cells. Transferrin is also believed to be antimicrobial because it withholds iron from microorganisms. 

The dramatic role of the anion can perhaps best be appreciated from simple quantitative considerations. In the absence of a suitable anion, specific binding of iron to transferrin does not occur at all the effective binding constant is zero. At physiologic pH and bicarbonate concentrations, however, the effective binding constant is about 5 X 1023 M"1 24, 50). This means that in 1 L of blood plasma, in which the transferrin is only about 30% saturated with iron, there will be less than one free ferric ion or that a molecule of the ferric—transferrin complex will spontaneously dissociate only about once in 10,000 years. Since iron is readily removed from the transferrin molecule during its interaction with the reticulocyte without disrupting protein structure 51, 52), a... 

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