Diferrous/ferric iron

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). 

For diiron complexes Mossbauer spectroscopy allows to asses (1) oxidation and spin states of the iron atoms, (2) diamagnetism and ferromagnetism of the groimd state for diferric and mixed-valent oxidation levels and (3) valence (de)localisation in the solid state for mixed-valence complexes [2,3]. Isomer shifts (IS) in the range 0.35-0.60 mm/s are characteristic of 5- or 6-coordinate high-spin diferric p-hydroxo complexes [2,3], Tetrahedral high-spin ferric iron has lower isomeric shifts in the range of 0.22 mm/s [2,3]. For isolated ferric iron with S =... 

Figure 11.1 Schematic representation of iron uptake mechanisms, (a) The transferrin-mediated pathway in animals involves receptor-mediated endocytosis of diferric transferrin (Tf), release of iron at the lower pH of the endocytic vesicle and recycling of apoTf. (b) The mechanism in H. influenzae involves extraction of iron from Tf at outer membrane receptors and transport to the inner membrane permease system by a periplasmic ferric binding protein (Fbp). From Baker, 1997. Reproduced by permission of Nature Publishing Group.

TfR-mediated endocytosis is a well-known uptake system Tf binds one or two Fe atoms, but only diferric Tf (Fe2Tf) has a high affinity for TfR to be taken up by the receptor-mediated endocytosis. This system uses a mobilization pathway that involves endosomal acidification, reduction of ferric Fe, and ferrous Fe transport [8]. Recently, it was clarified that divalent cation/ metal ion transporter (DCT1) or Nramp2 involves iron transport from the endosome to the cytosol [9, 10]. Al resembles Fe in chemical characteristics ionic radius, charge density, and coordination number [11]. Therefore, Al binds with Tf to form di—Al—Tf. Al bound to Tf even passes through the blood-brain barrier to enter the neuronal cells via Tf receptor-mediated endocytosis [12]. 

As noted in Section 3, some pathogenic bacteria have transferrin receptors on their outer membranes to acquire diferric transferrin from their host. These outer membrane receptors extract the iron from the transferrin and transport it into the periplasm where it is picked up by the periplasmic ferric binding proteins (Fbp), which carry the iron to a transmembrane protein in the inner membrane that conveys it into the cytoplasm. A considerable amount of chemical and structural information has been gathered for Fbp, which is sometimes referred to as bacterial transferrin in recognition of its similarities with animal transferrin. ... 

Ellis and Morris (10) tested di- and tetraferric phytates as dietary iron sources for rats. We harvested diferric phytate from the precipitate that formed when monoferric phytate was suspended in dilute hydrochloric acid and we made tetraferric phytate by adding excess ferric ion to a dilute acid solution of sodium phytate and harvesting the resultant precipitate. After a 3-week feeding period, the hemoglobin responses to monoferric phytate and ferrous ammonium sulfate were about equal (Table II). 

However, the hemoglobin response of rats fed a diet that contained diferric phytate was only slightly better than that supported by the low iron basal diet. The response to the tetra-ferric phytate was intermediate between responses to the di- and monoferric phytate. The bioavailabilities of the iron of the three ferric phytates are markedly different. In another experiment (10), a 60-fold excess of phytic acid as sodium phytate did not depress the ability of monoferric phytate to support hemoglobin formation in growing rats. 

The iron center of protein R2, which is one of the focal points of this review, is an antiferromagnetically coupled pair of high-spin ferric ions in the active state. Figure 3 shows the known redox states of the iron/ tyrosyl radical site in the protein. The crystal structure of the met form, i.e., the diferric form without radical, around the iron site (Figs. 

The three-dimensional structure of the human H ferritin has been solved (i 78) and shows that the putative /t-oxo-bridged ferric dimer is located in the middle of and along the length of a four-helix bundle, similar to the situation in . coli RNR protein R2. In a bacterial ferritin, three iron sites per subunit have been found in an X-ray crystallographic study (22). Two of the iron ions make up the diferric site. The third ferric site remains an enigma as to its functional role, if any. Also here, it is interesting to compare protein R2 in RNR, where a third ferrous iron has been shown to participate in formation of the iron/free radical site (78, 84, 82). 

Structurally characterized models for the diferrous oxidation state thus far number only three. The first reported by Wieghardt, [(Fe2(0H)(0Ac)2(Me3TACN)2](C104) (70, 87), has a (p.-hydroxo)bis( x-carboxylato)diiron(II) core. Its structure is closely related to that of the diferric form, but the Fe-fi-O and Fe-Fe distances of 1.99 and 3.32 A, respectively, are longer than their ferric counterparts. The Fe(II) ions in this complex are antiferromagnetically coupled with aJ of —13 cm" and the complex is thus EPR silent. The J value of the complex is comparable to that found for deoxyHr, suggesting that deoxyHr is likely to have a hydroxide bridging the iron centers. 

The purple acid phosphatases can occur in two diferric forms—one as the tightly bound phosphate complex (characterized for the bovine and porcine enzymes) (45, 171, 203) and the other derived from peroxide or ferricyanide oxidation of the reduced enzyme (thus far accessible for only the porcine enzyme) (206). These oxidized forms are catalytically inactive. They are EPR silent because of antiferromagnetic coupling of the two Fe(IIl) ions and exhibit visible absorption maxima near 550-570 nm associated with the tyrosinate-to-Fe(III) charge-transfer transition. The unchanging value of the molar extinction coefficient between the oxidized and reduced enzymes indicates that the redox-active iron does not contribute to the visible chromophore and that tyrosine is coordinated only to the iron that remains ferric in agreement with the NMR spectrum of Uf, (45). 

Rates of Fe binding/ oxidation by recombinant H and L ferritins differ over a 1000-fold. The L type of ferritin protein forms polynuclear complexes, as soon as the iron is oxidized, that are indistinguishable from the mineral (B. H. Huynh and E. C. Theil, unpublished results), whereas the H type ferritin proteins form a series of ferric intermediates that include a diferric-peroxo as the first product. The di-ferric peroxo species is similar to complexes that form in methane monoxygenase and ribonucleotide reductase (see Chapter 16). Thus, the Fe - - O2 inorganic chemistry... 

Biochemical experiments and crystal structures of apo, mono, and diferric serum transferrin greatly enhance our understanding of the mechanism by which Tfs strongly chelate ferric ion and then release it within the endosome. These processes are inherently related the iron-binding steps occur in the opposite order to the steps leading to iron release from transferrin. Binding of iron to the tyrosine residues and to the synergistic anion while the Tf lobe is in the open conformation appears to be the first step. " " Once the ferric-loaded domain samples the closed... 

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