Transport, Storage, and Homeostasis in Mammals

Most mammalian cells take up iron transported in serum by transferrin, an 80 kD bilobal protein with two identical iron-binding sites, one in each half of the molecule. The coordination of the iron atom involves four protein ligands and a carbonate anion, as we described in Chapter 4, and the transferrin to cell cycle for delivering iron was outlined in Chapter 7. Iron release from the extremely stable diferric transferrrin bound to its receptor is facilitated by the acidic pH prevailing in the endosome and by the fact that the receptor imposes a conformation on the bound transferrin that is essentially that of the open apotransferrin form. 

FIGURE 8.17 Schematics of cellular iron uptake and utilisation. Adapted from Richardson et al., 2010.) 

About a quarter of total body iron is stored in macrophages and hepatocytes as a reserve which can be readily mobilised for red blood cell formation (erythropoiesis). This storage iron is mostly in the form of ferritin like bacterioferritin, a 24-subunit protein in the form of a spherical protein shell enclosing a cavity within which up to 4500 atoms of iron can be stored, essentially as the mineral ferrihydrite. Despite the water insolubility of ferri-hydrite, it is kept in solution within the protein shell, such that one can easily prepare mammalian ferritin solutions which contain 1 M ferric iron (i.e., 56 mg/ml ). Mammalian ferritins, unlike most bacterial and plant ferritins, have the particularity that they are heteropolymers, made up of two subunit types, H and L. Whereas H-subunits have a ferroxidase activity, catalysing the oxidation of two Fe atoms to Fe, L subunits appear to be involved in the nucleation of the mineral iron core once this has formed an initial critical mass, further iron oxidation and deposition in the biomineral takes place on the surface of the ferrihydrite crystallite itself (for a more detailed discussion, see Chapter 19). 

The regulation of cellular iron homeostasis is to a large degree controlled at the level of the translation of the mRNAs of proteins involved in cellular iron metabolism (Rouault, 2006 Wallander et al., 2006). The key players in this post-transcriptional regulation are two iron regulatory proteins (IRPl and 1RP2), which function as 

unoccupied, allowing polyeoma formation and increased ferritin synthesis 

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