Ferritin Biosynthesis

A low molecular weight protein, different from metallothionine which reversibly binds iron with high affinity has been isolated from rabbit reticulocyte cytosol (54, 55, 56). Although very little is yet known about its physiological properties, the molecular weight is around 6000, and iron appears to be reversibly bound under physiological conditions. This protein may be able to mobilize iron from the plasma membrane and donate it for heme and ferritin biosynthesis (56), but no definitive physiological role for siderochelin has been established. 

For a more detailed discussion of ferritin biosynthesis and the possible physiological roles of isoferritins of different subunit compositions, the reader is referred to the recent literature (12, 13, 16, 18-22). In this paper the structures of the iron cores and protein coats of ferritins and the hemoferritins of bacteria are compared and the current state of knowledge concerning mineralization processes in these molecules is discussed in relation to this structural information. 

Figure 5 IRP binding to IREs. In cells that are depleted of iron, IRPl and 2 bind to IREs. When IRPs bind to IREs at the 5 end of the transcript, they inhibit translation and new protein synthesis from the transcript. When they bind at the 3 end of the TfR, they protect the transcript from endonucleolytic cleavage. In iron-replete cells, IRPs do not bind to transcripts. Ferritin biosynthesis accordingly increases, whereas TfR biosynthesis drops because the transcript levels decrease...

Fineberg, R.A., Greenberg, D.M. Ferritin biosynthesis acceleration of synthesis by administration of iron. J. biol. Chem. 214, 97-106 (1955)... 

Caughman SW, Hentze MW, Rouault TA, Harford JB, Klausner RD (1988) The iron-responsive element is the single element responsible for iron-depen-dent translational regulation of ferritin biosynthesis. Evidence for function as the binding site for a translational repressor. J Biol Chem 263 19048-19052... 

Intracellular Fe is usually tightly regulated, being bound by ferritin in an insoluble ferrihydrite core, and impaired Fe homeostasis has been linked to Parkinson s disease and Alzheimer s disease. A consistent neurochemical abnormality in Parkinson s disease is degeneration of dopaminergic neurons relating to a reduction of striatal dopamine levels. As tyrosine hydroxylase (Fig. 24) (494), an Fe enzyme, catalyzes the formation of l-DOPA, the rate-limiting step in the biosynthesis of dopamine, the disease can be considered as a tyrosine... 

The Protein Coat. Twenty-four polypeptides assemble into a hollow sphere, of ca. 100-120 X in outer diameter, to form the protein coat of ferritin. The diameter of the interior, which becomes filled with hydrous ferric oxide, is ca. 70-80 A. Subunit assembly appears to be spontaneous the coat remains assembled even without the iron core. Subunit biosynthesis is actually controlled by the amount of iron to be stored by a cell the subunit templates (mRNAs) are stored in the cytoplasm of a cell in a repressed form and are recruited for biosynthesis when the concentration of iron increases (3). 

The sequence of steps in the biosynthesis of the ferritin iron core has been studied by analyzing the incorporation of Fe into ferritin during synthesis of the protein vivo. Ferritin, collected at various intervals after the induction of synthesis, was fractionated according to iron core size by sedimentation through gradients of sucrose (32). Fe appeared first in ferritin with small amounts of Fe, and later, the Fe appeared in fractions further down the gradient as the core size and the ratio... 

Aminolevulinic acid, an element in the biosynthesis of heme proteins, may be overexpressed under certain pathological conditions and its accumulation has been correlated with some hepatitic cancers. It is in equilibrium with its enol form and can complex transition-metal ions. In the presence of 02, this may lead to the formation of OH and hence in the presence of DNA to DNA damage which is enhanced in the presence of ferritin (Douki et al. 1998 di Mascio et al. 2000). Superoxide radicals have been assumed to be intermediates in these reactions. Mechanistically, the formation of 02 is certainly very complex, because even in the case of the Fe(II)-EDTA-complex the reduction potential is not low enough to reduce O2 by simple one-electron donation. 

Electron microscopy has revealed the existence of two types of polyribosomes—some bound to the membrane and others free. It is believed that the bound polyribosomes are involved in elaboration of export proteins, while nonbound polyribosomes are involved in the biosynthesis of proteins to be used for local consumption. In the pancreas, it has been shown that chymotrypsin is formed on bound ribosomes. Redman studied the incorporation of labeled amino acid in vivo and in vitro in purified serum proteins and ferritin of rat liver and showed that the radioactivity incorporated in albumin is associated with the bound ribosome, whereas that of ferritin is associated with free ribosomes [220]. 

Redman, C.M. Biosynthesis of serum proteins and ferritin by free and attached ribosomes of rat liver. J. biol. Chem. 244, 4308-4315 (1969)... 

Ferritin Structure and Biosynthesis 363 Release of Iron from Ferritin 364 Transferrin 365 Iron Secretion 365 Tissue Iron 365... 

A delicate control mechanism for the biosynthesis of apoferritin has been proposed. The cell does not contain free apoferritin—iron induces the synthesis of apoferritin. Apoferritin exerts a feedback inhibition on its own biosynthesis, which is relieved when apoferritin is converted to ferritin. Of course, the mechanism of induction at the nucleic acid level remains to be studied. 

Formation of a site-specific mRNA-protein complex is involved in the translational control of the biosynthesis of ferritin, an iron storage protein, which is stimulated in response to the presence of iron. In this instance, a cytoplasmic repressor protein of 85 kDa binds to a highly conserved 28-nucleotide stem-loop structure in the 5 untranslated region of ferritin mRNAs in the absence of iron. In the presence of iron, the protein dissociates from the mRNA, which is then available for translation. A similar loop motif occurs in the 3 untranslated region of transferrin receptor mRNA, which is also subject to translational control by an iron-responsive repressor. 

---