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Children's Hospital and Research Center at Oakland and Center for BioIron, Oakland, CA 94609
3 To whom correspondence should be addressed. E-mail: etheil{at}chori.org.
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ABSTRACT |
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 TOP ABSTRACT LITERATURE CITED |
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KEY WORDS: • ferritin • iron nutrition • chelators • protein pores • combinatorial mRNA
Iron has been central to life since the beginning. Environmental dioxygen, a newer component of terrestrial life, was likely to have been the worst environmental pollutant of all time, but evolution has made oxygen so crucial that both iron and oxygen are absolute requirements for contemporary organisms. The chemistry of iron and oxygen under physiological conditions is corrosive (Fig. 1), producing insoluble rust and soluble oxy radicals. Ferritin evolved as the only protein able to solve the problem of iron/oxygen chemistry and metabolism. Aquated, ferrous iron is oxidized with oxygen to concentrate as many as 4000 iron atoms as a solid oxo-mineral in the center of the ferritin protein. Iron inside ferritin comfortably matches iron and oxygen chemistry with cellular concentration requirements of 
10-4 M compared to the 10-18 M solubility of the ion, a gradient of 100 trillion fold (1,
2). The biosynthesis of key proteins for iron and oxygen, including ferritin, is coordinately regulated by a combinatorial array of iron regulatory proteins (IRP)
4 and mRNA [noncoding iron-responsive elements (IRE)] structures that interact with varying efficiencies (3,
4).
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Combinatorial RNA IRE/IRP structural interactions (3– 6) explain the differential effect of iron in a cell on the level of protein synthesis for proteins encoded in IRE-mRNAs (Table 1). One illustration of this are the different levels of induced synthesis of ferritin (iron metabolism) and mitochondrial aconitase (oxygen metabolism) in the liver of rats exposed to high levels of iron (7, 8). Environmental signals that control the IRE/IRP combinatorial system include Fe, O (H2O2, anoxia), nitric oxide (NO) and IRP kinases (Table 1). Many signals acting through IRP kinases, and those as yet unidentified, could alter iron and oxygen homeostasis through the IRE/IRP combinatorial system (3, 9).
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The impact of genomic research on knowledge of ferritin has been large (Table 2). Ferritin expression varies in response to signals acting on both mRNA (Table 2) and DNA (10). At normal levels of body iron, the expression of ferritin in the average cell is quite low (e.g., fibroblasts), which contrasts with cells that have specialized functions in iron and possible oxygen homeostasis (e.g., liver and heart). In many cells, both ferritin and iron uptake proteins are upregulated early in differentiation and downregulated as the amount of iron needed for cell-specific homeostasis is achieved, in analogy to whole-body iron uptake during growth and maturation. An example of the developmental changes in iron homeostasis at the cellular level is the erythroid cell where both ferritin and transferrin receptors increase during the normoblast stage and decrease in the erythrocyte (11). During normal growth and development, some specialized cells accumulate iron and ferritin for use by other cells later in development, exemplified by the erythrocytes of embryos and the liver of the fetus (12). In disease, other specialized cells and tissues accumulate iron and ferritin to detoxify excess iron and possibly oxygen. During stress and disease, ferritin accumulates in liver, spleen, kidney, heart and serum. During iron deficiency, the loss of ferritin and redistribution of iron from specialized cells and tissues "spares" average cells from iron deficiency, although the loss of tissue ferritin coincides with increased oxidative damage (13).
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Conservation of ferritin protein sequence, folding, tertiary and quaternary structure among plants and animals is very high, emphasized by the use of an animal sequence (frog) to clone the first plant (soybean) ferritin (14). In addition, structures of plant and animal ferritin are superimposable (15). Ferritin in contemporary bacteria diverges considerably in sequence, but not in secondary, tertiary and quaternary structure (1, 2), suggesting evolutionary convergence with eukaryotic ferritins.
Ferritin is a large protein (12-nm diameter, 480,000 Da) with a large cavity (256 nm3) for the mineral that is created by the spontaneous assembly of 24 ferritin polypeptides folded into four-helix bundles bound to each other by hydrogen and salt (ionic) bonds. The structure appears to have evolved as a patchwork of other proteins such as non-heme di-iron oxygenases that share with ferritin the binding of Fe and O2. Iron in the dioxygenases is a cofactor, but iron in ferritin is a substrate. Ion channel/pore proteins share properties with ferritin Fe entry and exit sites and may be progenitors of ferritin pores. Protein mineralization surfaces are shared among ferritin and other proteins in matrices that form biominerals. The numbers of functional sites in ferritin are: one mineral cavity in the protein center, eight entry and exit pores on the outer surface, 12 mineral attachment sites on the protein cavity surface and a variable number of catalytic ferroxidase sites in the center of each subunit (3– 24), depending on the number of H and L subunits per ferritin molecule.
H-ferritin subunits have an active ferroxidase site and occur in multiple forms in humans, animals, plants and bacteria. L-ferritin subunits have a degenerate ferroxidase site and the gene duplication to encode L-ferritin subunits is found only in vertebrate animals. H- and L-ferritin subunit expression is set by gene transcription during cell differentiation. Changes in ferritin H/L ratios are known to occur in animals or cells responding to very high levels of iron (16– 19) or growth factors (20) and to hypertransfusion in humans with sickle cell disease and ß-thalassemia (Hagar, Harmatz, Vichinsky, and Theil, 2003, unpublished results).
Ferritin function
Ferritin is required, not a luxury, as shown by the lethality of ferritin gene deletion during mouse embryonic life (21) and presence even in strictly anaerobic bacteria (22). In humans, the only diseases related to ferritin mutations were discovered very recently (Table 2) and are relatively benign or appear late in life. The human ferritin gene mutations that are compatible with survival modulate expression (4, 23) or change the protein structure in a variable region (24), which suggests the lethality of mutations in major ferritin features.
Understanding the multiple functions of ferritin requires defining and studying each type of functional site (Fe entry, oxidation, translocation, mineralization and exit). How each functional site interacts with the others of the same type (eight Fe entry sites, three to 24 Fe oxidation sites, 24 Fe translocation sites, 12 Fe mineral attachment/mineralization sites and eight Fe exit sites) and of the different types adds a unique type of complexity to understanding ferritin function. However, many lessons can be learned from oxygenases and pore proteins.
When Fe2+ enters the ferritin protein pores, it rapidly (in milliseconds) readies the ferroxidase site buried within each H-ferritin subunit. The ferroxidase site activity that oxidizes Fe2+ and forms diferroxo-mineral precursors (Fe3+-O-Fe3+) is the function best characterized in ferritin. Mossbauer, resonance Raman and EXAFS spectroscopies (1, 2, 25) have been used to analyze the fast ferroxidase reaction intermediates (in milliseconds) by rapid mixing and freezing to trap enough of a blue (A650 nm) diferric peroxo-transition state for the spectroscopic studies. Trapping the diferric complex in protein crystals has not been possible. The peroxo intermediate also forms in di-iron peroxo oxygenases. Iron is a substrate converted to the diferric peroxo intermediate in ferritin and is released into the interior of the protein as a diferric-oxo mineral precursor (Fig. 2). (Note that in di-iron oxygenases, the iron is retained at the active site as a cofactor, and O is activated for insertion into substrates such as methane, to make methanol). Ferritin releases H2O2 (26– 28) and diferric-oxo mineral precursors (Fig. 2), leaving behind an active site that is altered for a fairly long time (26, 29), presumably to allow peroxide to diffuse away before binding the next Fe(II) substrate atoms. In bacteria, the iron site in ferritin has a variety of Fe amino acid ligands. Heme is also a cofactor and mineralization does not produce peroxide (1). Other bacterial ferritin-like molecules do not bind oxygen, but rather bind peroxide and convert it to water (30).
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Identification of a "gate" in the ferritin pore occurred when the crystal structure of the –L134 mutated protein was examined (31). The entire helix-loop-helix of each subunit around the pore, amino acids 110–134, was completely disordered (unfolded), although the remainder of the subunit had folded and assembled normally, which was associated with enhancing the rate or reduction and chelation of iron in the ferritin mineral. When the ferritin polypeptide chain was extended by an insertion of five amino acids between 120 and 125 at the pore, the effect on Fe2+ exit was the same as the amino acid substitutions (34). The results suggest that gating the ferritin "pore" requires the set of interactions (hydrogen bonds: Leu 110/134, and ion pairs: Arg 72/Asp 122) with positions determined in part by the loop length. The selective advantage that conserved the exit pore amino acids in ferritin could be interactions with a cytoplasmic factor that "opens" the pore on demand. Recent studies with small chaotropic molecules show that the pore in the native protein is differentially accessible to solute molecules (35) and support the idea of regulated opening and closing of the ferritin pore.
Translating ferritin structure/function and regulation for new strategies in medicine and nutrition
Both ferritin mRNA and ferritin protein contain structures that could be selectively targeted to synthesize more protein for efficient iron detoxification or to "open" the ferritin pores to remove more iron. Enhanced synthesis of ferritin or removal of ferritin iron could improve the current regimens for iron chelation therapy in transfusional iron overload associated with genetic anemias. The lesson learned from nature's use of ferritin as a regulated source of iron during the development of plants and animals suggests that ferritin might be an efficient source of dietary iron. Preliminary results are encouraging (36– 38). Targeting ferritin in iron overload diseases to synthesize more ferritin protein is one approach to managing iron excess safely. Another approach is the faster removal of iron from existing ferritin molecules.
Manipulating the ferritin mRNA IRE can lead to increased synthesis of ferritin protein. During iron overload, a large increase occurs in the fraction of cellular iron that is bound to ribosomes to synthesize ferritin protein. However, a large fraction still remains inactive (39, 40), apparently because some IRE/IRP interactions remain. Recent studies, which show that the ferritin IRE-specific structure folds in vivo and is accessible to bind small molecules the same way as in vitro (41), open the way for manipulating the ferritin IRE in vivo to increase the synthesis of ferritin protein and safe storage of iron. Overexpression of L-ferritin in humans due to IRE mutations has relatively few physiological effects (23), indicating the potential efficacy of controlled manipulation of the ferritin IRE to manage iron overload.
Opening ferritin protein pores to enhance iron chelation can lead to faster removal of iron from ferritin during iron overload. The ferritin pores are almost closed in native proteins when examined in crystals. Nevertheless, molecules larger than the pore size in the protein crystals reach the protein cavity in solution [reviewed in (1)], which suggests that the pores "flex" or "open". Recent studies have identified several features of "gating" the ferritin pores (31, 34), measured in mutated proteins as changes in the rate of Fe2+ chelation, triggered by the addition of a reductant (FMN/NADH) or by blocking Fe2+ entry (42). Because small chaotropic molecules also open ferritin pores in the native structure without altering the global properties of the protein (35), it should be possible to develop new chelators targeted to ferritin pores that will remove iron more quickly than current chelators that are mainly targeted to iron outside cells or in the "labile iron pool".
Ferritin in nutrition
Iron deficiency is a human problem for which the treatment has been known since medieval times. Nevertheless, over 30% of the world's population is thought to suffer from iron deficiency anemia with associated economic and cognitive loss. Clearly the solution lies in improved access to bioavailable forms of iron. Many seeds such as legume seeds store iron in ferritin, which is a bioavailable iron source (36– 38) (Fig. 3). When women with borderline iron deficiency consumed meals with intrinsically labeled soybean iron, high absorbance levels were also observed (43). The mechanisms of iron uptake into the gut in humans and animals are not known; nor is it known what impact the differences in the plant ferritin mineral (amorphous, high phosphate) and the animal ferritin mineral (crystalline, little phosphorus) have on digestion. Whether the differences in the subcellular location of ferritin in plants, inside a seed organelle, the amyloplast, or animal tissue, mostly in the cytoplasm, affect digestion and interaction with other food components such as phytate, is completely unknown. Experiments to analyze how ferritin absorption occurs from food have just begun, but the potential impact of ferritin, "nature's iron", on global iron deficiency could be immense.
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FOOTNOTES |
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2 Supported in part by National Institutes of Health grants DK-20251, DK-58882, HL-56169 and HL-20985.
4 Abbreviations used: IRE, iron-responsive element; IRP, iron regulatory protein.
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LITERATURE CITED |
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N. Surguladze, K. M. Thompson, J. L. Beard, J. R. Connor, and M. G. Fried Interactions and Reactions of Ferritin with DNA J. Biol. Chem., April 9, 2004; 279(15): 14694 - 14702. [Abstract] [Full Text] [PDF]
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