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Recently, the roles of a number of proteins involved in regulating iron metabolism have been elucidated.
Iron response elements are stem-looped sections of mRNA that are involved in the production of ferritin and transferrin receptors. These elements are 'responsive' to iron because their binding proteins (below) change their conformation in response to intracellular iron levels, thus providing a feedback mechanism to regulate intracellular iron [16]. In response to high intracellular iron levels, increased production of ferritin provides additional storage capacity, and concomitant decreased production of transferrin receptor reduces the cellular uptake of iron.
[Source: http://pdbbeta.rcsb.org/pdb/explore.do?structureId=1AQO] PDB ID: 1AQO Addess KJ, Basilion JP, Klausner RD, Rouault TA, Pardi A. Structure and dynamics of the iron responsive element RNA: Implications for binding of the RNA by iron regulatory binding proteins. J Mol Biol. 1997; 274 (1):72-83.
In response to elevated intracellular iron concentrations, IRE BPs change their conformation to promote degradation of transferrin receptor mRNA. Other IRE BPs change their conformation to promote increased ferritin translation [16].
Hepcidin is a peptide hormone that helps to control iron distribution: low hepcidin levels lead to intracellular iron overload, while hepcidin overproduction leads to hypoferremia. Hepcidin regulates cellular iron export by binding to ferroportin on cell surfaces, decreasing the cell's ability to export iron [17]. This, in turn, leads to decreased extracellular iron levels. Preliminary data indicate that duodenal DMT1 and Dcytb are also negatively regulated by hepcidin, although whether there is a direct or indirect interaction between hepcidin and these transporters remains to be elucidated [18, 19].
[Source: http://pdbbeta.rcsb.org/pdb/explore.do?structureId=1M4E] PDB ID: 1M4E Hunter HN, Fulton DB, Ganz T, Vogel HJ. The solution structure of human hepcidin, a peptide hormone with antimicrobial activity that is involved in iron uptake and hereditary hemochromatosis. J Biol Chem. 2002:277(40);37597-603.
Hepcidin is secreted by the liver in response to several physiologic states including inflammation, raised body iron, hypoxia, and anemia. In response to these states, a number of signals that have not yet been clearly defined are transmitted to receptor mechanisms, such as transferrin receptor 2, IL-6 receptor, HFE and hemojuvelin, which act on hepatocytes to induce the synthesis and release of hepcidin. There may be interactions between these different signals and receptor mechanisms and it is not yet known how these are processed to modulate hepcidin. However, it is known that malfunction of transferrin receptor 2, IL-6 receptor, HFE, and hemojuvelin in different types of hemochromatosis decreases hepcidin output.
Since inflammation and IL-6 are strong stimuli for human hepcidin production, and hepcidin excretion is greatly increased during inflammation in humans, IL-6-induced hepcidin could be the mediator responsible for the iron restriction and inadequate erythropoiesis in anemia of inflammation. The development of hepcidin analogues may therefore have future therapeutic applications [7].
Located on the basolateral surface of iron-absorptive enterocytes, hephaestin facilitates iron egress from enterocytes by oxidizing iron released through ferroportin [20]; this oxidation prepares the iron molecules for loading onto transferrin. Ceruloplasmin (located in the plasma) plays a similar role in macrophages.
[Source: http://pdbbeta.rcsb.org/pdb/explore.do?structureId=1A6Z]PDB ID: 1A6Z Lebrón JA, Bennett MJ, Vaughn DE, et al. Crystal structure of the hemochromatosis protein HFE and characterization of its interaction with transferrin receptor. Cell. 1998:93;111-23.
First identified in humans in 1996 [21], the HFE gene is located on the short arm of chromosome 6. HFE is a 343-amino acid cell surface protein with homology to the major histocompatibility complex (MHC) class I molecules. In hereditary hemochromatosis, a C282Y mutation to the HFE gene causes a structural distortion to the HFE protein that prevents its transport to the cell surface, thereby disabling its ability to downregulate cellular iron uptake. HFE mutations other than C282Y have been identified in a comparatively small number of patients with iron overload. The most common of these is H63D. Compared with HFE knockout mice or C282Y homozygous mice, mice homozygous for H63D have mild increases in parameters of iron status [22].
The role that HFE plays in the physiology of intestinal iron absorption remains uncertain. Two major models have been proposed: 1) HFE exerts its effects on iron homeostasis indirectly, by modulating the expression of hepcidin; and 2) HFE exerts its effects directly, by changing the iron status (and therefore the iron absorptive activity) of intestinal enterocytes. The first model places the primary role of HFE in the liver (hepatocytes and/or Kupffer cells), while the second model places the primary role in the duodenum (crypt cells or villus enterocytes). These models are not mutually exclusive, and it is possible that HFE influences the iron status in each of these cell populations, leading to cell type-specific downstream effects on intestinal iron absorption and body iron distribution [22].
 [Source: http://pdbbeta.rcsb.org/pdb/explore.do?structureId=1KCW] PDB ID: 1KCW Zaitseva I, Zaitsev V, Card G, et al. The X-ray structure of human ceruloplasmin at 3.1 angstrom: Nature of the copper centres. J Biol Inorg Chem. 1996:1;15-23.
Located in the plasma, ceruloplasmin is implicated in the release of iron from macrophages and hepatocytes. Ceruloplasmin is decreased in hereditary hemochromatosis due to a mutation in the HFE gene [23].
 References
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(13) Knutson MD, Vafa MR, Haile DJ, et al. Iron loading and erythrophagocytosis increase ferroportin 1 (FPN1) expression in J774 macrophages. Blood. 2003;102(12):4191-7.
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(15) Harrison, PM, Ferritin: an iron-storage molecule. Semin Hematol. 1977;14(1):55-70.
(16) Haile DJ, Hentze MW, Rouault TA, et al. Regulation of interaction of the iron-responsive element binding protein with iron-responsive RNA elements. Mol Cell Biol. 1989;9(11):5055-61.
(17) Nemeth E, Tuttle MS, Powelson J, et al. Hepcidin regulates iron efflux by binding to ferroportin and inducing its internalization. Science. 2004; 306:2090-3.
(18) Mena NP, Esparza AL, Nunez MT. Regulation of transepithelial transport of iron by hepcidin. Biol Res. 2006;39:191-3.
(19) Viatte L, Lesbordes-Brion JC, Lou DQ, et al. Deregulation of proteins involved in iron metabolism in hepcidin-deficient mice. Blood. 2005;105(12):4861-4.
(20) Zoller H, Theurl I, Koch RO, et al. Duodenal cytochrome b and hephaestin expression in patients with iron deficiency and hemochromatosis. Gastroenterology. 2003;125(3):746-54.
(21) Feder JN, Gnirke A, Thomas W, et al. A novel MHC class I-like gene is mutated in patients with hereditary hemochromatosis. Nat Genet. 1996;13(4):399-408.
(22) Fleming RE, Britton RS. Iron Imports. VI. HFE and regulation of intestinal iron absorption. Am J Physiol Gastrointest Liver Physiol. 2006;290(4):G590-4.
(23) Laine F, Ropert M, Lan Cl, et al. Serum ceruloplasmin and ferroxidase activity are decreased in HFE C282Y homozygote male iron-overloaded patients. J Hepatol. 2002; 36(1):60-5.
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