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Recent progress in elucidating the genetic and molecular mechanisms of iron metabolism provides insight into diseases of iron balance. These discoveries have identified molecules that can serve as targets for blood tests to monitor and screen for iron overload.
[Source: http://www.pdb.org/pdb/explore/explore.do?structureId=1H76] PDB ID: 1H76. Hall DR, Hadden JM, Leonard GA, Bailey S, Neu M, Winn M, Lindley PF. The crystal and molecular structures of diferric porcine and rabbit serum transferrins at resolutions of 2.15 and 2.60 Å, respectively. Acta Crystallogr D Biol Crystallogr. 2002;58(Pt 1):70-80.
Transferrin is an iron-transport protein that binds tightly to iron and protects tissues from iron toxicity. The molecule has two iron-binding sites for ferric (Fe3+) iron. Monoferric transferrin carries one iron atom; diferric carries two. When 'empty' it is called apotransferrin. The total iron-binding capacity of transferrin is limited. Hypotransferrinemia is a genetic disease in which insufficient transferrin production results in widespread toxicity from exposure to NTBI.
[Source: http://www.pdb.org/pdb/explore.do?structureId=1SUV]
PDB ID: 1SUV. Cheng Y, Zak O, Aisen P, Harrison SC, Walz T. Structure of the human transferrin receptor-transferrin complex. Cell. 2004 Feb 20;116(4):483-5.
The cellular uptake of transferrin bound iron is controlled by regulating the expression of cell surface transferrin receptors through iron response elements that regulate the transcription of transferrin receptors. Almost all cells have transferrin receptors, but they are found in greatest numbers on hepatocytes, immature erythrocytes, and both malignant and non-malignant rapidly dividing cells [10]. In contrast, the uptake of NTBI into cells is not regulated and eventually leads to iron loading of organs such as the liver, heart, and endocrine glands.
In the duodenal enterocyte, DMT1 is responsible for transporting dietary non-heme iron (Fe2+) unidirectionally across the apical membrane into the cell [5]. Divalent metal transporter protein is also involved in the transport of NTBI across cell membranes in both enterocytes and erythroid precursors.
Ferroportin is involved in the export of iron from inside cells. Like DMT1, ferroportin is specific for Fe2+ and functions unidirectionally. In enterocytes, ferroportin, with assistance from hephaestin, exports iron across the basolateral wall and into the plasma [11]. The transport of iron may also be aided by the soluble plasma ferroxidase,ceruloplasmin, which performs a similar role as hephaestin. In hepatocytes, ferroportin upregulation can prevent cell damage by facilitation of the excretion of excess iron [12]. In senescent red blood cells and reticuloendothelial macrophages, ferroportin is directly involved in the export of iron during erythrocyte-iron recycling [13].
[Source: http://www.pdb.org/pdb/explore/explore.do?structureId=1FHA] PDB ID: 1FHA. Lawson DM, Artymiuk PJ, Yewdall SJ, et al. Solving the structure of human H ferritin by genetically engineering intermolecular crystal contacts. Nature. 1991;349(6309):541-4.
Ferritin is an intracellular iron storage molecule that stores iron in a form readily accessible to cells and releases it in a controlled fashion in response to the body's needs. Therefore, ferritin can act as a 'buffer' against iron storage problems by releasing more if the body is iron deficient or, to some extent, by storing excess iron if the blood and body tissues are iron overloaded [14]. The ferritin molecule forms a hollow sphere capable of holding as many as 4500 ferric (Fe3+) iron atoms [15]. Ferritin is found in measurable quantities within the blood as serum ferritin, but is located predominantly within reticuloendothelial macrophages and hepatocytes. Presumably, most other cells synthesize ferritin as well.
Under steady-state conditions serum ferritin levels correlate with total body iron. However, ferritin is an acute-phase reactant so can be naturally elevated during the course of disease. Inflammation and infections, ascorbate levels, abnormal liver function, and increased erythropoiesis can influence circulating ferritin levels. As such, a single measure of ferritin is not clinically useful, although long-term serial assessment is convenient and valuable for estimating body iron stores and for monitoring chelation therapy.
Normal serum ferritin levels differ for males (<300 ng/mL) and females (<150 ng/mL). Mild-to-moderate iron overload is indicated by serum ferritin levels of 300-2500 ng/mL, while levels >2500 ng/mL are associated with an increased risk of cardiac disease. The predictive value of serum ferritin for the major complications of iron overload varies according to the type and severity of underlying anemia and the mechanism of iron loading [14].
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