How Iron is transported?

Iron Transport

Iron is normally transported via the specific binding of Fe3+ by transferrin in blood plasma. The Fe3+ transferrin complex is bound by transferrin receptors to cells of the target organs which allows specific iron uptake according to the individual needs of the various cells. Pronounced non-specific binding to other transport Proteins, such as albumin, occurs only in conditions of iron overload with high levels of transferrin saturation. Where there is an abundant supply of heme-bound iron, part of the Fe2+heme complex may escape oxidation in the cells of the mucosa and be transported to the liver after being bound by haptoglobin or hemopexin.

Proteins Involved in Iron Transport

Proteins are divided into families based on their function. This includes;

• The proteins that are involved in iron transport across cellular membranes
• The reductases and oxidases that facilitate the movement of iron across cell membranes
• Iron transport in the circulation and its intracellular storage
• The proteins that control iron homeostasis by regulating all of the above processes.
• Mutations in the genes encoding many of these proteins lead to a wide range of diseases.

Proteins Mediating Iron Transport Across Cellular Membranes

Divalent Metal-Ion Transporter 1

The divalent metal transporter, DMT1 – also known as the divalent cation transporter, DCT1, natural resistance associated macrophage protein (Nramp 2), transports ferrous iron across the apical membrane of the intestinal epithelium. In addition to its essential role in dietary non-heme iron absorption, DMT1 is also required for the endosomal release of transferrin-bound iron.

Heme Transporters

In addition to non-heme iron, the iron contained within heme also makes an important contribution to dietary iron absorption. Heme is absorbed intact and the iron is liberated intracellularly under the action of heme oxygenase.

Ferroportin

Transferrin Receptors

Transferrin and Iron-Binding Capacity:

Transferrin is synthesized in the liver, and has a half-life of 8 to 12 days in the blood. It is a glycoprotein having a molecular weight of 79.6 kD, and PI electrophoretic mobility. Its synthesis in the liver may be increased as a corrective measure, depending on iron requirements and iron reserves. Each transferrin molecule can bind a maximum of 2 Fe3+ Ions, corresponding to about 1041 flg of iron per mg of transferrin. Since transferrin is the only specific iron transport protein, the total specific iron-binding capacity can be measured indirectly via the immunological determination of transferrin.

Transferrin Receptor (TfR)

All tissues and cells which require iron regulate their iron uptake by expression of the transferrin receptor on the surface of the cell. Since most of the iron is required for hemoglobin synthesis in the Precursor cells of erythropoiesis in the bone marrow, approximately 80% of the transferrin receptors of the body can be found on these cells.

All cells are capable of regulating individual transferrin receptor expression according to the current iron requirement or the supply of iron at the cell level. A small but representative proportion of these transferrin receptors is also released into the blood as so-called soluble transferrin receptors and can be detected by immunochemical methods in a concentration of a few milligrams per liter.

It is a dimeric protein with a molecular weight of approximately 190 000 daltons, each of the two Sub-units is capable of binding a molecule of transferrin. In iron metabolism the transferrin receptor has a major role in supplying the cell with iron. The TtR-Tf-Fe complex is channeled through a pH gradient into the cell by the "endocytic residue".

The change from the alkaline pH of the blood to the acidic pH of the endosome changes the binding situation: Iron ions dissociate spontaneously from the transferrin while the bond between Tf and TtR is strengthened. Only when the TtR-Tf complex returns to the cell membrane does the pH change their cause the complex to dissociate. The transferrin reenters the plasma and is again available for Fe transport.

Mitoferrin

Mitoferrin, a member of the vertebrate mitochondrial solute carrier family (SLC25A37) was identified by positional cloning, and is highly expressed in hematopoietic tissue. A mutation in the mitoferrin gene in is responsible for the phenotype that shows profound hypochromic anemia and the arrest of erythroid maturation owing to defects in mitochondrial iron uptake.

Iron Reductases and Oxidases That Facilitate the Movement of Iron Across Membranes

Duodenal Cytochromes b (Dcytb)

the brush-border surface of duodenal enterocytes and cultured intestinal cells possess ferric reductase enzymic activity from Fe(III) to Fe(II). The enzyme responsible for this process, named Dcytb (duodenal cytochrome b). Dcytb is expressed at the apical membrane of duodenal enterocytes, the major site for the absorption of dietary iron and like other members of the cytochrome b 561 family is a heme-containing, ascorbate requiring protein. The mRNA expression of Dcytb is highly regulated by dietary iron status, hypoxia and in hemo-chromatosis, suggesting that it plays an important role in the maintenance of body iron homeostasis.

The Six Transmembrane Epithelial Antigen of the Prostate (STEAP) Family

A second family of reductase proteins

Ceruloplasmin

The essential role played by copper in the regulation of iron metabolism has been recognized for many years. However, it is only relatively recently that we have begun to understand the molecular basis for the biological interactions between these two metals.

Hephaestin (HEPH)

Hephaestin is a transmembrane copper-dependent ferroxidase, helps to export iron across the cell membrane using ferroxidase activity to oxidize iron to its ferric form so that it binds to transferrin. Another role for hephaestin is that it facilitates the absorption of iron from the intestine to the bloodstream.