User:KH1412/sandbox

DMT1 (Draft1)

Iron is not only essential for the human body, it is required for all organisms in order for them to be able to grow. Iron also participates in many metabolic pathways. Iron deficiency can lead to iron-deficiency anemia thus iron regulation is very crucial in the human body.

Iron Transport Process in Mammals

The process of iron transportation consists of iron being reduced by ferrireductases that are present on the cell surface or by dietary reductants such as ascorbate (Vitamin C). Once the Fe³⁺ has been reduced to Fe²⁺, the DMT1 transporter protein transports the Fe²⁺ ions into the cells that line the small intestine (enterocytes). From there, the ferroprotin/IREG1 transporter exports it across the cell membrane where is it oxidized to Fe³⁺ on the surface of the cell then bound by transferrin and released into the blood stream.

Low Selectivity of DMT1

DMT1 is not a 100% selective transporter as it also transports Zn²⁺, Mn²⁺, and Cd²⁺ which can lead to toxicity problems. The reason for this is because it cannot distinguish the difference between the different metal ions due to low selectivity for iron ions. In addition, it causes the metal ions to compete for transportation and the concentration of iron ions is typically substantially lower than that of other ions.

Compared to FTR1/Fet3

The iron uptake pathway in Saccharaomyces cerevisiae, which consists of a multicopper ferroxidase (Fet3) and an iron plasma permease (FTR1) has a high affinity for iron uptake compared to the DMT1 iron uptake process present in mammals. The iron uptake process in yeasts consists of Fe³⁺ which is reduced to Fe²⁺ by ferriductases. Ferrous iron may also be present outside of the cell due to other reductants present in the extracellular medium. Ferrous iron is then oxidized to ferric iron by Fet3 on the external surface of the cell. Then Fe³⁺ is transferred from Fet3 to FTR1 and transferred across the cell membrane into the cell.

Ferrous-oxidase mediated transport systems exist in order to transport specific ions opposed to DMT1, which does not have complete specificity. The Fet3/FTR1 iron uptake pathway is able to achieve complete specificity for iron over other ions due to the multi-step nature of the pathway. Each of the steps involved in the pathway is specific to either ferrous iron or ferric iron. The DMT1 transporter protein does not have specificity over the ions it transports because it is unable to distinguish between Fe²⁺ and the other divalent metal ions it transfer through the cell membrane. Although, the reason that non-specific ion transporters, such as DMT1, exist is due to their ability to function in anaerobic environments opposed to the Fet3/FTR1 pathway which requires oxygen as a co substrate. So in anaerobic environments the oxidase would not be able to function thus another means of iron uptake is necessary.

Structure and Transport Mechanisms for DMT1 (Additional 250 + 400 Word/Word Equivalency)

Iron uptake across the brush border membrane of enterocytes with DMT1 transporter protein.

Predicted topology model for DMT1 with 12 transmembrane domains as well as the N- and C- terminals both in the cytosol of the cell membrane.

There is no crystal structure available for DMT1 yet, however researchers have an idea of how the DMT1 transporter protein functions, although a thorough understanding of the transportation process has not been completed.

Iron uptake is facilitated by DMT1 in enterocyte cells and macrophages. DMT1 is present on the brush border membrane of the enterocytes cells. Iron in the ferric form (Fe³⁺) is reduced to its ferrous form (Fe²⁺) by DcytB. DcytB is an iron-regulated reductase that is present on the brush border membrane of enterocyte cells. In addition to transporting iron across the membrane, DMT1 acts as a symporter of other divalent metal-ions and H⁺.

The topology model that was predicted for DMT1 depicts that DMT1 has a 12 transmembrane (TM) domain with a glycosylated extracytoplasmic loop . In addition to that, transmembrane domains 1 and 6 are predicted to be critical in metal binding, uptake, and proton coupling. Along with the prediction for the number of TM domains, it is predicted that both the N- and C- terminals are in the cytosol, charged amino acids in the TM domains and a consensus transport motif present on one of the transmembrane loops.

Ferropotin Contribution

Transport Mechanism for FPN

Model of the exportation of iron through FPN with a ferroxidase present to facilitate the oxidation of iron from its ferrous form to its ferric form.

Model of the exportation of iron through FPN without a ferroxidase present leading FPN degradation.

The transporter protein that facilitates the exportation of iron to the extracellular membrane is ferropotin 1 (FPN). FPN begins to transport the ferrous iron across the membrane where it is oxidized by a ferroxidase to its ferric form. In this case, the ferroxidase is thought to be GPI-Cp which is a copper-containing protein ceruloplasmin. In order for the iron to be bound by transferrin (Tf) across the membrane it must be ferric iron. If there was no ferroxidase present to facilitate the oxidation of ferrous iron the metal would remain bound to FPN. FPN would be ubiquitinated thus head towards degradation.