Divalent metal transporter

Enterocytes in the proximal duodenum are responsible for absorption of iron. Incoming iron in the Fe " state is reduced to Fe " by a ferrireductase present on the surface of enterocytes. Vitamin C in food also favors reduction of ferric iron to ferrous iron. The transfer of iron from the apical surfaces of enterocytes into their interiors is performed by a proton-coupled divalent metal transporter (DMTl). This protein is not specific for iron, as it can transport a wide variety of divalent cations. 

Figure 7.13 The transferrin to cell cycle HOLO-TF, diferric transferrin TFR, transferrin receptor DMT1, divalent metal transporter. (From Andrews, 2000. Reproduced by permission of Nature Reviews Genetics.)...

Iron crosses the luminal membrane of the intestinal mucosal cell by two mechanisms active transport of ferrous iron and absorption of iron complexed with heme (Figure 33-1). The divalent metal transporter, DMT1, efficiently transports ferrous iron across the luminal membrane of the intestinal enterocyte. The rate of iron uptake is regulated by mucosal cell iron stores such that more iron is transported when stores are low. Together with iron split from absorbed heme, the newly absorbed iron can be actively transported into the blood across the basolateral membrane by a transporter known... 

Fig. 6.10 Divalent metal transporter 1 (DMT 1) immunoreactivity in field CA1 of the hippocampus. A section from a normal rat, showing light staining (asterisk). B section from a rat that had been injected with kainate 1 month earlier. Large numbers of DMT1 positive astrocytes (arrows) are present in the affected area (asterisk). Double arrow indicates glial end feet around blood vessels. Scale 150 //m. Reproduced with kind permission from Wang et al., 2002, Experimental Neurology, 177 193-201. Elsevier...

Huang E., Ong W. Y., and Connor J. R. (2004). Distribution of divalent metal transporter-1 in the monkey basal ganglia. Neuroscience 128 487 -496. 

Vanadate transport in the erythrocyte was shown to occur via facilitated diffusion in erythrocyte membranes and was inhibited by 4,4 -diisothiocyanostilbene-2,2 -disulfonic acid (DIDS), a specific inhibitor of the band 3 anion transport protein [23], Vanadium is also believed to enter cells as the vanadyl ion, presumably through cationic facilitated diffusion systems. The divalent metal transporter 1 protein (called DMT1, and also known as Nramp2), which carries iron into cells in the gastrointestinal system and out of endosomes in the transferrin cycle [24], has been proposed to also transport the vanadyl cation. In animal systems, specific transport protein systems facilitate the transport of vanadium across membranes into the cell and between cellular compartments, whereas the transport of vanadium through fluids in the organism occurs via binding to proteins that may not be specific to vanadium. 

Iron levels are tightly regulated through control of dietary absorption of iron. The duodenum and upper jejunum are the only areas of the body where this occurs. Since nonheme iron forms insoluble complexes when ingested, it must first be converted into soluble complexes. This is accomplished on the apical surface of duodenal villus enterocytes by duodenal ferric reductase, which converts insoluble duodenal ferric (Fe3+) iron into soluble and absorbable ferrous (Fe2+) iron. Iron is then transported across the membrane to the cytoplasm through a transporter known as the divalent metal transporter 1 (DMT-l), a proton sym-porter (Harrison and Bacon, 2003). 

Trinder, D., Oates, P. S., Thomas, C., Sadleir, J., and Morgan, E. H. (2000). Localisation of divalent metal transporter 1 (DMTl) to the microvillus membrane of rat duodenal enterocytes in iron deficiency, but to hepatocytes in-iron overload [See comments]. Gut 46, 270-276. 

Pathway (IMP) uptake of iron. Blood 81, 517-521,1993 Wolf, G. and Wessling-Resnick, M., An integrin-mobilferrin iron transport pathway in intestine and hematopoietic cells, Nutr. Rev. 52, 387-389, 1994 Conrad, M.E. and Umbreit, J.N., Iron absorption and transport — an npdate, Amer. J. Hema-tol 64, 287-298, 2000 Umbreit, J.N., Conrad, M.E., Hainsworth, L.N., and Simovich, M., The ferrireductase paraferritin contains divalent metal transporter as well as mobilferrin. Am. J. Physiol. Gastrointest. Liver Physiol 282, G534-G539, 2002. 

Abbreviations P-Gty. P-gtycoprotein GGT gamma glutamyl transpeptidase AmB. amphotericin B DMTI. divalent metal transporter OAT. organic anion transporter Ctrl, copper transporter TEER. transepithelial electrical resistance ROS. reactive oxygen species GST glutathione-S transferase GSH. glutathione Gd-MT cadmium-metallothionein. 

Abouhamed M, Wolff NA, Lee WK, Smith CP, and Thevenod F. Knockdown of endosomal/lysosomal divalent metal transporter 1 by RNA interference prevents cadmium-metallothionein-1 cytotoxicity in renal proximaltubulecells.AmJ Physiol Renal Physiol 293 F705-712, 2007. 

CIN chronic interstitial nephritis DMT divalent metal transporter... 

Figure 3f-l9 Schematic representation of some of the steps that may occur when iron is transported from the intestinal lumen to the blood. Heph, Hephaestln SFT, stimulator of iron transport DMT-/, divalent metal transporter-1. 

FIGURE 7.18 The transferrin to cell cycle. HOLO-TF diferric transferrin TfR, transferrin receptor DMTl, divalent metal transporter. 

A fundamental and still unanswered question in iron metabolism is how iron is released from hTi and when and where is it reduced to the ferrous state before being transported across the endosomal membrane to the cytoplasm by divalent metal transporter DMTl Experiments carried out at endosomal conditions indicate that iron released from Tf to most physiological iron binders is easily reducible." However, the time required for the release of iron from transferrin as Fe " to physiological chelators, even at endosomal pH, is much longer (>6 min) than that compared to the cell-cycling time of transferrin, which may be as little as 1-2 min. Transferrin completes some 100-200 cycles of iron uptake, transport and delivery to cells during its lifetime in the circulation, thus demanding a sophisticated and efficient iron-release process. 

Total-body iron of a 70-kg adult is about 4.2-4A g. The distribution of iron in various body compartments is given in Table 29-1. The key players of iron metabolism include iron-responsive elements of appropriate mRNAs, iron regulatory proteins divalent metal transporter 1, major histocompatibility complex (MHC) class I-like protein designated as HFE protein, d2-microglobulin, transferrin, transferrin receptor, and ferritin. 

Intestinal absorption of dietary iron. Ferrous iron is absorbed by the duodenal villus tip enterocytes mediated by divalent metal transporter-1 (DMTI). Iron transport mediated by DMTl of the apical surface and the basolateral tran.sporter at the basolateral surface are coupled to ferric reductase and ferroxidase that change the iron oxidation state, respectively. The degree of iron entry is determined by the level of DMTl and its level of expression is programmed in the crypt cells. The programming of the crypt cells is coupled to the body iron stores via transferrin-mediated and HFE protein-modulated iron transport. [Modified and reprinted with permission from B. R. Bacon, L. W. Powell,... 

Bannon DI, Portnoy ME, Olivi L, Lees PSJ, CuLOTTA VC and Bressler JP (2002) Uptake of lead and iron by divalent metal transporter 1 in yeast and mammalian cells. Biochem Biophys Res Commun 295 978-984. 

For example, astrocytes and neurons in the normal brain contain the divalent metal transporter DMT-1 (Burdo et al., 1999 Wang et al., 2001 Huang et al.,... 

Huang, E., W.Y. Ong and J.R. Connor. (2004) Distribution of divalent metal transporter-1 in the monkey basal gangha. Neuroscience 128 487-496 Huang, E. and W.Y. Ong. (2005) Distribution of ferritin in the rat hippocampus after kainate-induced neuronal injury. Exp. Brain Res. 161 502-511 Ide-Ektessabi, A., Y. Ota, R. Ishihara, Y. Mizuno and T. Takeuchi. (2005) Distribution of lead in the brain tissues from DNTC patients using synchrotron radiation microbeams. Nucl. Instrum. Methods Phys. Res. B 241 681-684... 

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