Molecular evidence for the role of a ferric reductase in iron transport

McKie, Andrew T.; Latunde-Dada, Gladys O.; Miret, Silvia; McGregor, J A; Anderson, Gregory J.; Vulpe, Chris D.; Wrigglesworth, John M.; Simpson, Robert J.

doi:10.1042/bst0300722

Cited by 54 publications

(26 citation statements)

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“…The Nramp2 mRNA contains IREs and the expression of Nramp2 is regulated post-transcriptionally by the iron level in the body. Defects in Nramp2 (mk mouse and Belgrade rat) lead to the impaired transport of iron and the defective endosomal transport of iron (Andrews 2002;McKie et al 2002). These results indicated that Nramp2 is also involved in the transport of ferrous ion across endosomal membrane into the cytoplasm after the transferrin-iron is released from transferrin in endosomes and reduced by ferrireductase.…”

Section: New Members Involved In the Regulation Of Intracellular Levementioning

confidence: 65%

“…After the absorption of iron by intestinal Nramp2, the transport of iron across the basolateral membrane to the portal vein occurs. An ironregulated transporter, IREG1, specially expressed in the duodenal mucosa has been cloned, and functions in the stimulation of iron efflux from the cells (McKie et al 2002). The expression of IREG1 is increased dependent on the increase in iron absorption and the 5´-uncoding region of IREG1 mRNA contains an IRE.…”

Section: New Members Involved In the Regulation Of Intracellular Levementioning

confidence: 99%

“…Before the entry of iron into enterocytes, insoluble ferric ion can be reduced by a cytochrome b-like hemoprotein Dcytb at the plasma membrane (Fig. 4) (McKie et al 2002). A transmembrane protein Nramp2 (also known as DCT1 or DMT1) is expressed on the lumen of the intestine and transports ferrous ion across the membrane.…”

Section: New Members Involved In the Regulation Of Intracellular Levementioning

confidence: 99%

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Aquisition, Mobilization and Utilization of Cellular Iron and Heme: Endless Findings and Growing Evidence of Tight Regulation

Taketani

2005

Tohoku J. Exp. Med.

100

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Iron is fastidiously utilized by living cells, since it is an essential element, but is toxic in excess. Cells take up iron via a transferrin-transferrin receptor-dependent endocytotic process. The iron thus taken up is used for essential biological functions including oxygen transport, electron transfer, and DNA synthesis. The intracellular level of iron is tightly controlled, through regulation of the cellular uptake of iron and the sequestering of low molecular labile iron into the storage protein ferritin. The known proteins of iron transport and storage, transferrin, transferrin receptor and ferritin, have been recently linked with a number of newly identified proteins that are responsible for inherited diseases of iron metabolisms and play critical roles in the maintenance of iron homeostasis. These proteins are involved in regulation of intracellular levels of iron, iron transport, and heme transport and the oxygen-dependent regulation of gene expression. On the other hand, most iron is transported into mitochondria and immediately used for the biosynthesis of heme in erythroid cells. The heme biosynthesis in mitochondria is coupled with the supply of iron, and the heme, exported from mitochondria, is utilized as prosthetic groups of hemeproteins. Furthermore, non-erythroid and erythroid cells possess the different regulatory systems for the biosynthesis of heme; iron positively regulates the biosynthesis in erythroid cells while heme negatively regulates it in non-erythroid cells. Because of the toxicity and insolubility of heme, the intracellular level of uncommitted heme is maintained at a low concentration (< 10 -9 M). The influx and efflux of heme also help to prevent cytotoxicity. Finally, heme-binding transcriptional factors such as Bach1 and NPAS2 regulate the transcription of several genes involved in the synthesis and degradation of heme-hemeproteins. The discovery of new molecules related to disorders of iron and heme metabolism is ascribable to a complete mechanistic understanding of the cellular network of iron homeostasis. The network of interactions that link iron and heme metabolisms with functions of cellular regulation involving oxidative stress and inflammations contributes to new insights into clinical aspects of disorders.

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Section: New Members Involved In the Regulation Of Intracellular Levementioning

confidence: 65%

Section: New Members Involved In the Regulation Of Intracellular Levementioning

confidence: 99%

Section: New Members Involved In the Regulation Of Intracellular Levementioning

confidence: 99%

See 1 more Smart Citation

Aquisition, Mobilization and Utilization of Cellular Iron and Heme: Endless Findings and Growing Evidence of Tight Regulation

Taketani

2005

Tohoku J. Exp. Med.

100

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“…However, the vitamin has other important, non-antioxidant biological functions [16,17], of which some are related to its ability to reduce ferric (Fe 3+ ) to ferrous (Fe 2+ ) iron. AA promotes intestinal absorption of dietary non-haem Fe 2+ iron through the divalent metal transporter 1 [18] and increases the activity of Fe 2+ -dependent prolyl hydroxylases that participate in the synthesis of collagen and carnitine [19,20]. The ability of AA to reduce ferric to ferrous iron may, Vitamin C, DNA damage and iron homeostasis 5 however, have deleterious consequences.…”

Section: Introductionmentioning

confidence: 99%

Vitamin C modulation of H2O2-induced damage and iron homeostasis in human cells

Duarte

Jones

2007

Free Radical Biology and Medicine

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Vitamin C (ascorbic acid, AA) is an important antioxidant in human plasma. It is clear, however, that AA has other important, non-antioxidant roles in cells. Of particular interest is its involvement in iron metabolism, since AA enhances dietary iron absorption, increases the activity of Fe 2+ -dependent cellular enzymes, promotes Fenton reactions in vitro and was reported to have deleterious effects in individuals with iron overload. Nevertheless, the ability of AA to modulate iron metabolism and enhance iron-dependent damage in cells, tissues and organisms has not been fully elucidated. Here we investigated the effect of AA on iron-mediated oxidative stress in normal human fibroblasts. Incubation with physiologically relevant concentrations of AA was not harmful but sensitised cells towards H 2 O 2 -induced, iron-dependent DNA strand breakage and cell death. We also report that AA increased the levels of intracellular catalytic iron and concomitantly modulated the expression of two wellestablished iron-regulated genes, ferritin and transferrin receptor. In summary, we present evidence of a novel, non-antioxidant role of AA in human cells, where it increases iron availability and enhances ROS-mediated, iron-dependent damage. We suggest that AA may exacerbate the deleterious effects of metals in vivo and promote normal tissue injury in situations associated with elevated ROS production.

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“…(72). The cytoplasmic Fe(II) can efflux from the enterocyte at the basolateral surface via the Fe(II) permease Fpn.…”

Section: Ferrireductases and Ferroxidases Are The Iron Metabolic Pathwaymentioning

confidence: 99%

Redox Cycling in Iron Uptake, Efflux, and Trafficking

Kosman

2010

Journal of Biological Chemistry

106

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Aerobic organisms are faced with a dilemma. Environmental iron is found primarily in the relatively inert Fe(III) form, whereas the more metabolically active ferrous form is a strong pro-oxidant. This conundrum is solved by the redox cycling of iron between Fe(III) and Fe(II) at every step in the iron metabolic pathway. As a transition metal ion, iron can be "metabolized" only by this redox cycling, which is catalyzed in aerobes by the coupled activities of ferric iron reductases (ferrireductases) and ferrous iron oxidases (ferroxidases).Following the first crystallization of a protein, jack bean urease, reported by Sumner in 1926 (1), the evolution of protein chemistry remained a slow process, hampered by limitations in techniques for protein resolution and analysis. Not surprisingly, many proteins obtained in relatively pure form were those with prosthetic metal ion groups that imparted a visible absorbance to guide the purification. Some were copper proteins whose Cu(II) spectral properties gave their protein host a greenish blue to bright blue hue. Two of these were from mammalian whole blood: hemocuprein (cupric species from erythrocytes, superoxide dismutase) and ceruloplasmin (cerulean blue species from plasma). Superoxide dismutase was first isolated in 1938 by Mann and Keilin (5); Cp 2 was first isolated in 1948 by Holmberg and Laurell (6). Both proteins play essential roles in aerobic homeostasis. In the case of ceruloplasmin and the other copper proteins that share its substrate specificity, this role is to manage the redox state of iron in the metabolism of this essential yet potentially cytotoxic transition metal ion. These proteins, all of which are members of the MCO family (7-9), and the mechanism by which they provide this function are a focus of this minireview.

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Molecular evidence for the role of a ferric reductase in iron transport

Cited by 54 publications

References 4 publications

Aquisition, Mobilization and Utilization of Cellular Iron and Heme: Endless Findings and Growing Evidence of Tight Regulation

Aquisition, Mobilization and Utilization of Cellular Iron and Heme: Endless Findings and Growing Evidence of Tight Regulation

Vitamin C modulation of H2O2-induced damage and iron homeostasis in human cells

Redox Cycling in Iron Uptake, Efflux, and Trafficking

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