Substrate Profile and Metal-ion Selectivity of Human Divalent Metal-ion Transporter-1

Illing, Anthony C; Shawki, Ali; Cunningham, Christopher L.; Mackenzie, Bryan

doi:10.1074/jbc.m112.364208

Cited by 226 publications

(208 citation statements)

References 65 publications

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“…1) Previous studies demonstrated that Ctr1 is a primary high-affinity Cu ϩ transporter in mammals, particularly within the intestine; however, a Ctr1-independent transport activity has been detected in Ctr1 Ϫ/Ϫ mouse embryonic fibroblasts (33). 2) Whereas we previously found no evidence that copper is a transported substrate of DMT1 in vitro (27), others have measured copper transport in vitro and concluded that DMT1 can transport Cu ϩ or Cu 2ϩ (1,2,16,29,34). Conversely, in two of the studies just cited, investigators proposed that Ctr1 is also capable of transporting Fe 2ϩ (16,34), so we also examined the expression of Ctr1 in the intestinal DMT1 int/int mouse.…”

mentioning

confidence: 42%

“…We concluded that intestinal DMT1 is not required for zinc homeostasis, an anticipated outcome since 1) Zn 2ϩ is a weak DMT1 substrate in vitro, relative to Fe 2ϩ (Ref. 27), and 2) ZIP4, a metal ϩ/ϩ (gray) and DMT1 int/int (black) mice as a function of time after the oral radiotracer dose. Each plot depicts the data for an individual mouse.…”

Section: G642 Role Of Intestinal Dmt1 In Metal Homeostasismentioning

confidence: 99%

“…We have more directly tested this possibility here in heterozygotes (DMT1 ϩ/int ) of the intestinal knockout mouse model. Whereas DMT1 is reactive with a broad range of divalent metal ions in vitro, it exhibits a strong preference for Fe 2ϩ over the other physiologically relevant metal ions it can transport (27). We ranked these according to the specificity constant as follows: Fe 2ϩ Ͼ Co 2ϩ , Mn 2ϩ ϾϾ Zn 2ϩ .…”

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Intestinal DMT1 is critical for iron absorption in the mouse but is not required for the absorption of copper or manganese

Shawki

Anthony

Nose

et al. 2015

American Journal of Physiology-Gastrointestinal and Liver Physi

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111

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Divalent metal-ion transporter-1 (DMT1) is a widely expressed iron-preferring membrane-transport protein that serves a critical role in erythroid iron utilization. We have investigated its role in intestinal metal absorption by studying a mouse model lacking intestinal DMT1 (i.e., DMT1 int/int ). DMT1 int/int mice exhibited a profound hypochromicmicrocytic anemia, splenomegaly, and cardiomegaly. That the anemia was due to iron deficiency was demonstrated by the following observations in DMT1 int/int mice: 1) blood iron and tissue nonheme-iron stores were depleted; 2) mRNA expression of liver hepcidin (Hamp1) was depressed; and 3) intraperitoneal iron injection corrected the anemia, and reversed the changes in blood iron, nonheme-iron stores, and hepcidin expression levels. We observed decreased total iron content in multiple tissues from DMT1 int/int mice compared with DMT1 ϩ/ϩ mice but no meaningful change in copper, manganese, or zinc. DMT1 int/int mice absorbed 64 Cu and 54 Mn from an intragastric dose to the same extent as did DMT1 ϩ/ϩ mice but the absorption of 59 Fe was virtually abolished in DMT1 int/int mice. This study reveals a critical function for DMT1 in intestinal nonheme-iron absorption for normal growth and development. Further, this work demonstrates that intestinal DMT1 is not required for the intestinal transport of copper, manganese, or zinc. copper absorption; iron deficiency; iron-deficiency anemia; iron-refractive iron-deficiency anemia; manganese absorption; SLC11A2; zinc metabolism IRON DEFICIENCY is the most prevalent micronutrient deficiency worldwide (4, 50). Its deficiency leads to irondeficiency anemia, and to neurological and developmental disorders in children (3, 4). Since there exists no regulated mechanism for the excretion of iron, regulation of the whole body iron economy is achieved by tightly controlling absorption of the metal (21). Failure to regulate iron absorption in a manner appropriate to iron status is characteristic of several hereditary iron-overload disorders and iron-refractive iron-deficiency anemia (12,19,21).Divalent metal-ion transporter-1 (DMT1; reviewed in Ref. 52) is a widely expressed mammalian proton-coupled iron transporter (23,38). Mice in which the SLC11A2 gene coding for DMT1 was globally inactivated (i.e., SLC11A2 Ϫ/Ϫ ) exhibited a severe hypochromic-microcytic anemia and did not survive more than 7 days (22). A critical role for DMT1 in erythroid iron acquisition was confirmed by the following observations: 1) transfusion of red blood cells, but not parenteral iron injections, improved survival of SLC11A2 Ϫ/Ϫ mice; and 2) lethal dose-irradiated wild-type mice into which the investigators transplanted hematopoietic stem cells from SLC11A2 Ϫ/Ϫ mice exhibited defective erythropoiesis (22). The microcytic (mk) mouse and Belgrade (b) rat models, inbred strains that harbor a Gly185¡Arg mutation in DMT1 (17, 18), also exhibited an anemia phenotype. Parenteral iron injections partially improved the condition, and tissue or vesicle preparations from the m...

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confidence: 42%

Section: G642 Role Of Intestinal Dmt1 In Metal Homeostasismentioning

confidence: 99%

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confidence: 99%

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Intestinal DMT1 is critical for iron absorption in the mouse but is not required for the absorption of copper or manganese

Shawki

Anthony

Nose

et al. 2015

American Journal of Physiology-Gastrointestinal and Liver Physi

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111

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“…The H ϩ gradient that drives DMT1-mediated iron uptake is generated by intestinal brushborder Na ϩ /H ϩ exchanger 3 (NHE3) (12). DMT1 transports only Fe 2ϩ , but most dietary iron is Fe 3ϩ (13); hence, a reduction step is needed before iron transport by DMT1. This activity is generally thought to be mediated by the ferrireductase duodenal cytochrome B (DCYTB 2 ; CYBRD1) located at the apical membrane of enterocytes (14).…”

Section: Dietary Iron Absorption By the Enterocytementioning

confidence: 99%

Iron transport proteins: Gateways of cellular and systemic iron homeostasis

Knutson

2017

Journal of Biological Chemistry

117

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Edited by F. Peter GuengerichCellular iron homeostasis is maintained by iron and heme transport proteins that work in concert with ferrireductases, ferroxidases, and chaperones to direct the movement of iron into, within, and out of cells. Systemic iron homeostasis is regulated by the liver-derived peptide hormone, hepcidin. The interface between cellular and systemic iron homeostasis is readily observed in the highly dynamic iron handling of four main cell types: duodenal enterocytes, erythrocyte precursors, macrophages, and hepatocytes. This review provides an overview of how these cell types handle iron, highlighting how iron and heme transporters mediate the exchange and distribution of body iron in health and disease.

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“…Nramps are generally thought to function as metal-proton symporters (1) and are able to bind and/or transport a wide range of divalent transition metal substrates, including the biologically useful metals Mn 2+ , Fe 2+ , Co 2+ , Ni 2+ , Cu 2+ , and Zn 2+ , as well as the toxic heavy metals Cd 2+ , Pb 2+ , and Hg 2+ (4,(9)(10)(11)(12)(13). Nramps do discriminate against the divalent alkaline earth metal ions Mg 2+ and Ca 2+ (9,14), which are typically several orders of magnitude more abundant than the transition metals (15).…”

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Conserved methionine dictates substrate preference in Nramp-family divalent metal transporters

Bozzi

Bane

Weihofen

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

110

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Natural resistance-associated macrophage protein (Nramp) family transporters catalyze uptake of essential divalent transition metals like iron and manganese. To discriminate against abundant competitors, the Nramp metal-binding site should favor softer transition metals, which interact either covalently or ionically with coordinating molecules, over hard calcium and magnesium, which interact mainly ionically. The metal-binding site contains an unusual, but conserved, methionine, and its sulfur coordinates transition metal substrates, suggesting a vital role in their transport. Using a bacterial Nramp model system, we show that, surprisingly, this conserved methionine is dispensable for transport of the physiological manganese substrate and similar divalents iron and cobalt, with several small amino acid replacements still enabling robust uptake. Moreover, the methionine sulfur's presence makes the toxic metal cadmium a preferred substrate. However, a methionine-to-alanine substitution enables transport of calcium and magnesium. Thus, the putative evolutionary pressure to maintain the Nramp metal-binding methionine likely exists because it-more effectively than any other amino acid-increases selectivity for low-abundance transition metal transport in the presence of high-abundance divalents like calcium and magnesium.transition metals | MntH | divalent metal transporter DMT1 | hard-soft acid-base theory | ion selectivity filters A ll organisms require transition metal ions as cofactors in proteins that perform a variety of essential cellular tasks. Through evolution, organisms have developed mechanisms to acquire, transport, and safely store essential metals such as manganese, iron, cobalt, and zinc. The natural resistance-associated macrophage protein (Nramp) family of metal transporters represents a common transition metal acquisition strategy conserved across all kingdoms of life (1). The first discovered mammalian Nramp (Nramp1) is expressed in phagosomal membranes and likely extracts essential metals to help kill engulfed pathogens (2, 3). Mammals use Nramp2, an essential gene also called DMT1, to absorb dietary iron into the enterocytes that line the small intestine (4) and to extract iron from transferrin-containing endosomes in all tissues. Bacteria express their own Nramp homologs, which they typically use to scavenge manganese and other first row divalent transition metals (5, 6). Last, most plants have several Nramp homologs that take up iron and manganese, the essential cofactor in photosystem II, from the soil or vacuolar stores (7,8).Nramps are generally thought to function as metal-proton symporters (1) and are able to bind and/or transport a wide range of divalent transition metal substrates, including the biologically useful metals Mn 2+ , Fe 2+ , Co 2+ , Ni 2+ , Cu 2+ , and Zn 2+ , as well as the toxic heavy metals Cd 2+ , Pb 2+ , and Hg 2+ (4, 9-13). Nramps do discriminate against the divalent alkaline earth metal ions Mg 2+ and Ca 2+ (9, 14), which are typically several orders of magnitude mor...

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Substrate Profile and Metal-ion Selectivity of Human Divalent Metal-ion Transporter-1

Cited by 226 publications

References 65 publications

Intestinal DMT1 is critical for iron absorption in the mouse but is not required for the absorption of copper or manganese

Intestinal DMT1 is critical for iron absorption in the mouse but is not required for the absorption of copper or manganese

Iron transport proteins: Gateways of cellular and systemic iron homeostasis

Conserved methionine dictates substrate preference in Nramp-family divalent metal transporters

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