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Cited by 3,166Iron Metabolism and DisordersTrace Elements in HealthPlant Micronutrient Interactions and Effects

Cloning and characterization of a mammalian proton-coupled metal-ion transporter

Gunshin, Hiromi, Mackenzie, Bryan, Berger, Urs V., Gunshin, Yoshimi, Romero, Michael F., Boron, Walter F., Nussberger, Stephan, Gollan, John L. +1 more·1997·Nature
DOI 10.1038/41343
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Abstract

Metal ions are essential cofactors for a wealth of biological processes, including oxidative phosphorylation, gene regulation and free-radical homeostasis. Failure to maintain appropriate levels of metal ions in humans is a feature of hereditary haemochromatosis, disorders of metal-ion deficiency, and certain neurodegenerative diseases. Despite their pivotal physiological roles, however, there is no molecular information on how metal ions are actively absorbed by mammalian cells. We have now identified a new metal-ion transporter in the rat, DCT1, which has an unusually broad substrate range that includes Fe2+, Zn2+, Mn2+, Co2+, Cd2+, Cu2+, Ni2+ and Pb2+. DCT1 mediates active transport that is proton-coupled and depends on the cell membrane potential. It is a 561-amino-acid protein with 12 putative membrane-spanning domains and is ubiquitously expressed, most notably in the proximal duodenum. DCT1 is upregulated by dietary iron deficiency, and may represent a key mediator of intestinal iron absorption. DCT1 is a member of the 'natural-resistance-associated macrophage protein' (Nramp) family and thus its properties provide insight into how these proteins confer resistance to pathogens.

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  • Uptake of ionic non-heme iron is a sequential process: ferric iron is reduced by DCYTB at the luminal surface of enterocytes, and DMT1 imports iron into the cytoplasm.

    “The uptake of ionic NHI in contrast, is a sequential process that is well characterized: Following the reduction of ferric iron by DCYTB (for duodenal cytochrome B) at the luminal surface of enterocytes (ENT), it is DMT1 (for divalent metal transporter-1) that imports iron into the cytoplasm (Gunshin et al., 1997;McKie et al., 2001).”

    From Iron in infection and immunity (2020) · cites this paper as Gunshin et al., 1997

  • The freed ferric iron is reduced to Fe2+ by STEAP3 and shuttled into the cytosol from the endosome by DMT1.

    “The freed ferric iron is then reduced to its bio-active ferrous form, Fe2+ by the ferrireductase STEAP3 (six-transmembrane epithelial antigen of prostate 3) and shuttled into the cytosol from the endosome by DMT1 (Fleming et al., 1997; Gunshin et al., 1997; Ohgami et al., 2005; Figure 1).”

    From The Role of Iron Regulation in Immunometabolism and Immune-Related Disease (2019) · cites this paper as Gunshin et al., 1997

  • Iron absorption in the duodenum is controlled via DMT1 on the luminal side of enterocytes and by ferroportin on the basal side.

    “Iron absorption in the duodenum is controlled via the expression and transport activity of divalent metal transporter 1 (DMT1) on the luminal side of enterocytes [6] and by ferroportin (FPN1), the sole known iron exporter on the basal side, which transfers iron into the bloodstream [7].”

    From Iron in immune cell function and host defense (2021) · cites this paper as [6]

  • DMT1 is electrogenic, requiring proton cotransport to move Fe2+ across the membrane.

    “Gunshin 13 and Hediger 15 showed that DMT1 is electrogenic, requiring proton cotransport to move Fe 2ϩ across the membrane.”

    From Forging a field: the golden age of iron biology. (2008) · cites this paper as [13]

  • The first mammalian transmembrane iron transporter was discovered simultaneously in 2 laboratories in Boston using modern techniques.

    “In spite of these obstacles and entirely by chance, the first mammalian transmembrane iron transporter was discovered simultaneously in 2 laboratories, located within a city block of each other in Boston, using singularly modern techniques.12,13”

    From Forging a field: the golden age of iron biology. (2008) · cites this paper as [13]

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Authors
Gunshin, H., Mackenzie, B., Berger, U. V., Gunshin, Y., Romero, M. F., Boron, W. F., Nussberger, S., Gollan, J. L., & Hediger, M. A.
Affiliations
  • Brigham and Women's Hospital (US)
  • Yale University (US)
Corresponding author
Gunshin, Hiromi
ORCID
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
1997-07-31
Volume
388
Issue
6641
Pages
482-488
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/41343
OpenAlex
W1568628619
Cited by
3,166
References
30
Citations by year
2026: 47 · 2025: 70 · 2024: 60 · 2023: 69 · 2022: 85 · 2021: 82 · 2020: 94 · 2019: 100 · 2018: 98 · 2017: 102 · 2016: 82 · 2015: 98 · 2014: 129 · 2013: 92 · 2012: 129
FWCI
68.59
Type
journal article
Language
en
Open access
closed
Licence
Locations
  • Nature (publishedVersion)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
Funders
  • National Science Foundation
  • Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
  • National Institutes of Health
  • National Institute of Diabetes and Digestive and Kidney Diseases (F32DK009342)
Topics
  • Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
  • Health Sciences › Nursing › Nutrition and Dietetics › Trace Elements in Health
  • Life Sciences › Agricultural and Biological Sciences › Plant Science › Plant Micronutrient Interactions and Effects
Keywords
metal transporters, intestinal iron absorption, Nramp family, dietary iron deficiency, proximal duodenum, metal homeostasis, membrane potential dependence
MeSH terms
Iron Deficiencies, Natural Resistance-associated Macrophage Protein 1, Solute Carrier Family 11, Member 2, Amino Acid Sequence, Animals, Carrier Proteins, Cations, Divalent, Cells, Cultured, Cloning, Molecular, Humans, Iron, Membrane Potentials, Membrane Proteins, Metals, Molecular Sequence Data, Oocytes, Organ Specificity, RNA, Messenger, Xenopus, Sequence Homology, Amino Acid, Cation Transport Proteins, Iron-Binding Proteins, Rats

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