Natural resistance-associated macrophage protein 2
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Natural resistance-associated macrophage protein 2 (NRAMP 2), also known as divalent metal transporter 1 (DMT1) and divalent cation transporter 1 (DCT1),[5] is a protein that in humans is encoded by the SLC11A2 (solute carrier family 11, member 2) gene.[6] DMT1 represents a large family of orthologous metal ion transporter proteins that are highly conserved from bacteria to humans.[7]
As its name suggests, DMT1 binds a variety of divalent metals including
Function
Iron is not only essential for the human body, it is required for all organisms in order for them to be able to grow.[9] 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.
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 (
Ion selectivity
DMT1 is not a 100% selective transporter as it also transports Zn2+, Mn2+, and Ca2+ which can lead to toxicity problems.[10] 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.[10]
Yeast vs. mammal pathway
The iron uptake pathway in Saccharomyces 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.[11] The iron uptake process in yeasts consists of Fe3+ which is reduced to Fe2+ by ferriductases.[10] Ferrous iron may also be present outside of the cell due to other reductants present in the extracellular medium.[10] Ferrous iron is then oxidized to ferric iron by Fet3 on the external surface of the cell.[10] Then Fe3+ is transferred from Fet3 to FTR1 and transferred across the cell membrane into the cell.[10]
Ferrous-oxidase mediated transport systems exist in order to transport specific ions opposed to DMT1, which does not have complete specificity.[10] 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.[10] Each of the steps involved in the pathway is specific to either ferrous iron or ferric iron.[10] 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.[10] 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.[10] So in anaerobic environments the oxidase would not be able to function thus another means of iron uptake is necessary.[10]
Role in neurodegenerative diseases
Toxic accumulation of divalent metals, especially iron and/or manganese, are frequently discussed aetiological factors in a variety of neurodegenerative diseases, including
The DMT1 encoding gene SLC11A2 is located on the long arm of chromosome 12 (12q13) close to susceptibility regions for Alzheimer's disease
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000110911 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000023030 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Solute carrier family 11 (proton-coupled divalent metal ion transporters), member 2". GeneCards. Retrieved 2011-12-16.
- S2CID 22656880.
- PMID 18565586.
- S2CID 4416482.
- PMID 10373684.
- ^ OCLC 65400780.
- PMID 9516467.
- PMID 16460806.
- S2CID 21925120.
- ^ S2CID 6176823.
- S2CID 22098012.
- S2CID 22188818.
- S2CID 22609489.
Further reading
- Fleming MD, Trenor CC, Su MA, Foernzler D, Beier DR, Dietrich WF, Andrews NC (August 1997). "Microcytic anaemia mice have a mutation in Nramp2, a candidate iron transporter gene". Nature Genetics. 16 (4): 383–6. S2CID 41548981.
- Kishi F, Tabuchi M (1998). "Complete nucleotide sequence of human NRAMP2 cDNA". Molecular Immunology. 34 (12–13): 839–42. PMID 9464519.
- Lee PL, Gelbart T, West C, Halloran C, Beutler E (June 1998). "The human Nramp2 gene: characterization of the gene structure, alternative splicing, promoter region and polymorphisms". Blood Cells, Molecules & Diseases. 24 (2): 199–215. PMID 9642100.
- Kishi F, Tabuchi M (October 1998). "Human natural resistance-associated macrophage protein 2: gene cloning and protein identification". Biochemical and Biophysical Research Communications. 251 (3): 775–83. PMID 9790986.
- Tabuchi M, Yoshimori T, Yamaguchi K, Yoshida T, Kishi F (July 2000). "Human NRAMP2/DMT1, which mediates iron transport across endosomal membranes, is localized to late endosomes and lysosomes in HEp-2 cells". The Journal of Biological Chemistry. 275 (29): 22220–8. PMID 10751401.
- Griffiths WJ, Kelly AL, Smith SJ, Cox TM (September 2000). "Localization of iron transport and regulatory proteins in human cells". QJM. 93 (9): 575–87. PMID 10984552.
- Georgieff MK, Wobken JK, Welle J, Burdo JR, Connor JR (November 2000). "Identification and localization of divalent metal transporter-1 (DMT-1) in term human placenta". Placenta. 21 (8): 799–804. PMID 11095929.
- Tallkvist J, Bowlus CL, Lönnerdal B (June 2001). "DMT1 gene expression and cadmium absorption in human absorptive enterocytes". Toxicology Letters. 122 (2): 171–7. PMID 11439223.
- Sharp P, Tandy S, Yamaji S, Tennant J, Williams M, Singh Srai SK (January 2002). "Rapid regulation of divalent metal transporter (DMT1) protein but not mRNA expression by non-haem iron in human intestinal Caco-2 cells". FEBS Letters. 510 (1–2): 71–6. S2CID 12296540.
- Umbreit JN, Conrad ME, Hainsworth LN, Simovich M (March 2002). "The ferrireductase paraferritin contains divalent metal transporter as well as mobilferrin". American Journal of Physiology. Gastrointestinal and Liver Physiology. 282 (3): G534–9. S2CID 6295186.
- Simovich MJ, Conrad ME, Umbreit JN, Moore EG, Hainsworth LN, Smith HK (March 2002). "Cellular location of proteins related to iron absorption and transport". American Journal of Hematology. 69 (3): 164–70. S2CID 43201066.
- Rolfs A, Bonkovsky HL, Kohlroser JG, McNeal K, Sharma A, Berger UV, Hediger MA (April 2002). "Intestinal expression of genes involved in iron absorption in humans". American Journal of Physiology. Gastrointestinal and Liver Physiology. 282 (4): G598–607. PMID 11897618.
- Wang X, Ghio AJ, Yang F, Dolan KG, Garrick MD, Piantadosi CA (May 2002). "Iron uptake and Nramp2/DMT1/DCT1 in human bronchial epithelial cells". American Journal of Physiology. Lung Cellular and Molecular Physiology. 282 (5): L987–95. PMID 11943663.
- I Bannon D, Portnoy ME, Olivi L, Lees PS, Culotta VC, Bressler JP (July 2002). "Uptake of lead and iron by divalent metal transporter 1 in yeast and mammalian cells". Biochemical and Biophysical Research Communications. 295 (4): 978–84. PMID 12127992.
- Zoller H, Decristoforo C, Weiss G (August 2002). "Erythroid 5-aminolevulinate synthase, ferrochelatase and DMT1 expression in erythroid progenitors: differential pathways for erythropoietin and iron-dependent regulation". British Journal of Haematology. 118 (2): 619–26. S2CID 35114057.
- Hubert N, Hentze MW (September 2002). "Previously uncharacterized isoforms of divalent metal transporter (DMT)-1: implications for regulation and cellular function". Proceedings of the National Academy of Sciences of the United States of America. 99 (19): 12345–50. PMID 12209011.
- Tabuchi M, Tanaka N, Nishida-Kitayama J, Ohno H, Kishi F (December 2002). "Alternative splicing regulates the subcellular localization of divalent metal transporter 1 isoforms". Molecular Biology of the Cell. 13 (12): 4371–87. PMID 12475959.
- Okubo M, Yamada K, Hosoyamada M, Shibasaki T, Endou H (March 2003). "Cadmium transport by human Nramp 2 expressed in Xenopus laevis oocytes". Toxicology and Applied Pharmacology. 187 (3): 162–7. PMID 12662899.
External links
- DMT1+protein+(iron+transporter) at the U.S. National Library of Medicine Medical Subject Headings (MeSH)