Natural resistance-associated macrophage protein 2 explained

Natural resistance-associated macrophage protein 2 (NRAMP 2), also known as divalent metal transporter 1 (DMT1) and divalent cation transporter 1 (DCT1),^[1] is a protein that in humans is encoded by the SLC11A2 (solute carrier family 11, member 2) gene.^[2] DMT1 represents a large family of orthologous metal ion transporter proteins that are highly conserved from bacteria to humans.^[3]

As its name suggests, DMT1 binds a variety of divalent metals including cadmium (Cd²⁺), copper (Cu²⁺), and zinc (Zn^2+,); however, it is best known for its role in transporting ferrous iron (Fe²⁺). DMT1 expression is regulated by body iron stores to maintain iron homeostasis. DMT1 is also important in the absorption and transport of manganese (Mn²⁺).^[4] In the digestive tract, it is located on the apical membrane of enterocytes, where it carries out H⁺-coupled transport of divalent metal cations from the intestinal lumen into the cell.

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.^[5] 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 (Vitamin C).^[6] Once the Fe³⁺ has been reduced to Fe²⁺, the DMT1 transporter protein transports the Fe²⁺ ions into the cells that line the small intestine (enterocytes). From there, the ferroportin/IREG1 transporter exports it across the cell membrane where is it oxidized to Fe³⁺ on the surface of the cell then bound by transferrin and released into the blood stream.

Ion selectivity

DMT1 is not a 100% selective transporter as it also transports Zn²⁺, Mn²⁺, and Ca²⁺ which can lead to toxicity problems. 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.

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.^[7] The iron uptake process in yeasts consists of Fe³⁺ which is reduced to Fe²⁺ by ferriductases. Ferrous iron may also be present outside of the cell due to other reductants present in the extracellular medium. Ferrous iron is then oxidized to ferric iron by Fet3 on the external surface of the cell. Then Fe³⁺ is transferred from Fet3 to FTR1 and transferred across the cell membrane into the cell.

Ferrous-oxidase mediated transport systems exist in order to transport specific ions opposed to DMT1, which does not have complete specificity. 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. Each of the steps involved in the pathway is specific to either ferrous iron or ferric iron. 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. 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. So in anaerobic environments the oxidase would not be able to function thus another means of iron uptake is necessary.

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 Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis. DMT1 may be the major transporter of manganese across the blood brain barrier and expression of this protein in the nasal epithelium provides a route for direct absorption of metals into the brain.^[8] DMT1 expression in the brain may increase with age,^[9] increasing susceptibility to metal induced pathologies. DMT1 expression is found to be increased in the substantia nigra of Parkinson's patients and in the ventral mesencephalon of animal models intoxicated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) - a neurotoxin widely used experimentally to produce Parkinsonian symptoms.

The DMT1 encoding gene SLC11A2 is located on the long arm of chromosome 12 (12q13) close to susceptibility regions for Alzheimer's disease^[10] and restless legs syndrome. The C allele of SNP rs407135 on the DMT1 encoding gene SLC11A2 is associated with shorter disease duration in cases of spinal onset amyotrophic lateral sclerosis,^[11] and is implicated in Alzheimer's disease onset in males as well.^[10] The CC haplotype for SNPs 1254T/C IVS34+44C/A is associated with Parkinson's disease susceptibility.^[12] Finally, variant alleles on several SLC11A2 SNPs are associated with iron anemia, a risk factor for manganese intoxication and restless legs syndrome.^[13]

Further reading

• Fleming MD, Trenor CC, Su MA, Foernzler D, Beier DR, Dietrich WF, Andrews NC . Microcytic anaemia mice have a mutation in Nramp2, a candidate iron transporter gene . Nature Genetics . 16 . 4 . 383–6 . August 1997 . 9241278 . 10.1038/ng0897-383 . 41548981 .
• Kishi F, Tabuchi M . Complete nucleotide sequence of human NRAMP2 cDNA . Molecular Immunology . 34 . 12–13 . 839–42 . 1998 . 9464519 . 10.1016/S0161-5890(97)00110-7 .
• Lee PL, Gelbart T, West C, Halloran C, Beutler E . The human Nramp2 gene: characterization of the gene structure, alternative splicing, promoter region and polymorphisms . Blood Cells, Molecules & Diseases . 24 . 2 . 199–215 . June 1998 . 9642100 . 10.1006/bcmd.1998.0186 .
• Kishi F, Tabuchi M . Human natural resistance-associated macrophage protein 2: gene cloning and protein identification . Biochemical and Biophysical Research Communications . 251 . 3 . 775–83 . October 1998 . 9790986 . 10.1006/bbrc.1998.9415 .
• Tabuchi M, Yoshimori T, Yamaguchi K, Yoshida T, Kishi F . 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 . July 2000 . 10751401 . 10.1074/jbc.M001478200 . free .
• Griffiths WJ, Kelly AL, Smith SJ, Cox TM . Localization of iron transport and regulatory proteins in human cells . QJM . 93 . 9 . 575–87 . September 2000 . 10984552 . 10.1093/qjmed/93.9.575 .
• Georgieff MK, Wobken JK, Welle J, Burdo JR, Connor JR . Identification and localization of divalent metal transporter-1 (DMT-1) in term human placenta . Placenta . 21 . 8 . 799–804 . November 2000 . 11095929 . 10.1053/plac.2000.0566 .
• Tallkvist J, Bowlus CL, Lönnerdal B . DMT1 gene expression and cadmium absorption in human absorptive enterocytes . Toxicology Letters . 122 . 2 . 171–7 . June 2001 . 11439223 . 10.1016/S0378-4274(01)00363-0 .
• Sharp P, Tandy S, Yamaji S, Tennant J, Williams M, Singh Srai SK . 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 . January 2002 . 11755534 . 10.1016/S0014-5793(01)03225-2 . 12296540 .
• Umbreit JN, Conrad ME, Hainsworth LN, Simovich M . The ferrireductase paraferritin contains divalent metal transporter as well as mobilferrin . American Journal of Physiology. Gastrointestinal and Liver Physiology . 282 . 3 . G534–9 . March 2002 . 11842004 . 10.1152/ajpgi.00199.2001 . 6295186 .
• Simovich MJ, Conrad ME, Umbreit JN, Moore EG, Hainsworth LN, Smith HK . Cellular location of proteins related to iron absorption and transport . American Journal of Hematology . 69 . 3 . 164–70 . March 2002 . 11891802 . 10.1002/ajh.10052 . 43201066 . free .
• Rolfs A, Bonkovsky HL, Kohlroser JG, McNeal K, Sharma A, Berger UV, Hediger MA . Intestinal expression of genes involved in iron absorption in humans . American Journal of Physiology. Gastrointestinal and Liver Physiology . 282 . 4 . G598–607 . April 2002 . 11897618 . 10.1152/ajpgi.00371.2001 .
• Wang X, Ghio AJ, Yang F, Dolan KG, Garrick MD, Piantadosi CA . Iron uptake and Nramp2/DMT1/DCT1 in human bronchial epithelial cells . American Journal of Physiology. Lung Cellular and Molecular Physiology . 282 . 5 . L987–95 . May 2002 . 11943663 . 10.1152/ajplung.00253.2001 . 10.1.1.854.2791 .
• I Bannon D, Portnoy ME, Olivi L, Lees PS, Culotta VC, Bressler JP . Uptake of lead and iron by divalent metal transporter 1 in yeast and mammalian cells . Biochemical and Biophysical Research Communications . 295 . 4 . 978–84 . July 2002 . 12127992 . 10.1016/S0006-291X(02)00756-8 .
• Zoller H, Decristoforo C, Weiss G . 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 . August 2002 . 12139757 . 10.1046/j.1365-2141.2002.03626.x . 35114057 .
• Hubert N, Hentze MW . 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 . September 2002 . 12209011 . 129447 . 10.1073/pnas.192423399 . 2002PNAS...9912345H . free .
• Tabuchi M, Tanaka N, Nishida-Kitayama J, Ohno H, Kishi F . Alternative splicing regulates the subcellular localization of divalent metal transporter 1 isoforms . Molecular Biology of the Cell . 13 . 12 . 4371–87 . December 2002 . 12475959 . 138640 . 10.1091/mbc.E02-03-0165 .
• Okubo M, Yamada K, Hosoyamada M, Shibasaki T, Endou H . Cadmium transport by human Nramp 2 expressed in Xenopus laevis oocytes . Toxicology and Applied Pharmacology . 187 . 3 . 162–7 . March 2003 . 12662899 . 10.1016/S0041-008X(02)00078-9 .

Notes and References

1. Web site: GeneCards. Solute carrier family 11 (proton-coupled divalent metal ion transporters), member 2. 2011-12-16.
2. Vidal S, Belouchi AM, Cellier M, Beatty B, Gros P . Cloning and characterization of a second human NRAMP gene on chromosome 12q13 . Mammalian Genome . 6 . 4 . 224–30 . April 1995 . 7613023 . 10.1007/BF00352405 . 22656880 .
3. Au C, Benedetto A, Aschner M . Manganese transport in eukaryotes: the role of DMT1 . Neurotoxicology . 29 . 4 . 569–76 . July 2008 . 18565586 . 2501114 . 10.1016/j.neuro.2008.04.022 .
4. Gunshin H, Mackenzie B, Berger UV, Gunshin Y, Romero MF, Boron WF, Nussberger S, Gollan JL, Hediger MA . Cloning and characterization of a mammalian proton-coupled metal-ion transporter . Nature . 388 . 6641 . 482–8 . July 1997 . 9242408 . 10.1038/41343 . 1997Natur.388..482G . 4416482 . free .
5. Rolfs A, Hediger MA . Metal ion transporters in mammals: structure, function and pathological implications . The Journal of Physiology . 518 . Pt 1 . 1–12 . July 1999 . 10373684 . 2269412 . 10.1111/j.1469-7793.1999.0001r.x .
6. Book: Bertini, Ivano . Biological inorganic chemistry : structure and reactivity. 2007. University Science Books. vanc . 978-1891389436. Sausalito, Calif.. 65400780.
7. Hassett RF, Romeo AM, Kosman DJ . Regulation of high affinity iron uptake in the yeast Saccharomyces cerevisiae. Role of dioxygen and Fe . The Journal of Biological Chemistry . 273 . 13 . 7628–36 . March 1998 . 9516467 . 10.1074/jbc.273.13.7628 . free .
8. Aschner M . The transport of manganese across the blood-brain barrier . Neurotoxicology . 27 . 3 . 311–4 . May 2006 . 16460806 . 10.1016/j.neuro.2005.09.002 .
9. Ke Y, Chang YZ, Duan XL, Du JR, Zhu L, Wang K, Yang XD, Ho KP, Qian ZM . Age-dependent and iron-independent expression of two mRNA isoforms of divalent metal transporter 1 in rat brain . Neurobiology of Aging . 26 . 5 . 739–48 . May 2005 . 15708449 . 10.1016/j.neurobiolaging.2004.06.002 . 21925120 . 10397/15266 . free .
10. Jamieson SE, White JK, Howson JM, Pask R, Smith AN, Brayne C, Evans JG, Xuereb J, Cairns NJ, Rubinsztein DC, Blackwell JM . Candidate gene association study of solute carrier family 11a members 1 (SLC11A1) and 2 (SLC11A2) genes in Alzheimer's disease . Neuroscience Letters . 374 . 2 . 124–8 . February 2005 . 15644277 . 10.1016/j.neulet.2004.10.038 . 6176823 .
11. Blasco H, Vourc'h P, Nadjar Y, Ribourtout B, Gordon PH, Guettard YO, Camu W, Praline J, Meininger V, Andres CR, Corcia P . Association between divalent metal transport 1 encoding gene (SLC11A2) and disease duration in amyotrophic lateral sclerosis . Journal of the Neurological Sciences . 303 . 1–2 . 124–7 . April 2011 . 21276595 . 10.1016/j.jns.2010.12.018 . 22098012 .
12. He Q, Du T, Yu X, Xie A, Song N, Kang Q, Yu J, Tan L, Xie J, Jiang H . DMT1 polymorphism and risk of Parkinson's disease . Neuroscience Letters . 501 . 3 . 128–31 . September 2011 . 21777657 . 10.1016/j.neulet.2011.07.001 . 22188818 .
13. Xiong L, Dion P, Montplaisir J, Levchenko A, Thibodeau P, Karemera L, Rivière JB, St-Onge J, Gaspar C, Dubé MP, Desautels A, Turecki G, Rouleau GA . Molecular genetic studies of DMT1 on 12q in French-Canadian restless legs syndrome patients and families . American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics . 144B . 7 . 911–7 . October 2007 . 17510944 . 10.1002/ajmg.b.30528 . 22609489 .