Natural resistance-associated macrophage protein 2

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]

SLC11A2
Identifiers
AliasesSLC11A2, DCT1, DMT1, NRAMP2, AHMIO1, solute carrier family 11 member 2, divalent metal transporter 1, natural resistance-associated macrophage protein 2, divalent cation transporter 1
External IDsOMIM: 600523 MGI: 1345279 HomoloGene: 55471 GeneCards: SLC11A2
Orthologs
SpeciesHumanMouse
Entrez

4891

18174

Ensembl

ENSG00000110911

ENSMUSG00000023030

UniProt

P49281

P49282

RefSeq (mRNA)

NM_001146161
NM_008732
NM_001356952

RefSeq (protein)

NP_001139633
NP_032758
NP_001343881

Location (UCSC)Chr 12: 50.98 – 51.03 MbChr 15: 100.29 – 100.32 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

As its name suggests, DMT1 binds a variety of divalent metals including cadmium (Cd2+), copper (Cu2+), and zinc (Zn2+,); 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+).[8] 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.[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 (Vitamin C).[10] 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).[10] 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.[10]

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 Saccharaomyces 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 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.[12] DMT1 expression in the brain may increase with age,[13] 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[14] 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,[15] and is implicated in Alzheimer's disease onset in males as well.[14] The CC haplotype for SNPs 1254T/C IVS34+44C/A is associated with Parkinson's disease susceptibility.[16] Finally, variant alleles on several SLC11A2 SNPs are associated with iron anemia, a risk factor for manganese intoxication and restless legs syndrome.[17]

References
  1. GRCh38: Ensembl release 89: ENSG00000110911 - Ensembl, May 2017
  2. GRCm38: Ensembl release 89: ENSMUSG00000023030 - Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. "Solute carrier family 11 (proton-coupled divalent metal ion transporters), member 2". GeneCards. Retrieved 2011-12-16.
  6. Vidal S, Belouchi AM, Cellier M, Beatty B, Gros P (April 1995). "Cloning and characterization of a second human NRAMP gene on chromosome 12q13". Mammalian Genome. 6 (4): 224–30. doi:10.1007/BF00352405. PMID 7613023. S2CID 22656880.
  7. Au C, Benedetto A, Aschner M (July 2008). "Manganese transport in eukaryotes: the role of DMT1". Neurotoxicology. 29 (4): 569–76. doi:10.1016/j.neuro.2008.04.022. PMC 2501114. PMID 18565586.
  8. Gunshin H, Mackenzie B, Berger UV, Gunshin Y, Romero MF, Boron WF, Nussberger S, Gollan JL, Hediger MA (July 1997). "Cloning and characterization of a mammalian proton-coupled metal-ion transporter". Nature. 388 (6641): 482–8. Bibcode:1997Natur.388..482G. doi:10.1038/41343. PMID 9242408. S2CID 4416482.
  9. Rolfs A, Hediger MA (July 1999). "Metal ion transporters in mammals: structure, function and pathological implications". The Journal of Physiology. 518 (Pt 1): 1–12. doi:10.1111/j.1469-7793.1999.0001r.x. PMC 2269412. PMID 10373684.
  10. Bertini I (2007). Biological inorganic chemistry : structure and reactivity. Sausalito, Calif.: University Science Books. ISBN 978-1891389436. OCLC 65400780.
  11. Hassett RF, Romeo AM, Kosman DJ (March 1998). "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. doi:10.1074/jbc.273.13.7628. PMID 9516467.
  12. Aschner M (May 2006). "The transport of manganese across the blood-brain barrier". Neurotoxicology. 27 (3): 311–4. doi:10.1016/j.neuro.2005.09.002. PMID 16460806.
  13. Ke Y, Chang YZ, Duan XL, Du JR, Zhu L, Wang K, Yang XD, Ho KP, Qian ZM (May 2005). "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. doi:10.1016/j.neurobiolaging.2004.06.002. hdl:10397/15266. PMID 15708449. S2CID 21925120.
  14. Jamieson SE, White JK, Howson JM, Pask R, Smith AN, Brayne C, Evans JG, Xuereb J, Cairns NJ, Rubinsztein DC, Blackwell JM (February 2005). "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. doi:10.1016/j.neulet.2004.10.038. PMID 15644277. S2CID 6176823.
  15. Blasco H, Vourc'h P, Nadjar Y, Ribourtout B, Gordon PH, Guettard YO, Camu W, Praline J, Meininger V, Andres CR, Corcia P (April 2011). "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. doi:10.1016/j.jns.2010.12.018. PMID 21276595. S2CID 22098012.
  16. He Q, Du T, Yu X, Xie A, Song N, Kang Q, Yu J, Tan L, Xie J, Jiang H (September 2011). "DMT1 polymorphism and risk of Parkinson's disease". Neuroscience Letters. 501 (3): 128–31. doi:10.1016/j.neulet.2011.07.001. PMID 21777657. S2CID 22188818.
  17. 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 (October 2007). "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. doi:10.1002/ajmg.b.30528. PMID 17510944. S2CID 22609489.

Further reading
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