Natural resistance-associated macrophage protein 2

SLC11A2
Identifiers
Aliases	SLC11A2, 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 IDs	OMIM: 600523; MGI: 1345279; HomoloGene: 55471; GeneCards: SLC11A2; OMA:SLC11A2 - orthologs
Gene location (Human) Chr. Chromosome 12 (human) Band 12q13.12 Start 50,979,401 bp End 51,028,566 bp
Gene location (Mouse) Chr. Chromosome 15 (mouse) Band 15 F1|15 56.29 cM Start 100,285,779 bp End 100,322,953 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in inferior ganglion of vagus nerve buccal mucosa cell caput epididymis corpus callosum cartilage tissue oral cavity minor salivary glands superior vestibular nucleus subthalamic nucleus Pons Top expressed in epithelium of small intestine Ileal epithelium spermatocyte duodenum lip right kidney primary oocyte fetal liver hematopoietic progenitor cell proximal tubule yolk sac More reference expression data BioGPS More reference expression data
Gene ontology Molecular function vanadium ion transmembrane transporter activity transporter activity transition metal ion transmembrane transporter activity lead ion transmembrane transporter activity proton transmembrane transporter activity cadmium ion binding manganese ion transmembrane transporter activity cobalt ion transmembrane transporter activity zinc ion transmembrane transporter activity chromium ion transmembrane transporter activity solute:proton symporter activity protein binding copper ion transmembrane transporter activity nickel cation transmembrane transporter activity calcium ion transmembrane transporter activity inorganic cation transmembrane transporter activity cadmium ion transmembrane transporter activity iron ion transmembrane transporter activity ferrous iron transmembrane transporter activity iron ion binding copper ion binding zinc ion binding nickel cation binding manganese ion binding metal ion transmembrane transporter activity cobalt ion binding Cellular component cytoplasm endosome membrane basal part of cell retromer complex trans-Golgi network perinuclear region of cytoplasm nucleus late endosome membrane cell surface mitochondrial outer membrane apical plasma membrane lysosome integral component of membrane recycling endosome late endosome plasma membrane apical part of cell early endosome brush border endosome membrane paraferritin complex integral component of plasma membrane brush border membrane lysosomal membrane vacuole cytoplasmic vesicle endomembrane system mitochondrion extracellular vesicle Biological process cadmium ion transmembrane transport activation of cysteine-type endopeptidase activity involved in apoptotic process proton transmembrane transport lead ion transport iron ion homeostasis ion transport heme biosynthetic process multicellular organismal iron ion homeostasis learning or memory iron ion transmembrane transport dendrite morphogenesis porphyrin-containing compound biosynthetic process response to iron ion iron ion transport copper ion transport response to hypoxia cobalt ion transport detection of oxygen cellular response to oxidative stress manganese ion transport nickel cation transport erythrocyte development porphyrin-containing compound metabolic process cellular iron ion homeostasis cation transmembrane transport manganese ion transmembrane transport vanadium ion transport zinc ion transmembrane transport nickel cation transmembrane transport copper ion transmembrane transport transport metal ion transport iron import into cell Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 4891 18174 Ensembl ENSG00000110911 ENSMUSG00000023030 UniProt P49281 P49282 RefSeq (mRNA) NM_000617 NM_001174125 NM_001174126 NM_001174127 NM_001174128 NM_001174129 NM_001174130 NM_001379446 NM_001379447 NM_001379448 NM_001379455 NM_001146161 NM_008732 NM_001356952 RefSeq (protein) NP_000608 NP_001167596 NP_001167597 NP_001167598 NP_001167599 NP_001167600 NP_001167601 NP_001366375 NP_001366376 NP_001366377 NP_001366384 NP_001139633 NP_032758 NP_001343881 Location (UCSC) Chr 12: 50.98 – 51.03 Mb Chr 15: 100.29 – 100.32 Mb PubMed search
Wikidata
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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), is a protein that in humans is encoded by the SLC11A2 (solute carrier family 11, member 2) gene. DMT1 represents a large family of orthologous metal ion transporter proteins that are highly conserved from bacteria to humans.

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

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. doi:10.1038/ng0897-383. PMID 9241278. S2CID 41548981.
• Kishi F, Tabuchi M (1998). "Complete nucleotide sequence of human NRAMP2 cDNA". Molecular Immunology. 34 (12–13): 839–42. doi:10.1016/S0161-5890(97)00110-7. 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. doi:10.1006/bcmd.1998.0186. 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. doi:10.1006/bbrc.1998.9415. 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. doi:10.1074/jbc.M001478200. 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. doi:10.1093/qjmed/93.9.575. 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. doi:10.1053/plac.2000.0566. 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. doi:10.1016/S0378-4274(01)00363-0. 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. doi:10.1016/S0014-5793(01)03225-2. PMID 11755534. 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. doi:10.1152/ajpgi.00199.2001. PMID 11842004. 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. doi:10.1002/ajh.10052. PMID 11891802. 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. doi:10.1152/ajpgi.00371.2001. 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. CiteSeerX 10.1.1.854.2791. doi:10.1152/ajplung.00253.2001. 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. doi:10.1016/S0006-291X(02)00756-8. 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. doi:10.1046/j.1365-2141.2002.03626.x. PMID 12139757. 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. Bibcode:2002PNAS...9912345H. doi:10.1073/pnas.192423399. PMC 129447. 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. doi:10.1091/mbc.E02-03-0165. PMC 138640. 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. doi:10.1016/S0041-008X(02)00078-9. PMID 12662899.

External links

• DMT1+protein+(iron+transporter) at the U.S. National Library of Medicine Medical Subject Headings (MeSH)