Biology:DMT1
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The divalent metal transporter 1 (DMT1), also known as natural resistance-associated macrophage protein 2 (NRAMP 2), 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 (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+).[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.
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.[5] DMT1 expression in the brain may increase with age,[6] 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[7] 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,[8] and is implicated in Alzheimer's disease onset in males as well.[7] The CC haplotype for SNPs 1254T/C IVS34+44C/A is associated with Parkinson's disease susceptibility.[9] Finally, variant alleles on several SLC11A2 SNPs are associated with iron anemia, a risk factor for manganese intoxication and restless legs syndrome.[10]
References
- ↑ "Solute carrier family 11 (proton-coupled divalent metal ion transporters), member 2". GeneCards. https://www.genecards.org/cgi-bin/carddisp.pl?gene=SLC11A2. Retrieved 2011-12-16.
- ↑ "Cloning and characterization of a second human NRAMP gene on chromosome 12q13". Mamm. Genome 6 (4): 224–30. April 1995. doi:10.1007/BF00352405. PMID 7613023.
- ↑ "Manganese transport in eukaryotes: the role of DMT1". Neurotoxicology 29 (4): 569–76. July 2008. doi:10.1016/j.neuro.2008.04.022. PMID 18565586.
- ↑ "Cloning and characterization of a mammalian proton-coupled metal-ion transporter". Nature 388 (6641): 482–8. July 1997. doi:10.1038/41343. PMID 9242408.
- ↑ 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.
- ↑ "Age-dependent and iron-independent expression of two mRNA isoforms of divalent metal transporter 1 in rat brain". Neurobiol. Aging 26 (5): 739–48. May 2005. doi:10.1016/j.neurobiolaging.2004.06.002. PMID 15708449.
- ↑ 7.0 7.1 "Candidate gene association study of solute carrier family 11a members 1 (SLC11A1) and 2 (SLC11A2) genes in Alzheimer's disease". Neurosci. Lett. 374 (2): 124–8. February 2005. doi:10.1016/j.neulet.2004.10.038. PMID 15644277.
- ↑ "Association between divalent metal transport 1 encoding gene (SLC11A2) and disease duration in amyotrophic lateral sclerosis". J. Neurol. Sci. 303 (1-2): 124–7. April 2011. doi:10.1016/j.jns.2010.12.018. PMID 21276595.
- ↑ "DMT1 polymorphism and risk of Parkinson's disease". Neurosci. Lett. 501 (3): 128–31. September 2011. doi:10.1016/j.neulet.2011.07.001. PMID 21777657.
- ↑ "Molecular genetic studies of DMT1 on 12q in French-Canadian restless legs syndrome patients and families". Am. J. Med. Genet. B Neuropsychiatr. Genet. 144B (7): 911–7. October 2007. doi:10.1002/ajmg.b.30528. PMID 17510944.
Further reading
- "Microcytic anaemia mice have a mutation in Nramp2, a candidate iron transporter gene.". Nat. Genet. 16 (4): 383–6. 1997. doi:10.1038/ng0897-383. PMID 9241278.
- "Complete nucleotide sequence of human NRAMP2 cDNA.". Mol. Immunol. 34 (12–13): 839–42. 1998. doi:10.1016/S0161-5890(97)00110-7. PMID 9464519.
- "The human Nramp2 gene: characterization of the gene structure, alternative splicing, promoter region and polymorphisms". Blood Cells Mol. Dis. 24 (2): 199–215. 1998. doi:10.1006/bcmd.1998.0186. PMID 9642100.
- "Human natural resistance-associated macrophage protein 2: gene cloning and protein identification". Biochem. Biophys. Res. Commun. 251 (3): 775–83. 1998. doi:10.1006/bbrc.1998.9415. PMID 9790986.
- "Human NRAMP2/DMT1, which mediates iron transport across endosomal membranes, is localized to late endosomes and lysosomes in HEp-2 cells". J. Biol. Chem. 275 (29): 22220–8. 2000. doi:10.1074/jbc.M001478200. PMID 10751401.
- "Localization of iron transport and regulatory proteins in human cells". QJM : Monthly Journal of the Association of Physicians 93 (9): 575–87. 2000. doi:10.1093/qjmed/93.9.575. PMID 10984552.
- "Identification and localization of divalent metal transporter-1 (DMT-1) in term human placenta". Placenta 21 (8): 799–804. 2001. doi:10.1053/plac.2000.0566. PMID 11095929.
- "DMT1 gene expression and cadmium absorption in human absorptive enterocytes". Toxicol. Lett. 122 (2): 171–7. 2001. doi:10.1016/S0378-4274(01)00363-0. PMID 11439223.
- "Rapid regulation of divalent metal transporter (DMT1) protein but not mRNA expression by non-haem iron in human intestinal Caco-2 cells". FEBS Lett. 510 (1–2): 71–6. 2002. doi:10.1016/S0014-5793(01)03225-2. PMID 11755534.
- "The ferrireductase paraferritin contains divalent metal transporter as well as mobilferrin". Am. J. Physiol. Gastrointest. Liver Physiol. 282 (3): G534–9. 2002. doi:10.1152/ajpgi.00199.2001. PMID 11842004.
- "Cellular location of proteins related to iron absorption and transport". Am. J. Hematol. 69 (3): 164–70. 2002. doi:10.1002/ajh.10052. PMID 11891802.
- "Intestinal expression of genes involved in iron absorption in humans". Am. J. Physiol. Gastrointest. Liver Physiol. 282 (4): G598–607. 2002. doi:10.1152/ajpgi.00371.2001. PMID 11897618.
- "Iron uptake and Nramp2/DMT1/DCT1 in human bronchial epithelial cells". Am. J. Physiol. Lung Cell Mol. Physiol. 282 (5): L987–95. 2002. doi:10.1152/ajplung.00253.2001. PMID 11943663.
- "Uptake of lead and iron by divalent metal transporter 1 in yeast and mammalian cells". Biochem. Biophys. Res. Commun. 295 (4): 978–84. 2002. doi:10.1016/S0006-291X(02)00756-8. PMID 12127992.
- "Erythroid 5-aminolevulinate synthase, ferrochelatase and DMT1 expression in erythroid progenitors: differential pathways for erythropoietin and iron-dependent regulation". Br. J. Haematol. 118 (2): 619–26. 2002. doi:10.1046/j.1365-2141.2002.03626.x. PMID 12139757.
- "Previously uncharacterized isoforms of divalent metal transporter (DMT)-1: Implications for regulation and cellular function". Proc. Natl. Acad. Sci. U.S.A. 99 (19): 12345–50. 2002. doi:10.1073/pnas.192423399. PMID 12209011.
- "Alternative Splicing Regulates the Subcellular Localization of Divalent Metal Transporter 1 Isoforms". Mol. Biol. Cell 13 (12): 4371–87. 2003. doi:10.1091/mbc.E02-03-0165. PMID 12475959.
- "Cadmium transport by human Nramp 2 expressed in Xenopus laevis oocytes". Toxicol. Appl. Pharmacol. 187 (3): 162–7. 2003. doi:10.1016/S0041-008X(02)00078-9. PMID 12662899.
External links
- DMT1+protein+(iron+transporter) at the US National Library of Medicine Medical Subject Headings (MeSH)
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