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{{Infobox_gene}}
{{Infobox_gene}}
The '''divalent metal transporter 1''' (DMT1), also known as '''natural resistance-associated macrophage protein 2''' (NRAMP 2), and '''divalent cation transporter 1''' (DCT1),<ref>{{cite web|publisher=GeneCards|title=Solute carrier family 11 (proton-coupled divalent metal ion transporters), member 2|url=http://www.genecards.org/cgi-bin/carddisp.pl?gene=SLC11A2|accessdate=2011-12-16}}</ref> is a [[protein]] that in humans is encoded by the ''SLC11A2'' (solute carrier family 11, member 2) [[gene]].<ref name="pmid7613023">{{cite journal | vauthors = Vidal S, Belouchi AM, Cellier M, Beatty B, Gros P | title = Cloning and characterization of a second human NRAMP gene on chromosome 12q13 | journal = Mamm. Genome | volume = 6 | issue = 4 | pages = 224–30 |date=April 1995 | pmid = 7613023 | doi = 10.1007/BF00352405 }}</ref> DMT1 represents a large family of [[Homology (biology)#Orthology|orthologous]] metal ion transporter proteins that are highly conserved from bacteria to humans.<ref name="pmid18565586">{{cite journal | vauthors = Au C, Benedetto A, Aschner M | title = Manganese transport in eukaryotes: the role of DMT1 | journal = Neurotoxicology | volume = 29 | issue = 4 | pages = 569–76 |date=July 2008 | pmid = 18565586 | pmc = 2501114 | doi = 10.1016/j.neuro.2008.04.022 }}</ref>
The '''divalent metal transporter 1''' (DMT1), also known as '''natural resistance-associated macrophage protein 2''' (NRAMP 2), and '''divalent cation transporter 1''' (DCT1),<ref>{{cite web|publisher=GeneCards|title=Solute carrier family 11 (proton-coupled divalent metal ion transporters), member 2|url=https://www.genecards.org/cgi-bin/carddisp.pl?gene=SLC11A2|access-date=2011-12-16}}</ref> is a [[protein]] that in humans is encoded by the ''SLC11A2'' (solute carrier family 11, member 2) [[gene]].<ref name="pmid7613023">{{cite journal | vauthors = Vidal S, Belouchi AM, Cellier M, Beatty B, Gros P | title = Cloning and characterization of a second human NRAMP gene on chromosome 12q13 | journal = Mammalian Genome | volume = 6 | issue = 4 | pages = 224–30 | date = April 1995 | pmid = 7613023 | doi = 10.1007/BF00352405 }}</ref> DMT1 represents a large family of [[Homology (biology)#Orthology|orthologous]] metal ion transporter proteins that are highly conserved from bacteria to humans.<ref name="pmid18565586">{{cite journal | vauthors = Au C, Benedetto A, Aschner M | title = Manganese transport in eukaryotes: the role of DMT1 | journal = Neurotoxicology | volume = 29 | issue = 4 | pages = 569–76 | date = July 2008 | pmid = 18565586 | pmc = 2501114 | doi = 10.1016/j.neuro.2008.04.022 }}</ref>


As its name suggests, DMT1 binds a variety of divalent metals including [[cadmium]] (Cd<sup>2+</sup>), [[copper]] (Cu<sup>2+</sup>), and [[zinc]] (Zn<sup>2+,</sup>,) however it is best known for its role in transporting ferrous [[iron]] (Fe<sup>2+</sup>); DMT1 expression is regulated by body iron stores to maintain iron homeostasis. DMT1 is also important in the absorption and transport of [[manganese]] (Mn<sup>2+</sup>).<ref name="pmid9242408">{{cite journal | vauthors = Gunshin H, Mackenzie B, Berger UV, Gunshin Y, Romero MF, Boron WF, Nussberger S, Gollan JL, Hediger MA | title = Cloning and characterization of a mammalian proton-coupled metal-ion transporter | journal = Nature | volume = 388 | issue = 6641 | pages = 482–8 |date=July 1997 | pmid = 9242408 | doi = 10.1038/41343 | url = }}</ref> In the digestive tract, it is located on the apical membrane of [[enterocytes]], where it carries out H<sup>+</sup> coupled transport of divalent metal cations from the intestinal lumen into the cell. <nowiki/><nowiki/>
As its name suggests, DMT1 binds a variety of divalent metals including [[cadmium]] (Cd<sup>2+</sup>), [[copper]] (Cu<sup>2+</sup>), and [[zinc]] (Zn<sup>2+,</sup>); however, it is best known for its role in transporting ferrous [[iron]] (Fe<sup>2+</sup>). DMT1 expression is regulated by body iron stores to maintain iron homeostasis. DMT1 is also important in the absorption and transport of [[manganese]] (Mn<sup>2+</sup>).<ref name="pmid9242408">{{cite journal | vauthors = Gunshin H, Mackenzie B, Berger UV, Gunshin Y, Romero MF, Boron WF, Nussberger S, Gollan JL, Hediger MA | title = Cloning and characterization of a mammalian proton-coupled metal-ion transporter | journal = Nature | volume = 388 | issue = 6641 | pages = 482–8 | date = July 1997 | pmid = 9242408 | doi = 10.1038/41343 }}</ref> In the digestive tract, it is located on the apical membrane of [[enterocytes]], where it carries out H<sup>+</sup> coupled transport of divalent metal cations from the intestinal lumen into the cell. <nowiki/><nowiki/>
 
== 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.<ref name=":2">{{cite journal | vauthors = Rolfs A, Hediger MA | title = Metal ion transporters in mammals: structure, function and pathological implications | journal = The Journal of Physiology | volume = 518 | issue = Pt 1 | pages = 1–12 | date = July 1999 | pmid = 10373684 | pmc = 2269412 | doi = 10.1111/j.1469-7793.1999.0001r.x }}</ref> Iron also participates in many metabolic pathways. Iron deficiency can lead to [[iron-deficiency anemia]] thus [[Human iron metabolism|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]]).<ref name=":0">{{Cite book|url=https://www.worldcat.org/oclc/65400780|title=Biological inorganic chemistry : structure and reactivity|date=2007|publisher=University Science Books| last = Bertini | first = Ivano | name-list-format = vanc |isbn=1891389432|location=Sausalito, Calif.|oclc=65400780}}</ref> Once the Fe<sup>3+</sup> has been reduced to Fe<sup>2+</sup>, the DMT1 transporter protein transports the Fe<sup>2+</sup> ions into the cells that line the small intestine ([[Enterocyte|enterocytes)]].<ref name=":0" /> From there, the [[Ferroportin|ferroprotin]]/[[IREG1]] transporter exports  it across the cell membrane where is it oxidized to Fe<sup>3+</sup> on the surface of the cell then bound by [[transferrin]] and released into the blood stream.<ref name=":0" />
 
=== Ion selectivity ===
DMT1 is not a 100% selective transporter as it also transports Zn<sup>2+</sup>, Mn<sup>2+</sup>, and Cd<sup>2+</sup> which can lead to toxicity problems.<ref name=":0" /> 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.<ref name=":0" />
 
=== Yeast vs. mammal pathway ===
The iron uptake pathway in ''[[Saccharomyces cerevisiae|Saccharaomyces cerevisiae]]'', which consists of a multicopper ferroxidase ([[Fet3p|Fet3]]) and an iron plasma permease (FTR1) has a high affinity for iron uptake compared to the DMT1 iron uptake process present in mammals.<ref name=":1">{{cite journal | vauthors = Hassett RF, Romeo AM, Kosman DJ | title = Regulation of high affinity iron uptake in the yeast Saccharomyces cerevisiae. Role of dioxygen and Fe | journal = The Journal of Biological Chemistry | volume = 273 | issue = 13 | pages = 7628–36 | date = March 1998 | pmid = 9516467 | doi = 10.1074/jbc.273.13.7628 }}</ref> The iron uptake process in yeasts consists of Fe<sup>3+</sup> which is reduced to Fe<sup>2+</sup> by ferriductases.<ref name=":0" /> Ferrous iron may also be present outside of the cell due to other reductants present in the extracellular medium.<ref name=":0" /> Ferrous iron is then oxidized to ferric iron by Fet3 on the external surface of the cell.<ref name=":0" /> Then Fe<sup>3+</sup> is transferred from Fet3 to FTR1 and transferred across the cell membrane into the cell.<ref name=":0" />
 
Ferrous-oxidase mediated transport systems exist in order to transport specific ions opposed to DMT1, which does not have complete specificity.<ref name=":0" /> 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.<ref name=":0" /> Each of the steps involved in the pathway is specific to either ferrous iron or ferric iron.<ref name=":0" /> The DMT1 transporter protein does not have specificity over the ions it transports because it is unable to distinguish between Fe<sup>2+</sup> and the other divalent metal ions it transfer through the cell membrane.<ref name=":0" /> 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.<ref name=":0" /> So in anaerobic environments the oxidase would not be able to function thus another means of iron uptake is necessary.<ref name=":0" />


== Role in neurodegenerative diseases ==
== 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.<ref name="pmid16460806">{{cite journal | author = Aschner M | title = The transport of manganese across the blood–brain barrier | journal = Neurotoxicology | volume = 27 | issue = 3 | pages = 311–4 |date=May 2006 | pmid = 16460806 | doi = 10.1016/j.neuro.2005.09.002 }}</ref> DMT1 expression in the brain may increase with age,<ref name="pmid15708449">{{cite journal | vauthors = Ke Y, Chang YZ, Duan XL, Du JR, Zhu L, Wang K, Yang XD, Ho KP, Qian ZM | title = Age-dependent and iron-independent expression of two mRNA isoforms of divalent metal transporter 1 in rat brain | journal = Neurobiol. Aging | volume = 26 | issue = 5 | pages = 739–48 |date=May 2005 | pmid = 15708449 | doi = 10.1016/j.neurobiolaging.2004.06.002 }}</ref> 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.
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.<ref name="pmid16460806">{{cite journal | vauthors = Aschner M | title = The transport of manganese across the blood-brain barrier | journal = Neurotoxicology | volume = 27 | issue = 3 | pages = 311–4 | date = May 2006 | pmid = 16460806 | doi = 10.1016/j.neuro.2005.09.002 }}</ref> DMT1 expression in the brain may increase with age,<ref name="pmid15708449">{{cite journal | vauthors = Ke Y, Chang YZ, Duan XL, Du JR, Zhu L, Wang K, Yang XD, Ho KP, Qian ZM | title = Age-dependent and iron-independent expression of two mRNA isoforms of divalent metal transporter 1 in rat brain | journal = Neurobiology of Aging | volume = 26 | issue = 5 | pages = 739–48 | date = May 2005 | pmid = 15708449 | doi = 10.1016/j.neurobiolaging.2004.06.002 }}</ref> 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<ref name="pmid15644277">{{cite journal | vauthors = Jamieson SE, White JK, Howson JM, Pask R, Smith AN, Brayne C, Evans JG, Xuereb J, Cairns NJ, Rubinsztein DC, Blackwell JM | title = Candidate gene association study of solute carrier family 11a members 1 (SLC11A1) and 2 (SLC11A2) genes in Alzheimer's disease | journal = Neurosci. Lett. | volume = 374 | issue = 2 | pages = 124–8 |date=February 2005 | pmid = 15644277 | doi = 10.1016/j.neulet.2004.10.038 }}</ref> and [[restless legs syndrome]]. The C allele of [[Single-nucleotide polymorphism|SNP]] rs407135 on the DMT1 encoding gene SLC11A2 is associated with shorter disease duration in cases of spinal onset [[amyotrophic lateral sclerosis]],<ref name="pmid21276595">{{cite journal | vauthors = Blasco H, Vourc'h P, Nadjar Y, Ribourtout B, Gordon PH, Guettard YO, Camu W, Praline J, Meininger V, Andres CR, Corcia P | title = Association between divalent metal transport 1 encoding gene (SLC11A2) and disease duration in amyotrophic lateral sclerosis | journal = J. Neurol. Sci. | volume = 303 | issue = 1-2 | pages = 124–7 |date=April 2011 | pmid = 21276595 | doi = 10.1016/j.jns.2010.12.018 }}</ref> and is implicated in Alzheimer's disease onset in males as well.<ref name="pmid15644277"/> The CC [[haplotype]] for SNPs 1254T/C IVS34+44C/A is associated with Parkinson's disease susceptibility.<ref name="pmid21777657">{{cite journal | vauthors = He Q, Du T, Yu X, Xie A, Song N, Kang Q, Yu J, Tan L, Xie J, Jiang H | title = DMT1 polymorphism and risk of Parkinson's disease | journal = Neurosci. Lett. | volume = 501 | issue = 3 | pages = 128–31 |date=September 2011 | pmid = 21777657 | doi = 10.1016/j.neulet.2011.07.001 }}</ref> Finally, variant alleles on several SLC11A2 SNPs are associated with iron anemia, a risk factor for manganese intoxication and restless legs syndrome.<ref name="pmid17510944">{{cite journal | vauthors = 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 | title = Molecular genetic studies of DMT1 on 12q in French-Canadian restless legs syndrome patients and families | journal = Am. J. Med. Genet. B Neuropsychiatr. Genet. | volume = 144B | issue = 7 | pages = 911–7 |date=October 2007 | pmid = 17510944 | doi = 10.1002/ajmg.b.30528 }}</ref>
The DMT1 encoding gene SLC11A2 is located on the long arm of chromosome 12 (12q13) close to susceptibility regions for Alzheimer's disease<ref name="pmid15644277">{{cite journal | vauthors = Jamieson SE, White JK, Howson JM, Pask R, Smith AN, Brayne C, Evans JG, Xuereb J, Cairns NJ, Rubinsztein DC, Blackwell JM | title = Candidate gene association study of solute carrier family 11a members 1 (SLC11A1) and 2 (SLC11A2) genes in Alzheimer's disease | journal = Neuroscience Letters | volume = 374 | issue = 2 | pages = 124–8 | date = February 2005 | pmid = 15644277 | doi = 10.1016/j.neulet.2004.10.038 }}</ref> and [[restless legs syndrome]]. The C allele of [[Single-nucleotide polymorphism|SNP]] rs407135 on the DMT1 encoding gene SLC11A2 is associated with shorter disease duration in cases of spinal onset [[amyotrophic lateral sclerosis]],<ref name="pmid21276595">{{cite journal | vauthors = Blasco H, Vourc'h P, Nadjar Y, Ribourtout B, Gordon PH, Guettard YO, Camu W, Praline J, Meininger V, Andres CR, Corcia P | title = Association between divalent metal transport 1 encoding gene (SLC11A2) and disease duration in amyotrophic lateral sclerosis | journal = Journal of the Neurological Sciences | volume = 303 | issue = 1-2 | pages = 124–7 | date = April 2011 | pmid = 21276595 | doi = 10.1016/j.jns.2010.12.018 }}</ref> and is implicated in Alzheimer's disease onset in males as well.<ref name="pmid15644277"/> The CC [[haplotype]] for SNPs 1254T/C IVS34+44C/A is associated with Parkinson's disease susceptibility.<ref name="pmid21777657">{{cite journal | vauthors = He Q, Du T, Yu X, Xie A, Song N, Kang Q, Yu J, Tan L, Xie J, Jiang H | title = DMT1 polymorphism and risk of Parkinson's disease | journal = Neuroscience Letters | volume = 501 | issue = 3 | pages = 128–31 | date = September 2011 | pmid = 21777657 | doi = 10.1016/j.neulet.2011.07.001 }}</ref> Finally, variant alleles on several SLC11A2 SNPs are associated with iron anemia, a risk factor for manganese intoxication and restless legs syndrome.<ref name="pmid17510944">{{cite journal | vauthors = 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 | title = Molecular genetic studies of DMT1 on 12q in French-Canadian restless legs syndrome patients and families | journal = American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics | volume = 144B | issue = 7 | pages = 911–7 | date = October 2007 | pmid = 17510944 | doi = 10.1002/ajmg.b.30528 }}</ref>
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==References==
== References ==
{{Reflist|colwidth=30em}}
{{Reflist}}


==Further reading==
== Further reading ==
{{refbegin | 2}}
{{refbegin | 2}}
*{{cite journal | vauthors=Fleming MD, Trenor CC, Su MA |title=Microcytic anaemia mice have a mutation in Nramp2, a candidate iron transporter gene. |journal=Nat. Genet. |volume=16 |issue= 4 |pages= 383–6 |year= 1997 |pmid= 9241278 |doi= 10.1038/ng0897-383 }}
* {{cite journal | vauthors = Fleming MD, Trenor CC, Su MA, Foernzler D, Beier DR, Dietrich WF, Andrews NC | title = Microcytic anaemia mice have a mutation in Nramp2, a candidate iron transporter gene | journal = Nature Genetics | volume = 16 | issue = 4 | pages = 383–6 | date = August 1997 | pmid = 9241278 | doi = 10.1038/ng0897-383 }}
*{{cite journal | vauthors=Kishi F, Tabuchi M |title=Complete nucleotide sequence of human NRAMP2 cDNA. |journal=Mol. Immunol. |volume=34 |issue= 12–13 |pages= 839–42 |year= 1998 |pmid= 9464519 |doi=10.1016/S0161-5890(97)00110-7 }}
* {{cite journal | vauthors = Kishi F, Tabuchi M | title = Complete nucleotide sequence of human NRAMP2 cDNA | journal = Molecular Immunology | volume = 34 | issue = 12-13 | pages = 839–42 | year = 1998 | pmid = 9464519 | doi = 10.1016/S0161-5890(97)00110-7 }}
*{{cite journal | vauthors=Lee PL, Gelbart T, West C |title=The human Nramp2 gene: characterization of the gene structure, alternative splicing, promoter region and polymorphisms |journal=Blood Cells Mol. Dis. |volume=24 |issue= 2 |pages= 199–215 |year= 1998 |pmid= 9642100 |doi= 10.1006/bcmd.1998.0186 }}
* {{cite journal | vauthors = Lee PL, Gelbart T, West C, Halloran C, Beutler E | title = The human Nramp2 gene: characterization of the gene structure, alternative splicing, promoter region and polymorphisms | journal = Blood Cells, Molecules & Diseases | volume = 24 | issue = 2 | pages = 199–215 | date = June 1998 | pmid = 9642100 | doi = 10.1006/bcmd.1998.0186 }}
*{{cite journal | vauthors=Kishi F, Tabuchi M |title=Human natural resistance-associated macrophage protein 2: gene cloning and protein identification |journal=Biochem. Biophys. Res. Commun. |volume=251 |issue= 3 |pages= 775–83 |year= 1998 |pmid= 9790986 |doi= 10.1006/bbrc.1998.9415 }}
* {{cite journal | vauthors = Kishi F, Tabuchi M | title = Human natural resistance-associated macrophage protein 2: gene cloning and protein identification | journal = Biochemical and Biophysical Research Communications | volume = 251 | issue = 3 | pages = 775–83 | date = October 1998 | pmid = 9790986 | doi = 10.1006/bbrc.1998.9415 }}
*{{cite journal | vauthors=Tabuchi M, Yoshimori T, Yamaguchi K |title=Human NRAMP2/DMT1, which mediates iron transport across endosomal membranes, is localized to late endosomes and lysosomes in HEp-2 cells |journal=J. Biol. Chem. |volume=275 |issue= 29 |pages= 22220–8 |year= 2000 |pmid= 10751401 |doi= 10.1074/jbc.M001478200 }}
* {{cite journal | vauthors = Tabuchi M, Yoshimori T, Yamaguchi K, Yoshida T, Kishi F | title = Human NRAMP2/DMT1, which mediates iron transport across endosomal membranes, is localized to late endosomes and lysosomes in HEp-2 cells | journal = The Journal of Biological Chemistry | volume = 275 | issue = 29 | pages = 22220–8 | date = July 2000 | pmid = 10751401 | doi = 10.1074/jbc.M001478200 }}
*{{cite journal | vauthors=Griffiths WJ, Kelly AL, Smith SJ, Cox TM |title=Localization of iron transport and regulatory proteins in human cells |journal=QJM : Monthly Journal of the Association of Physicians |volume=93 |issue= 9 |pages= 575–87 |year= 2000 |pmid= 10984552 |doi=10.1093/qjmed/93.9.575 }}
* {{cite journal | vauthors = Griffiths WJ, Kelly AL, Smith SJ, Cox TM | title = Localization of iron transport and regulatory proteins in human cells | journal = QJM | volume = 93 | issue = 9 | pages = 575–87 | date = September 2000 | pmid = 10984552 | doi = 10.1093/qjmed/93.9.575 }}
*{{cite journal | vauthors=Georgieff MK, Wobken JK, Welle J |title=Identification and localization of divalent metal transporter-1 (DMT-1) in term human placenta |journal=Placenta |volume=21 |issue= 8 |pages= 799–804 |year= 2001 |pmid= 11095929 |doi= 10.1053/plac.2000.0566 }}
* {{cite journal | vauthors = Georgieff MK, Wobken JK, Welle J, Burdo JR, Connor JR | title = Identification and localization of divalent metal transporter-1 (DMT-1) in term human placenta | journal = Placenta | volume = 21 | issue = 8 | pages = 799–804 | date = November 2000 | pmid = 11095929 | doi = 10.1053/plac.2000.0566 }}
*{{cite journal | vauthors=Tallkvist J, Bowlus CL, Lönnerdal B |title=DMT1 gene expression and cadmium absorption in human absorptive enterocytes |journal=Toxicol. Lett. |volume=122 |issue= 2 |pages= 171–7 |year= 2001 |pmid= 11439223 |doi=10.1016/S0378-4274(01)00363-0 }}
* {{cite journal | vauthors = Tallkvist J, Bowlus CL, Lönnerdal B | title = DMT1 gene expression and cadmium absorption in human absorptive enterocytes | journal = Toxicology Letters | volume = 122 | issue = 2 | pages = 171–7 | date = June 2001 | pmid = 11439223 | doi = 10.1016/S0378-4274(01)00363-0 }}
*{{cite journal | vauthors=Sharp P, Tandy S, Yamaji S |title=Rapid regulation of divalent metal transporter (DMT1) protein but not mRNA expression by non-haem iron in human intestinal Caco-2 cells |journal=FEBS Lett. |volume=510 |issue= 1–2 |pages= 71–6 |year= 2002 |pmid= 11755534 |doi=10.1016/S0014-5793(01)03225-2 }}
* {{cite journal | vauthors = Sharp P, Tandy S, Yamaji S, Tennant J, Williams M, Singh Srai SK | title = Rapid regulation of divalent metal transporter (DMT1) protein but not mRNA expression by non-haem iron in human intestinal Caco-2 cells | journal = FEBS Letters | volume = 510 | issue = 1-2 | pages = 71–6 | date = January 2002 | pmid = 11755534 | doi = 10.1016/S0014-5793(01)03225-2 }}
*{{cite journal | vauthors=Umbreit JN, Conrad ME, Hainsworth LN, Simovich M |title=The ferrireductase paraferritin contains divalent metal transporter as well as mobilferrin |journal=Am. J. Physiol. Gastrointest. Liver Physiol. |volume=282 |issue= 3 |pages= G534–9 |year= 2002 |pmid= 11842004 |doi= 10.1152/ajpgi.00199.2001 }}
* {{cite journal | vauthors = Umbreit JN, Conrad ME, Hainsworth LN, Simovich M | title = The ferrireductase paraferritin contains divalent metal transporter as well as mobilferrin | journal = American Journal of Physiology. Gastrointestinal and Liver Physiology | volume = 282 | issue = 3 | pages = G534-9 | date = March 2002 | pmid = 11842004 | doi = 10.1152/ajpgi.00199.2001 }}
*{{cite journal | vauthors=Simovich MJ, Conrad ME, Umbreit JN |title=Cellular location of proteins related to iron absorption and transport |journal=Am. J. Hematol. |volume=69 |issue= 3 |pages= 164–70 |year= 2002 |pmid= 11891802 |doi=10.1002/ajh.10052 }}
* {{cite journal | vauthors = Simovich MJ, Conrad ME, Umbreit JN, Moore EG, Hainsworth LN, Smith HK | title = Cellular location of proteins related to iron absorption and transport | journal = American Journal of Hematology | volume = 69 | issue = 3 | pages = 164–70 | date = March 2002 | pmid = 11891802 | doi = 10.1002/ajh.10052 }}
*{{cite journal | vauthors=Rolfs A, Bonkovsky HL, Kohlroser JG |title=Intestinal expression of genes involved in iron absorption in humans |journal=Am. J. Physiol. Gastrointest. Liver Physiol. |volume=282 |issue= 4 |pages= G598–607 |year= 2002 |pmid= 11897618 |doi= 10.1152/ajpgi.00371.2001 }}
* {{cite journal | vauthors = Rolfs A, Bonkovsky HL, Kohlroser JG, McNeal K, Sharma A, Berger UV, Hediger MA | title = Intestinal expression of genes involved in iron absorption in humans | journal = American Journal of Physiology. Gastrointestinal and Liver Physiology | volume = 282 | issue = 4 | pages = G598-607 | date = April 2002 | pmid = 11897618 | doi = 10.1152/ajpgi.00371.2001 }}
*{{cite journal | vauthors=Wang X, Ghio AJ, Yang F |title=Iron uptake and Nramp2/DMT1/DCT1 in human bronchial epithelial cells |journal=Am. J. Physiol. Lung Cell Mol. Physiol. |volume=282 |issue= 5 |pages= L987–95 |year= 2002 |pmid= 11943663 |doi= 10.1152/ajplung.00253.2001 }}
* {{cite journal | vauthors = Wang X, Ghio AJ, Yang F, Dolan KG, Garrick MD, Piantadosi CA | title = Iron uptake and Nramp2/DMT1/DCT1 in human bronchial epithelial cells | journal = American Journal of Physiology. Lung Cellular and Molecular Physiology | volume = 282 | issue = 5 | pages = L987-95 | date = May 2002 | pmid = 11943663 | doi = 10.1152/ajplung.00253.2001 }}
*{{cite journal | vauthors=I Bannon D, Portnoy ME, Olivi L |title=Uptake of lead and iron by divalent metal transporter 1 in yeast and mammalian cells |journal=Biochem. Biophys. Res. Commun. |volume=295 |issue= 4 |pages= 978–84 |year= 2002 |pmid= 12127992 |doi=10.1016/S0006-291X(02)00756-8 }}
* {{cite journal | vauthors = I Bannon D, Portnoy ME, Olivi L, Lees PS, Culotta VC, Bressler JP | title = Uptake of lead and iron by divalent metal transporter 1 in yeast and mammalian cells | journal = Biochemical and Biophysical Research Communications | volume = 295 | issue = 4 | pages = 978–84 | date = July 2002 | pmid = 12127992 | doi = 10.1016/S0006-291X(02)00756-8 }}
*{{cite journal | vauthors=Zoller H, Decristoforo C, Weiss G |title=Erythroid 5-aminolevulinate synthase, ferrochelatase and DMT1 expression in erythroid progenitors: differential pathways for erythropoietin and iron-dependent regulation |journal=Br. J. Haematol. |volume=118 |issue= 2 |pages= 619–26 |year= 2002 |pmid= 12139757 |doi=10.1046/j.1365-2141.2002.03626.x }}
* {{cite journal | vauthors = Zoller H, Decristoforo C, Weiss G | title = Erythroid 5-aminolevulinate synthase, ferrochelatase and DMT1 expression in erythroid progenitors: differential pathways for erythropoietin and iron-dependent regulation | journal = British Journal of Haematology | volume = 118 | issue = 2 | pages = 619–26 | date = August 2002 | pmid = 12139757 | doi = 10.1046/j.1365-2141.2002.03626.x }}
*{{cite journal | vauthors=Hubert N, Hentze MW |title=Previously uncharacterized isoforms of divalent metal transporter (DMT)-1: Implications for regulation and cellular function |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=99 |issue= 19 |pages= 12345–50 |year= 2002 |pmid= 12209011 |doi= 10.1073/pnas.192423399 | pmc=129447 }}
* {{cite journal | vauthors = Hubert N, Hentze MW | title = Previously uncharacterized isoforms of divalent metal transporter (DMT)-1: implications for regulation and cellular function | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 99 | issue = 19 | pages = 12345–50 | date = September 2002 | pmid = 12209011 | pmc = 129447 | doi = 10.1073/pnas.192423399 }}
*{{cite journal | vauthors=Tabuchi M, Tanaka N, Nishida-Kitayama J |title=Alternative Splicing Regulates the Subcellular Localization of Divalent Metal Transporter 1 Isoforms |journal=Mol. Biol. Cell |volume=13 |issue= 12 |pages= 4371–87 |year= 2003 |pmid= 12475959 |doi= 10.1091/mbc.E02-03-0165 | pmc=138640 }}
* {{cite journal | vauthors = Tabuchi M, Tanaka N, Nishida-Kitayama J, Ohno H, Kishi F | title = Alternative splicing regulates the subcellular localization of divalent metal transporter 1 isoforms | journal = Molecular Biology of the Cell | volume = 13 | issue = 12 | pages = 4371–87 | date = December 2002 | pmid = 12475959 | pmc = 138640 | doi = 10.1091/mbc.E02-03-0165 }}
*{{cite journal | vauthors=Okubo M, Yamada K, Hosoyamada M |title=Cadmium transport by human Nramp 2 expressed in Xenopus laevis oocytes |journal=Toxicol. Appl. Pharmacol. |volume=187 |issue= 3 |pages= 162–7 |year= 2003 |pmid= 12662899 |doi=10.1016/S0041-008X(02)00078-9 }}
* {{cite journal | vauthors = Okubo M, Yamada K, Hosoyamada M, Shibasaki T, Endou H | title = Cadmium transport by human Nramp 2 expressed in Xenopus laevis oocytes | journal = Toxicology and Applied Pharmacology | volume = 187 | issue = 3 | pages = 162–7 | date = March 2003 | pmid = 12662899 | doi = 10.1016/S0041-008X(02)00078-9 }}
{{refend}}
{{refend}}


==External links==
== External links ==
* {{MeshName|DMT1+protein+(iron+transporter)}}
* {{MeshName|DMT1+protein+(iron+transporter)}}


Latest revision as of 02:32, 10 December 2018

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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.

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).[6] From there, the ferroprotin/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.[6]

Ion selectivity

DMT1 is not a 100% selective transporter as it also transports Zn2+, Mn2+, and Cd2+ which can lead to toxicity problems.[6] 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.[6]

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.[7] The iron uptake process in yeasts consists of Fe3+ which is reduced to Fe2+ by ferriductases.[6] Ferrous iron may also be present outside of the cell due to other reductants present in the extracellular medium.[6] Ferrous iron is then oxidized to ferric iron by Fet3 on the external surface of the cell.[6] Then Fe3+ is transferred from Fet3 to FTR1 and transferred across the cell membrane into the cell.[6]

Ferrous-oxidase mediated transport systems exist in order to transport specific ions opposed to DMT1, which does not have complete specificity.[6] 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.[6] Each of the steps involved in the pathway is specific to either ferrous iron or ferric iron.[6] 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.[6] 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.[6] So in anaerobic environments the oxidase would not be able to function thus another means of iron uptake is necessary.[6]

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]

References

  1. ↑ "Solute carrier family 11 (proton-coupled divalent metal ion transporters), member 2". GeneCards. Retrieved 2011-12-16.
  2. ↑ 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.
  3. ↑ 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.
  4. ↑ 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. doi:10.1038/41343. PMID 9242408.
  5. ↑ 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.
  6. ↑ 6.00 6.01 6.02 6.03 6.04 6.05 6.06 6.07 6.08 6.09 6.10 6.11 6.12 6.13 6.14 Bertini I (2007). Biological inorganic chemistry : structure and reactivity. Sausalito, Calif.: University Science Books. ISBN 1891389432. OCLC 65400780.
  7. ↑ 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.
  8. ↑ 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.
  9. ↑ 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. PMID 15708449.
  10. ↑ 10.0 10.1 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.
  11. ↑ 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.
  12. ↑ 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.
  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 (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.

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.
  • 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.
  • 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.
  • 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.
  • 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. 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.
  • 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. 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

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