Natural resistance-associated macrophage protein 2

Last updated
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
Gene location (Human)
Ideogram human chromosome 12.svg
Chr. Chromosome 12 (human) [1]
Human chromosome 12 ideogram.svg
HSR 1996 II 3.5e.svg
Red rectangle 2x18.png
Band 12q13.12Start50,979,401 bp [1]
End51,028,566 bp [1]
RNA expression pattern
PBB GE SLC11A2 203125 x at fs.png

PBB GE SLC11A2 203124 s at fs.png

PBB GE SLC11A2 203123 s at fs.png
More reference expression data
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_001146161
NM_008732
NM_001356952

RefSeq (protein)

NP_001139633
NP_032758
NP_001343881

Location (UCSC) Chr 12: 50.98 – 51.03 Mb Chr 15: 100.39 – 100.43 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

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]

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]

Related Research Articles

Human iron metabolism

Human iron metabolism is the set of chemical reactions that maintain human homeostasis of iron at the systemic and cellular level. Iron is both necessary to the body and potentially toxic. Controlling iron levels in the body is a critically important part of many aspects of human health and disease. Hematologists have been especially interested in systemic iron metabolism because iron is essential for red blood cells, where most of the human body's iron is contained. Understanding iron metabolism is also important for understanding diseases of iron overload, such as hereditary hemochromatosis, and iron deficiency, such as iron deficiency anemia.

Ferroportin-1, also known as solute carrier family 40 member 1 (SLC40A1) or iron-regulated transporter 1 (IREG1), is a protein that in humans is encoded by the SLC40A1 gene, and is part of the Ferroportin (Fpn)Family. Ferroportin is a transmembrane protein that transports iron from the inside of a cell to the outside of the cell. Ferroportin is the only known iron exporter.

Magnesium transporters are proteins that transport magnesium across the cell membrane. All forms of life require magnesium, yet the molecular mechanisms of Mg2+ uptake from the environment and the distribution of this vital element within the organism are only slowly being elucidated.

Glucose transporter 1, also known as solute carrier family 2, facilitated glucose transporter member 1 (SLC2A1), is a uniporter protein that in humans is encoded by the SLC2A1 gene. GLUT1 facilitates the transport of glucose across the plasma membranes of mammalian cells. This gene encodes a major glucose transporter in the mammalian blood-brain barrier. The encoded protein is found primarily in the cell membrane and on the cell surface, where it can also function as a receptor for human T-cell leukemia virus (HTLV) I and II. One good source of GLUT1 is erythrocyte membranes. GLUT1 accounts for 2 percent of the protein in the plasma membrane of erythrocytes. GLUT1, found in the plasma membrane of erythrocytes, is a classic example of a uniporter. After glucose is transported into the erythrocyte, it is rapidly phosphorylated, forming glucose-6-phosphate, which cannot leave the cell. Mutations in this gene can cause GLUT1 deficiency syndrome 1, GLUT1 deficiency syndrome 2, idiopathic generalized epilepsy 12, dystonia 9, and stomatin-deficient cryohydrocytosis.

SLC22A5

SLC22A5 is a membrane transport protein associated with primary carnitine deficiency. This protein is involved in the active cellular uptake of carnitine. It acts a symporter, moving sodium ions and other organic cations across the membrane along with carnitine. Such polyspecific organic cation transporters in the liver, kidney, intestine, and other organs are critical for the elimination of many endogenous small organic cations as well as a wide array of drugs and environmental toxins. Mutations in the SLC22A5 gene cause systemic primary carnitine deficiency, which can lead to heart failure.

Thiamine transporter 2

Thiamine transporter 2 (ThTr-2), also known as solute carrier family 19 member 3, is a protein that in humans is encoded by the SLC19A3 gene. SLC19A3 is a thiamine transporter.

Sodium/glucose cotransporter 1

Sodium/glucose cotransporter 1 (SGLT1) also known as solute carrier family 5 member 1 is a protein in humans that is encoded by the SLC5A1 gene which encodes the production of the SGLT1 protein to line the absorptive cells in the small intestine and the epithelial cells of the kidney tubules of the nephron for the purpose of glucose uptake into cells. Through the use of the sodium glucose cotransporter 1 protein, cells are able to obtain glucose which is further utilized to make and store energy for the cell.

Natural resistance-associated macrophage protein 1

Natural resistance-associated macrophage protein 1 is a protein that in humans is encoded by the SLC11A1 gene.

SLC22A4

Solute carrier family 22, member 4, also known as SLC22A4, is a human gene; the encoded protein is known as the ergothioneine transporter.

Excitatory amino acid transporter 3

Excitatory amino acid transporter 3 (EAAT3), is a protein that in humans is encoded by the SLC1A1 gene.

SLC22A8

Solute carrier family 22 member 8, or organic anion transporter 3 (OAT3), is a protein that in humans is encoded by the SLC22A8 gene.

Solute carrier organic anion transporter family member 1A2

Solute carrier organic anion transporter family member 1A2 is a protein that in humans is encoded by the SLCO1A2 gene.

Mitoferrin-1

Mitoferrin-1 (Mfrn1) is a 38 kDa protein that is encoded by the SLC25A37 gene in humans. It is a member of the Mitochondrial carrier (MC) Superfamily, however, its metal cargo makes it distinct from other members of this family. Mfrn1 plays a key role in mitochondrial iron homeostasis as an iron transporter, importing ferrous iron from the intermembrane space of the mitochondria to the mitochondrial matrix for the biosynthesis of heme groups and Fe-S clusters. This process is tightly regulated, given the redox potential of Mitoferrin's iron cargo. Mfrn1 is paralogous to Mitoferrin-2 (Mfrn2), a 39 kDa protein encoded by the SLC25A28 gene in humans. Mfrn1 is highly expressed in differentiating erythroid cells and in other tissues at low levels, while Mfrn2 is expressed ubiquitously in non-erythroid tissues.

Choline transporter

The high-affinity choline transporter (ChT) also known as solute carrier family 5 member 7 is a protein in humans that is encoded by the SLC5A7 gene. It is a cell membrane transporter and carries choline into acetylcholine-synthesizing neurons.

Iron dependent repressor

In molecular biology, the iron dependent repressors are a family of bacterial and archaeal transcriptional repressors.

Ferric uptake regulator family

In molecular biology, the ferric uptake regulator family is a family of bacterial proteins involved in regulating metal ion uptake and in metal homeostasis. The family is named for its founding member, known as the ferric uptake regulator or ferric uptake regulatory protein (Fur). Fur proteins are responsible for controlling the intracellular concentration of iron in many bacteria. Iron is essential for most organisms, but its concentration must be carefully managed over a wide range of environmental conditions; high concentrations can be toxic due to the formation of reactive oxygen species.

Cation diffusion facilitators (CDFs) are transmembrane proteins that provide tolerance of cells to divalent metal ions, such as cadmium, zinc, and cobalt. These proteins are considered to be efflux pumps that remove these divalent metal ions from cells. However, some members of the CDF superfamily are implicated in ion uptake. All members of the CDF family possess six putative transmembrane spanners with strongest conservation in the four N-terminal spanners. The Cation Diffusion Facilitator (CDF) Superfamily includes the following families:

Ascorbate ferrireductase (transmembrane)

Ascorbate ferrireductase (transmembrane) is an enzyme with systematic name Fe(III):ascorbate oxidorectuctase (electron-translocating). This enzyme catalyses the following chemical reaction

Natural resistance-associated macrophage protein Family of transport proteins

Natural resistance-associated macrophage proteins (Nramps), also known as metal ion (Mn2+-iron) transporters (TC# 2.A.55), are a family of metal transport proteins found throughout all domains of life. Taking on an eleven-helix LeuT fold, the Nramp family is a member of the large APC Superfamily of secondary carriers. They transport a variety of transition metals such as manganese, cadmium, and manganese using an alternating access mechanism characteristic of secondary transporters.

Zinc transporter ZIP9

Zinc transporter ZIP9, also known as Zrt- and Irt-like protein 9 (ZIP9) and solute carrier family 39 member 9, is a protein that in humans is encoded by the SLC39A9 gene. This protein is the 9th member out of 14 ZIP family proteins, which is a membrane androgen receptor (mAR) coupled to G proteins, and also classified as a zinc transporter protein. ZIP family proteins transport zinc metal from the extracellular environment into cells through cell membrane.

References

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Further reading