<div class="infobox">
<table>
<tr><td><strong>Gene</strong></td><td>SLC11A2</td></tr>
<tr><td><strong>UniProt</strong></td><td>[P49281](https://www.uniprot.org/uniprot/P49281)</td></tr>
<tr><td><strong>Molecular Weight</strong></td><td>62 kDa</td></tr>
<tr><td><strong>Subcellular Localization</strong></td><td>Plasma membrane, Endosomes, Lysosomes</td></tr>
<tr><td><strong>PDB Structures</strong></td><td>[6M1P](https://www.rcsb.org/structure/6M1P) (bacterial homolog)</td></tr>
<tr><td><strong>Aliases</strong></td><td>Nramp2, DCT1, SLC11A2</td></tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/alzheimer" style="color:#ef9a9a">Alzheimer</a>, <a href="/wiki/cancer" style="color:#ef9a9a">Cancer</a>, <a href="/wiki/depression" style="color:#ef9a9a">Depression</a>, <a href="/wiki/inflammation" style="color:#ef9a9a">Inflammation</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">78 edges</a></td>
</tr>
</table>
</div>
Overview
...<div class="infobox">
<table>
<tr><td><strong>Gene</strong></td><td>SLC11A2</td></tr>
<tr><td><strong>UniProt</strong></td><td>[P49281](https://www.uniprot.org/uniprot/P49281)</td></tr>
<tr><td><strong>Molecular Weight</strong></td><td>62 kDa</td></tr>
<tr><td><strong>Subcellular Localization</strong></td><td>Plasma membrane, Endosomes, Lysosomes</td></tr>
<tr><td><strong>PDB Structures</strong></td><td>[6M1P](https://www.rcsb.org/structure/6M1P) (bacterial homolog)</td></tr>
<tr><td><strong>Aliases</strong></td><td>Nramp2, DCT1, SLC11A2</td></tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/alzheimer" style="color:#ef9a9a">Alzheimer</a>, <a href="/wiki/cancer" style="color:#ef9a9a">Cancer</a>, <a href="/wiki/depression" style="color:#ef9a9a">Depression</a>, <a href="/wiki/inflammation" style="color:#ef9a9a">Inflammation</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">78 edges</a></td>
</tr>
</table>
</div>
Overview
Mermaid diagram (expand to render)
DMT1 (Divalent Metal Transporter 1), encoded by the SLC11A2 gene, is a proton-coupled metal ion transporter responsible for the uptake of dietary iron and endosomal iron release following transferrin receptor-mediated endocytosis. DMT1 is essential for systemic iron homeostasis and is critically involved in iron accumulation in neurodegenerative diseases, particularly Parkinson's disease where iron accumulates in the substantia nigra.[@gunshin1997]
Structure and Domains
DMT1 is a 561-amino acid transmembrane protein with 12 predicted transmembrane domains:[@shawki2012]
Key structural features:
- 12 transmembrane helices: Form the transport channel
- Conserved transport motif: GXXXG motif in TM4 essential for function
- Iron-responsive element (IRE): Present in the 3' UTR of some isoforms, enabling post-transcriptional regulation by iron regulatory proteins (IRPs)
- Four isoforms: Generated by alternative splicing at the N-terminus (1A vs 1B) and C-terminus (+IRE vs -IRE)
The +IRE isoforms are regulated by cellular iron status through IRP binding, while -IRE isoforms show constitutive expression. The 1A isoforms localize primarily to the plasma membrane, while 1B isoforms are found in endosomal/lysosomal compartments.[@hubert2002]
Normal Function
DMT1 is the primary transporter for non-heme iron uptake:[@mims2005]
Dietary iron absorption: DMT1 in duodenal enterocytes transports ferrous iron (Fe²⁺) from the intestinal lumen into cells, coupled with proton co-transport
Endosomal iron transport: Following transferrin receptor internalization and endosomal acidification, DMT1 exports iron from endosomes to the cytosol
Transport mechanism:
Fe²⁺ (extracellular/endosomal) + H⁺ → Fe²⁺ (cytosol) + H⁺ (cytosol)
- Electroneutral exchange of Fe²⁺ for H⁺
- Optimal activity at acidic pH (~5.5-6.0)
Substrate specificity: Also transports Mn²⁺, Co²⁺, Cu²⁺, Zn²⁺, and other divalent metals
Iron regulation: +IRE isoforms are stabilized by IRPs under low iron conditions, increasing expressionRole in Neurodegeneration
Parkinson's Disease
DMT1 is critically implicated in the characteristic iron accumulation in the substantia nigra of PD patients:[@salazar2008]
Key findings:
- DMT1 expression is increased in dopaminergic neurons of the substantia nigra in PD
- The +IRE isoform shows the most significant upregulation
- DMT1 polymorphisms (IVS4+44C>A, 3' UTR IVS4+44C>A) are associated with PD risk
- Animal models with DMT1 mutations (Flatiron, mk mice) show resistance to neurotoxicity[@jiang2021]
Mechanism of iron accumulation:α-Synuclein aggregates → DMT1 upregulation → Fe²⁺ influx ↑ →
Fenton chemistry → ROS ↑ → Dopaminergic neuron death
The Belgrade rat (DMT1 G185R mutation) is protected from Parkinsonian neurotoxins (MPTP, 6-OHDA), demonstrating DMT1's essential role in iron-mediated neurodegeneration.[@shukla2022]
Alzheimer's Disease
DMT1 contributes to iron dysregulation in AD:
- DMT1 expression is altered in AD brain tissue
- [Aβ](/proteins/amyloid-beta) may interact with iron transport pathways
- Iron accumulation in amyloid plaques involves DMT1 activity
- The -IRE isoform shows increased expression in AD [neurons](/entities/neurons)
Other Neurodegenerative Disorders
Amyotrophic Lateral Sclerosis (ALS):
- Iron accumulation in motor [cortex](/brain-regions/cortex) and spinal cord
- DMT1 upregulation may contribute to motor neuron vulnerability
Friedreich's Ataxia:
- Mitochondrial iron overload
- Altered DMT1 expression pattern
Therapeutic Targeting
DMT1 Inhibition Strategies
| Strategy | Mechanism | Status |
|----------|-----------|--------|
| Small molecule inhibitors | Block iron transport | Preclinical |
| siRNA/shRNA | Reduce DMT1 expression | Research |
| Iron chelation | Reduce labile iron pool | Clinical trials |
| Metal ion competition | Mn²⁺ or Co²⁺ competition | Research |
Pharmacological Inhibitors
Several compounds show DMT1 inhibitory activity:[@zhang2023]
- Ferristatin II: Inhibits DMT1-mediated iron uptake
- XEN602: Competitive inhibitor
- Ebselen: Indirect inhibition via oxidative modification
Clinical Relevance
The most promising clinical approach combines DMT1 modulation with iron chelation:
- Deferiprone: Iron chelator in clinical trials for PD
- Shows neuroprotective effects in animal models
- May reduce DMT1 expression indirectly through improved iron homeostasis
Protein Interactions
| Interacting Partner | Function | Relevance |
|---------------------|----------|-----------|
| Transferrin Receptor | Endosomal iron uptake | Sequential transport pathway |
| Ferroportin | Iron export | Balance import/export |
| Hephaestin | Iron oxidation | Enterocyte iron handling |
| STEAP3 | Endosomal iron reduction | Provides Fe²⁺ substrate |
| IRP1/IRP2 | Post-transcriptional regulation | IRE binding |
Key Publications
[Fleming et al., Microcytic anaemia mice have a mutation in Nramp2 (1997)](https://doi.org/10.1038/43406) — Nature Genetics. Discovery of DMT1 as the iron transporter mutated in microcytic anemia.
[Salazar et al., DMT1 expression in substantia nigra in Parkinson's disease (2008)](https://pubmed.ncbi.nlm.nih.gov/18076991/) — Demonstrates DMT1 upregulation in PD substantia nigra.
[Garrick et al., DMT1 in neurodegeneration (2012)](https://doi.org/10.2174/157488612802084262) — Comprehensive review of DMT1's role in neurodegenerative diseases.
[Aguirre et al., Iron chelation and neuroprotection in Parkinson's disease (2021)](https://pubmed.ncbi.nlm.nih.gov/33497331/) — Reviews iron chelation strategies targeting DMT1-mediated iron uptake.
[Cheli et al., Nutritional iron regulation and DMT1 (2023)](https://doi.org/10.3390/nu15092227) — Updated review of DMT1 function and regulation.See Also
- [Transferrin Receptor](/proteins/transferrin-receptor)
- [Ferroportin](/proteins/ferroportin)
- [Ferritin Heavy Chain](/proteins/ferritin-h)
- [Ceruloplasmin](/proteins/ceruloplasmin)
- [Iron Metabolism in Neurodegeneration](/mechanisms/iron-metabolism-neurodegeneration)
- [Parkinson's Disease](/diseases/parkinsons-disease)
References
[Gunshin H, et al, Cloning and characterization of a mammalian proton-coupled metal-ion transporter (1997)](https://doi.org/10.1038/41343)
[Shawki A, et al, Molecular characterization of DMT1 (2012)](https://doi.org/10.1016/j.bbamcr.2012.05.006)
[Hubert N, Hentze MW, Previously uncharacterized isoforms of divalent metal transporter (DMT)-1: implications for regulation and cellular function (2002)](https://doi.org/10.1073/pnas.192449399)
[Mims MP, Prchal JT, Divalent metal transporter 1 (2005)](https://doi.org/10.1080/10245330500193856)
[Salazar J, et al, DMT1 expression in substantia nigra in Parkinson's disease (2008)](https://doi.org/10.1007/s00702-007-0826-y)
[Jiang H, et al, DMT1 regulation in Parkinson's disease (2021)](https://doi.org/10.1016/j.nbd.2021.105282)
[Shukla A, et al, Protection of the Belgrade rat against 6-OHDA toxicity (2022)](https://doi.org/10.1016/j.nbd.2022.105781)
[Zhang S, et al, Inhibition of DMT1: A therapeutic strategy for Parkinson's disease (2023)](https://doi.org/10.1016/j.neuropharm.2023.109421)Pathway Diagram
The following diagram shows the key molecular relationships involving DMT1 (Divalent Metal Transporter 1) discovered through SciDEX knowledge graph analysis:
Mermaid diagram (expand to render)