Affinage

SLC11A2

Natural resistance-associated macrophage protein 2 · UniProt P49281

Length
568 aa
Mass
62.3 kDa
Annotated
2026-06-10
100 papers in source corpus 34 papers cited in narrative 34 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SLC11A2 (DMT1/Nramp2/DCT1) is a 12-transmembrane-domain, heavily glycosylated integral membrane protein that functions as a proton-coupled divalent metal transporter and is the principal route for cellular acquisition of non-heme iron, with loss-of-function disrupting both dietary iron absorption and erythroid iron utilization (PMID:9241278, PMID:9448300, PMID:19621945). It transports Fe2+ (preferentially over Fe3+, which requires prior reduction by a membrane ferric reductase) as well as Mn2+, Co2+, and Cd2+ into the labile iron pool, driven by the proton electrochemical gradient with attendant intracellular acidification (PMID:10942769, PMID:12954986, PMID:18722041). Transport mechanism has been mapped to conserved residues: negatively charged residues in TM1/TM4/TM7 and a first-extracellular-loop region (G119, D124, Q126) govern cation transport and metal specificity, His267/His272 in TM6 regulate proton coupling rather than directly binding metal, and coupling efficiency reflects a non-obligatory proton-slippage mechanism in which TM2 and TM4 are functionally coupled (F227I, I144F) (PMID:12522007, PMID:12954986, PMID:15475345, PMID:17980698). DMT1 is generated as multiple isoforms through alternative 5' (exon 1A) and 3' (IRE/non-IRE) usage that direct tissue-specific iron regulation and distinct subcellular trafficking (PMID:12209011, PMID:16475818). At the duodenal brush border it mediates apical uptake of dietary iron and is upregulated under iron deprivation (isoform I) (PMID:10361139), whereas in erythroid and other cells isoform II colocalizes and traffics in parallel with the transferrin receptor, cycling between the plasma membrane and acidified recycling endosomes to release endosomal Fe2+ into the cytoplasm during the transferrin cycle; its C-terminal YLLNT motif directs clathrin/dynamin-dependent internalization and PI3K-dependent recycling, and ablating it redirects DMT1 to lysosomes (PMID:10049947, PMID:12724326, PMID:11739192, PMID:16142913). In vivo inactivation established DMT1 as essential for postnatal intestinal iron absorption and erythroid hemoglobin production but dispensable for materno-fetal iron transfer (PMID:15849611), and human disease mutations that impair folding, trafficking, or expression (e.g. R416C, N491S, G75R) cause microcytic anemia with hepatic iron overload (PMID:16584902, PMID:21871825, PMID:35457224). Beyond canonical iron handling, DMT1 is recruited to mature macrophage phagosomes and supports microglial iron import that drives pro-inflammatory activation in vivo (PMID:12239176, PMID:38141840).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 1998 High

    Established that SLC11A2/Nramp2 is itself an iron transporter whose loss causes systemic iron deficiency, answering whether a single gene links intestinal absorption and erythroid iron utilization.

    Evidence Positional cloning of the G185R mutation in mk mice and the Belgrade rat with functional transport assays in transfected cells

    PMID:9241278 PMID:9448300 PMID:9731075

    Open questions at the time
    • G185R conflates loss of transport with loss of membrane targeting
    • did not resolve substrate range or the driving force for transport
  2. 1998 High

    Demonstrated the transporter handles divalent cations beyond iron, framing it as a broad-specificity divalent metal transporter.

    Evidence Heterologous yeast smf1/smf2 double-null complementation with conserved-residue mutants

    PMID:9360964

    Open questions at the time
    • yeast assay does not quantify relative substrate selectivity in mammalian cells
    • did not establish proton coupling directly
  3. 2000 High

    Defined the proton-coupled, saturable transport of Fe2+/Co2+/Cd2+ into the cytoplasmic labile iron pool and fixed key topological features.

    Evidence Calcein fluorescence and 55Fe transport assays in stable CHO transfectants with surface biotinylation and ion-selectivity tests

    PMID:10625641 PMID:10942769

    Open questions at the time
    • the molecular determinants of proton coupling were not yet mapped
    • did not address physiological subcellular site of transport
  4. 2003 High

    Resolved the iron-acquisition mechanism in the transferrin cycle, showing DMT1 isoform II cycles with the transferrin receptor through acidified recycling endosomes via defined trafficking pathways.

    Evidence pH-sensitive labeling, surface kinetics, pharmacological inhibition (dynasore, wortmannin) and dual-label confocal microscopy; complemented by erythroid mk/mk reticulocyte analysis

    PMID:10049947 PMID:11739192 PMID:12724326

    Open questions at the time
    • conflicting reports placed DMT1 in late endosomes/lysosomes versus recycling endosomes (#7)
    • molecular adaptors for clathrin/PI3K-dependent steps not identified
  5. 2005 High

    Mapped sequence determinants of trafficking, identifying the C-terminal YLLNT motif as the internalization/recycling signal and showing C-terminal splicing dictates the subcellular site of Fe2+ transport.

    Evidence Truncation and isoform-comparison mutants in LLC-PK1 cells with 125I-antibody surface kinetics and marker colocalization

    PMID:16142913 PMID:16475818

    Open questions at the time
    • the trafficking machinery recognizing YLLNT was not identified
    • isoform-specific transport rates in native tissue not measured
  6. 2007 High

    Dissected the proton-metal coupling mechanism, showing coupling is non-obligatory proton slippage tunable by inter-helix interactions and gated by specific residues.

    Evidence Site-directed mutagenesis (His267/His272, TM1/TM4/TM7 residues, F227I, I144F, first-loop G119/D124/Q126) with Xenopus oocyte electrophysiology and uptake assays

    PMID:12522007 PMID:12954986 PMID:15475345 PMID:17980698

    Open questions at the time
    • no atomic-resolution structure of the human transporter
    • exact coordination geometry of bound metal not defined
  7. 2009 High

    Provided a validated 12-TM topology with intracellular N/C termini and identified functionally critical insertion-sensitive regions, constraining structural models.

    Evidence Systematic HA-epitope insertion at 13 positions with permeabilized-cell immunofluorescence and homology threading

    PMID:19621945

    Open questions at the time
    • threading model not validated against an experimental structure
    • conformational cycle during transport not resolved
  8. 2005 High

    Established the physiological non-redundant roles in vivo, separating intestinal/erythroid requirement from dispensability in materno-fetal transfer and revealing an alternative hepatocyte iron-uptake route.

    Evidence Global and conditional Slc11a2 knockout mice with iron-absorption, hemoglobin, and tissue-iron phenotyping

    PMID:15849611

    Open questions at the time
    • the alternative iron-uptake mechanism in hepatocytes was not identified
    • cell-autonomous roles in non-erythroid tissues left open
  9. 2022 Medium

    Connected biochemical trafficking defects to human disease, showing folding/trafficking-disrupting mutations cause microcytic anemia with hepatic iron overload.

    Evidence Functional characterization of R416C, N491S, and G75R in human cell lines with patient-derived cell validation and splicing analysis

    PMID:16023393 PMID:16584902 PMID:21871825 PMID:35457224

    Open questions at the time
    • single-lab functional assays for several variants
    • genotype-phenotype severity relationships not systematically established
  10. 2023 Medium

    Extended DMT1 function beyond classical iron handling to immune cells, linking microglial iron import to pro-inflammatory activation in vivo.

    Evidence Tamoxifen-inducible microglial-specific Slc11a2 knockdown mice with LPS challenge, plasma cytokine measurement, and microglial RNA-seq; plus phagosomal recruitment in macrophages

    PMID:12239176 PMID:38141840

    Open questions at the time
    • sex-specific effect (males only) mechanism not explained
    • no direct measurement of transport at the phagosomal/microglial membrane

Open questions

Synthesis pass · forward-looking unresolved questions
  • How DMT1 is allosterically regulated and pharmacologically targeted, and the structural basis of its transport cycle, remain open.
  • no experimental structure of the human transporter
  • allosteric modulatory site not defined
  • endogenous regulators of trafficking unidentified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 5 GO:0140104 molecular carrier activity 3
Localization
GO:0005764 lysosome 3 GO:0005768 endosome 3 GO:0005886 plasma membrane 3
Pathway
R-HSA-382551 Transport of small molecules 3 R-HSA-1430728 Metabolism 2 R-HSA-168256 Immune System 2
Partners
TFRC

Evidence

Reading pass · 34 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 A missense mutation (G185R) in Nramp2 (SLC11A2) was identified as the causative mutation in microcytic anemia (mk) mice, which have severe defects in intestinal iron absorption and erythroid iron utilization, establishing Nramp2 as an iron transporter. Positional cloning, missense mutation identification in mk/mk mice with microcytic hypochromic anemia phenotype Nature genetics High 9241278
1998 The same G185R missense mutation in Nramp2 was found in the anemic Belgrade (b) rat, and functional studies confirmed this mutation disrupts iron transport. The phenotype implicates Nramp2 in both intestinal iron absorption and transport of iron out of the transferrin cycle endosome. Genetic linkage analysis, mutation identification, functional iron transport studies in transfected cells Proceedings of the National Academy of Sciences of the United States of America High 9448300
1998 Site-directed mutagenesis of transmembrane domain 4 of Nramp2 showed that the G185R mutation causes near-total loss of iron transport function beyond what can be explained by reduced protein amount, indicating disruption of the transport mechanism itself rather than protein degradation. Site-directed mutagenesis, transfected cell iron transport assays, subcellular localization studies Blood High 9731075
1997 Nramp2 (SLC11A2) functionally complements the yeast smf1/smf2 double null mutant's hypersensitivity to EGTA and alkaline pH, indicating Nramp2 can transport Mn2+ (and other divalent cations) in yeast; complementation required a functional protein as conserved-residue mutations abrogated activity. Yeast complementation assay with smf1/smf2 double mutant, mutagenesis of conserved residues The Journal of biological chemistry High 9360964
1999 Nramp2 protein is localized to the apical brush border of duodenal enterocytes (columnar absorptive cells, not goblet cells), and isoform I is dramatically upregulated in the proximal duodenum under iron deprivation, supporting its role in transferrin-independent dietary iron uptake. Immunoblotting of membrane fractions, immunohistochemistry of intestinal tissue sections, dietary iron manipulation in mice Blood High 10361139
1999 Nramp2/NRAMP2 is expressed as a 90–100 kDa heavily glycosylated integral membrane protein and localizes primarily to recycling endosomes (colocalizing with transferrin), not lysosomes, in macrophages and hematopoietic cells, suggesting its role is transport of Fe2+ across the endosomal membrane into the cytoplasm during the transferrin cycle. Immunoblotting, immunofluorescence, confocal microscopy, subcellular fractionation, glycosylation analysis The Journal of experimental medicine High 10049947
1999 Nramp2 is expressed at the apical membrane of human intestinal Caco-2 cells and mediates proton-dependent iron transport with substrate preference for iron over other divalent cations, accompanied by intracellular acidification. Iron transport assays in Caco-2 TC7 cells, pH-dependency studies, substrate competition The Journal of biological chemistry Medium 10625641
2000 Human NRAMP2/DMT1 co-sediments with LAMP-1 and LAMP-2-positive late endosomes and lysosomes (not with early endosome marker EEA1 or transferrin receptor) in HEp-2 cells, suggesting it transfers endosomal free Fe2+ into the cytoplasm in the transferrin cycle. Subcellular fractionation, immunofluorescence of endogenous and GFP-tagged NRAMP2, colocalization with organelle markers The Journal of biological chemistry Medium 10751401
2000 Nramp2 isoform II expressed at the plasma membrane of CHO cells transports Fe2+, Co2+, and Cd2+ (but not Mg2+) into the calcein-accessible labile iron pool; transport is time- and pH-dependent, saturable, and proportional to Nramp2 expression level. The TM7-TM8 loop is extracytoplasmic. Stable CHO transfectants, calcein fluorescence assay, membrane-permeant/impermeant chelators, surface biotinylation, ion selectivity experiments The Journal of biological chemistry High 10942769
2002 DMT1 generates four distinct protein isoforms through alternative use of a 5' exon (exon 1A) in combination with IRE/non-IRE 3' variants; the exon 1A is tissue-specifically expressed in duodenum and kidney and adds 29–31 conserved amino acids to the N-terminus. Both the 5' promoter/exon 1A and the IRE-containing terminal exon participate in tissue-specific iron regulation of DMT1. cDNA cloning, 5' RACE, quantitative RT-PCR, reporter assays for IRE and 5' exon regulation Proceedings of the National Academy of Sciences of the United States of America High 12209011
2003 Two conserved histidines in transmembrane domain 6 of Nramp2/DMT1 (His267 and His272) regulate pH-dependent metal transport: inactive His267 and His272 mutants could be rescued by lowering pH, indicating these residues regulate proton coupling rather than directly binding metal substrates. Additionally, three conserved negatively charged residues in TM1, TM4, and TM7 are essential for cation transport. Site-directed mutagenesis, yeast complementation, mammalian cell iron transport assays, pH rescue experiments Blood High 12522007
2003 Nramp2 (isoform II) cycles between the plasma membrane and sorting/recycling endosomes (pH ~6.2, maintained by V-ATPase). Internalization is clathrin- and dynamin-dependent, and recycling to the plasma membrane is phosphatidylinositol 3-kinase-dependent. Cholesterol depletion does not affect internalization. Nramp2 and transferrin receptor colocalize and traffic in parallel, functionally coupling them for endosomal iron acquisition. pH-sensitive fluorescent labeling, 125I-antibody surface kinetics, pharmacological inhibitors (dynasore, wortmannin, cholesterol depletion), dual labeling confocal microscopy The Journal of biological chemistry High 12724326
2003 Nramp1 and Nramp2 have indistinguishable membrane topology and transport properties (Fe2+, Mn2+, Co2+) when both expressed at the plasma membrane; Nramp1 may be a more efficient Mn2+ transporter than Nramp2. This suggests Nramp1 divalent-metal transport at the phagosomal membrane is mechanistically similar to Nramp2 at endosomal membranes. Plasma membrane expression of HA-tagged Nramp1 and Nramp2 in CHO cells, immunofluorescence, surface biotinylation, calcein/Fura2 fluorescence assays, radioisotopic 55Fe2+/54Mn2+ transport assays Blood High 12750164
2001 In erythroid cells, DMT1 isoform II (non-IRE) co-localizes with the transferrin receptor and is required for iron transport across the endosomal membrane after transferrin-bound iron release; mk/mk reticulocytes show impaired Fe2+ transport across the endosomal membrane (despite normal iron release from transferrin inside the endosome) and express little DMT1 despite robust transferrin receptor expression, indicating the G185R mutation affects both transport function and protein stability/targeting in erythroid cells. Immunoblotting of membrane fractions, double immunofluorescence and confocal microscopy, isoform-specific antisera, iron uptake and heme incorporation assays in mk/mk reticulocytes Blood High 11739192
2005 Selective in vivo inactivation of murine Slc11a2 established that it is essential for intestinal non-heme iron absorption after birth and for normal hemoglobin production during erythroid precursor development, but is not required for materno-fetal iron transfer. Hepatocytes and most other cells have an alternative, unidentified iron uptake mechanism. Global and conditional Slc11a2 knockout mice, phenotypic analysis of iron absorption, hemoglobin production, and tissue iron levels The Journal of clinical investigation High 15849611
2000 The G185R mutation in mk/mk mice impairs both the transport activity and the targeting of DMT1 to the apical membrane of duodenal enterocytes; despite a dramatic increase in DMT1 mRNA and protein expression in the duodenum, little protein is seen at the apical brush border, suggesting the mutation affects both function and membrane targeting. Northern blot, immunoblotting, immunohistochemical analysis of mk/mk vs. heterozygote duodenum Blood High 11090085
2003 The first external loop of DCT1/SLC11A2 is involved in metal ion binding and specificity: mutation G119A nearly abolishes transport; Q126D abolishes transport but D124A/Q126D double mutant partially restores it and shifts specificity toward Fe2+; D124A retains Fe2+ uptake but markedly reduces Mn2+ transport. Site-directed mutagenesis, yeast complementation (smf1Δ), Xenopus oocyte electrophysiology, 54Mn2+ uptake assays Proceedings of the National Academy of Sciences of the United States of America High 12954986
2004 The mutation F227I in transmembrane domain 4 of DCT1/SLC11A2 increases the coupling efficiency between metal ion and proton transport by up to 14-fold, demonstrating that the normal low coupling ratio results from a proton slippage mechanism that is not mechanistically obligatory. Site-directed mutagenesis, yeast complementation, Xenopus oocyte electrophysiology The Journal of biological chemistry High 15475345
2005 The carboxyl-terminus YLLNT motif of DMT1 isoform II is the major signal for internalization from the plasma membrane into recycling endosomes; deletion of this motif increases surface expression due to impaired internalization and redirects internalized DMT1 to lysosomes rather than recycling endosomes. Carboxyl- and amino-terminus truncation mutants stably expressed in LLC-PK1 cells, surface labeling with 125I-antibody kinetics, immunofluorescence, subcellular localization Biochemistry High 16142913
2006 The two DMT1 isoforms (I/+IRE and II/-IRE) have distinct subcellular targeting and recycling properties in LLC-PK1 kidney cells: isoform I shows higher surface expression and slower internalization, and upon internalization is targeted to lysosomes rather than recycling endosomes (as isoform II is). Thus, alternative splicing at the C-terminus controls the subcellular site of Fe2+ transport. Stable transfection in LLC-PK1 cells, immunofluorescence, surface labeling, endocytosis kinetics, lysosomal/endosomal marker colocalization Biochemistry High 16475818
2006 The R416C mutation in transmembrane domain 9 of human DMT1 causes multiple functional deficiencies including defective protein processing, loss of transport activity, impaired cell surface targeting, and retention in the ER. Conservative substitution R416K preserves function, demonstrating R416 is essential for proper folding and trafficking. Site-directed mutagenesis (R416C, R416A, R416K, R416E), LLC-PK1 expression, transport assays, immunofluorescence subcellular localization, protein processing analysis Blood cells, molecules & diseases High 16584902
2009 Epitope-tagging topology mapping of Slc11a2 confirmed a 12-transmembrane domain architecture with intracellular N- and C-termini; loops TM4-5, TM6-7, and TM10-11 are intracellular, while loops TM5-6, TM7-8, and TM11-12 are extracellular. Insertions at positions 98, 131, 175, 403, and 432 abrogated transport, identifying functionally critical regions. Homology threading models show 2-fold structural symmetry for TM1-5 and TM6-10. HA epitope insertion mutagenesis at 13 positions, immunofluorescence in intact and permeabilized LLC-PK1 cells, transport activity assays, homology threading structural modeling Biochemistry High 19621945
2002 Nramp2/DMT1 is recruited to the phagosomal membrane of macrophages (RAW264.7) and Sertoli cells after phagocytosis, associating with LAMP1-, cathepsin D-, and rab7-positive mature phagosomes, suggesting DMT1 transports divalent metals out of the phagosomal lumen, analogous to Nramp1. Immunofluorescence, in vitro biochemical studies with purified latex bead-containing phagosomes, erythrocyte and sperm phagocytosis assays Blood Medium 12239176
2001 DMT1 is localized intracellularly (not at plasma membranes) in the adult rat testis, expressed in both Sertoli and germ cells in a stage-dependent manner during the spermatogenic cycle, suggesting a role in intracellular iron handling between compartments rather than transepithelial iron transport. Northern blot, RT-PCR, immunoblotting, immunohistochemistry of developing and adult rat testis American journal of physiology. Cell physiology Medium 15355847
2001 In rat kidney, DMT1 immunoreactivity is strongest in collecting ducts (both principal and intercalated cells) and distal convoluted tubules (apical staining), with intracellular staining throughout the nephron, consistent with DMT1 providing the molecular mechanism for apical iron entry in the distal nephron. Affinity-purified anti-DMT1 antibody, Western analysis, immunofluorescence, confocal microscopy in rat kidney sections American journal of physiology. Renal physiology Medium 11292622
2000 DMT1 is expressed in human term placenta syncytiotrophoblast, localizing to both the cytoplasm and the basal (fetal-side) membrane, distinct from transferrin receptor which is on the apical (maternal) side, suggesting DMT1 mediates iron transfer from endosomes to cytoplasm and across the basal membrane to the fetus. Immunohistochemistry of frozen term human placenta sections, double staining with anti-TfR antibody Placenta Medium 11095929
2008 Overexpression of DMT1 in CHO cells greatly increases ferrous iron uptake, with Fe(II) transported far more efficiently than Fe(III). Fe(III) transport by DMT1-expressing CHO cells can be inhibited by a membrane-impermeant oxidant, indicating that a membrane ferric reductase is needed to reduce Fe(III) to Fe(II) for DMT1-mediated transport. 59Fe transport assays in Nramp2-transfected vs. control CHO cells, oxidant inhibition experiments Experimental hematology Medium 18722041
2011 The N491S mutation in human SLC11A2 causes abnormal protein trafficking (as demonstrated in HuH7 hepatic cells with dsRed2-tagged DMT1), while the G212V mutation does not affect trafficking; N491S together with G212V leads to microcytic anemia and liver iron overload in a patient. Fluorescent protein tagging and live-cell imaging of DMT1 trafficking in HuH7 cells, splicing analysis in patient leukocytes, real-time qPCR of DMT1 isoforms in human liver Blood cells, molecules & diseases Medium 21871825
2011 The E399D mutation in DMT1 exon 12 does not affect protein stability, membrane targeting, endosomal trafficking, or transport activity in LLC-PK1 cells, establishing it as a functionally neutral polymorphism and indicating that disease in the patient bearing the 1285G>C mutation is caused by exon 12 skipping (reduced protein quantity) rather than the E399D amino acid change. Site-directed mutagenesis (E399D, E399Q, E399A) stably expressed in LLC-PK1 cells, transport assays, immunofluorescence Blood cells, molecules & diseases Medium 16023393
2010 Calcium reduces DMT1 protein expression at the apical cell membrane (not total cellular DMT1), as shown in fractionated Caco-2 cell lysates, suggesting that calcium inhibits non-heme iron absorption by decreasing DMT1 at the apical surface. Fractionation of Caco-2 cell membrane vs. whole cell lysates, Western blotting for DMT1 and ferroportin after iron and calcium treatments Journal of agricultural and food chemistry Low 20597505
2007 A single reciprocal mutation I144F in TM2 of DCT1/SLC11A2 abolishes metal ion transport and increases proton slip currents; a double mutant I144F/F227I restores uptake activity and reduces slip currents, demonstrating that TM2 and TM4 are functionally coupled in the proton-metal ion coupling mechanism. Site-directed mutagenesis, metal ion uptake assays, Xenopus oocyte electrophysiology Biochimica et biophysica acta High 17980698
2015 A non-competitive inhibitor (pyrimidinone 8, Ki ~20 μM) of human DMT1 was discovered that does not affect cell surface expression of hDMT1, providing the first experimental evidence that DMT1 can be allosterically modulated by pharmacological agents. Ligand-based virtual screening, radiolabeled iron uptake assay in hDMT1-expressing cells, surface expression analysis Biochemical pharmacology Medium 26047847
2023 Microglial-specific knockdown of Slc11a2 in male mice blunts LPS-induced pro-inflammatory cytokine expression (Il6, Tnfα, Il1β), reduces plasma cytokines, upregulates iron export/recycling genes, and improves acute sickness behavior in a sex-specific manner (males but not females), establishing a feed-forward link between microglial iron import via DMT1 and pro-inflammatory activation in vivo. Tamoxifen-inducible Cx3cr1Cre-ERT2 microglial-specific Slc11a2 knockdown mice, LPS challenge, plasma cytokine measurement, bulk RNA-seq of isolated microglia Brain, behavior, and immunity Medium 38141840
2022 The G75R mutation in SLC11A2 causes improper DMT1 accumulation in lysosomes in HuTu 80 cells, leading to significantly decreased DMT1 protein levels in patient-derived lymphoblastoid cell lines, thus producing loss-of-function microcytic anemia with iron overload. Functional characterization of G75R in HuTu 80 cells by immunofluorescence colocalization with lysosomal markers; patient-derived LCL DMT1 protein quantification International journal of molecular sciences Medium 35457224

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1997 Microcytic anaemia mice have a mutation in Nramp2, a candidate iron transporter gene. Nature genetics 955 9241278
1998 Nramp2 is mutated in the anemic Belgrade (b) rat: evidence of a role for Nramp2 in endosomal iron transport. Proceedings of the National Academy of Sciences of the United States of America 777 9448300
1999 Cellular and subcellular localization of the Nramp2 iron transporter in the intestinal brush border and regulation by dietary iron. Blood 364 10361139
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 339 12209011
2005 Slc11a2 is required for intestinal iron absorption and erythropoiesis but dispensable in placenta and liver. The Journal of clinical investigation 334 15849611
1998 The human Nramp2 gene: characterization of the gene structure, alternative splicing, promoter region and polymorphisms. Blood cells, molecules & diseases 261 9642100
1999 The iron transport protein NRAMP2 is an integral membrane glycoprotein that colocalizes with transferrin in recycling endosomes. The Journal of experimental medicine 248 10049947
2003 Iron, manganese, and cobalt transport by Nramp1 (Slc11a1) and Nramp2 (Slc11a2) expressed at the plasma membrane. Blood 221 12750164
2000 Nramp2 expression is associated with pH-dependent iron uptake across the apical membrane of human intestinal Caco-2 cells. The Journal of biological chemistry 220 10625641
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 199 10751401
1998 The G185R mutation disrupts function of the iron transporter Nramp2. Blood 193 9731075
2000 Nramp 2 (DCT1/DMT1) expressed at the plasma membrane transports iron and other divalent cations into a calcein-accessible cytoplasmic pool. The Journal of biological chemistry 152 10942769
1999 Duodenal metal-transporter (DMT-1, NRAMP-2) expression in patients with hereditary haemochromatosis. Lancet (London, England) 150 10382697
2014 KCNJ10 determines the expression of the apical Na-Cl cotransporter (NCC) in the early distal convoluted tubule (DCT1). Proceedings of the National Academy of Sciences of the United States of America 129 25071208
2001 Characterization of the iron transporter DMT1 (NRAMP2/DCT1) in red blood cells of normal and anemic mk/mk mice. Blood 127 11739192
2001 Cellular localization of divalent metal transporter DMT-1 in rat kidney. American journal of physiology. Renal physiology 112 11292622
1997 Functional complementation of the yeast divalent cation transporter family SMF by NRAMP2, a member of the mammalian natural resistance-associated macrophage protein family. The Journal of biological chemistry 103 9360964
2002 Expression of the two mRNA isoforms of the iron transporter Nramp2/DMTI in mice and function of the iron responsive element. The Biochemical journal 94 11964145
2003 Iron transport by Nramp2/DMT1: pH regulation of transport by 2 histidines in transmembrane domain 6. Blood 87 12522007
2003 Dynamic traffic through the recycling compartment couples the metal transporter Nramp2 (DMT1) with the transferrin receptor. The Journal of biological chemistry 87 12724326
2000 Identification and localization of divalent metal transporter-1 (DMT-1) in term human placenta. Placenta 87 11095929
2000 The Nramp2/DMT1 iron transporter is induced in the duodenum of microcytic anemia mk mice but is not properly targeted to the intestinal brush border. Blood 85 11090085
2001 Expression of the DMT1 (NRAMP2/DCT1) iron transporter in mice with genetic iron overload disorders. Blood 81 11159549
2001 Properties of the mammalian and yeast metal-ion transporters DCT1 and Smf1p expressed in Xenopus laevis oocytes. The Journal of experimental biology 77 11222124
1999 The effect of intracellular iron concentration and nitrogen monoxide on Nramp2 expression and non-transferrin-bound iron uptake. European journal of biochemistry 75 10429185
2002 Iron uptake and Nramp2/DMT1/DCT1 in human bronchial epithelial cells. American journal of physiology. Lung cellular and molecular physiology 68 11943663
2006 Distinct targeting and recycling properties of two isoforms of the iron transporter DMT1 (NRAMP2, Slc11A2). Biochemistry 63 16475818
2002 Iron transporter Nramp2/DMT-1 is associated with the membrane of phagosomes in macrophages and Sertoli cells. Blood 54 12239176
2001 Evidence for cadmium uptake through Nramp2: metal speciation studies with Caco-2 cells. Biochemical and biophysical research communications 53 11453644
2000 Interferon-gamma and lipopolysaccharide regulate the expression of Nramp2 and increase the uptake of iron from low relative molecular mass complexes by macrophages. European journal of biochemistry 53 11054110
2001 A light and electron microscopic study of the iron transporter protein DMT-1 in the monkey cerebral neocortex and hippocampus. Journal of neurocytology 49 11875282
2012 The metal transporter SMF-3/DMT-1 mediates aluminum-induced dopamine neuron degeneration. Journal of neurochemistry 46 23106139
2020 Transmembrane protein western blotting: Impact of sample preparation on detection of SLC11A2 (DMT1) and SLC40A1 (ferroportin). PloS one 43 32645092
1997 Complete nucleotide sequence of human NRAMP2 cDNA. Molecular immunology 43 9464519
2011 A novel N491S mutation in the human SLC11A2 gene impairs protein trafficking and in association with the G212V mutation leads to microcytic anemia and liver iron overload. Blood cells, molecules & diseases 41 21871825
2009 Transmembrane topology of the mammalian Slc11a2 iron transporter. Biochemistry 41 19621945
2001 Pharmacological characterization of the dermorphin analog [Dmt(1)]DALDA, a highly potent and selective mu-opioid peptide. European journal of pharmacology 41 11348625
2006 Immunolocalisation of the D. melanogaster Nramp homologue Malvolio to gut and Malpighian tubules provides evidence that Malvolio and Nramp2 are orthologous. The Journal of experimental biology 40 16651563
2007 Synthesis and characterization of potent and selective mu-opioid receptor antagonists, [Dmt(1), D-2-Nal(4)]endomorphin-1 (Antanal-1) and [Dmt(1), D-2-Nal(4)]endomorphin-2 (Antanal-2). Journal of medicinal chemistry 39 17266203
2003 Localization of the iron transport proteins Mobilferrin and DMT-1 in the duodenum: the surprising role of mucin. American journal of hematology 39 12949888
2006 A novel R416C mutation in human DMT1 (SLC11A2) displays pleiotropic effects on function and causes microcytic anemia and hepatic iron overload. Blood cells, molecules & diseases 36 16584902
2003 The first external loop of the metal ion transporter DCT1 is involved in metal ion binding and specificity. Proceedings of the National Academy of Sciences of the United States of America 34 12954986
2010 Inhibitory effect of calcium on non-heme iron absorption may be related to translocation of DMT-1 at the apical membrane of enterocytes. Journal of agricultural and food chemistry 33 20597505
2003 Distribution of DMT 1 within the human glandular system. Histology and histopathology 32 12973678
2008 Ascorbic acid uptake affects ferritin, Dcytb and Nramp2 expression in Caco-2 cells. European journal of nutrition 30 18815723
2005 Carboxyl-terminus determinants of the iron transporter DMT1/SLC11A2 isoform II (-IRE/1B) mediate internalization from the plasma membrane into recycling endosomes. Biochemistry 29 16142913
2015 Discovery and characterization of a novel non-competitive inhibitor of the divalent metal transporter DMT1/SLC11A2. Biochemical pharmacology 28 26047847
2011 Association between divalent metal transport 1 encoding gene (SLC11A2) and disease duration in amyotrophic lateral sclerosis. Journal of the neurological sciences 27 21276595
2003 Influence of parenteral iron preparations on non-transferrin bound iron uptake, the iron regulatory protein and the expression of ferritin and the divalent metal transporter DMT-1 in HepG2 human hepatoma cells. Biochemical pharmacology 27 12787877
2005 Functional characterization of the E399D DMT1/NRAMP2/SLC11A2 protein produced by an exon 12 mutation in a patient with microcytic anemia and iron overload. Blood cells, molecules & diseases 26 16023393
2012 Variation of the net charge, lipophilicity, and side chain flexibility in Dmt(1)-DALDA: Effect on Opioid Activity and Biodistribution. Journal of medicinal chemistry 25 23102273
2005 Candidate gene association study of solute carrier family 11a members 1 (SLC11A1) and 2 (SLC11A2) genes in Alzheimer's disease. Neuroscience letters 24 15644277
2016 Pharmacological studies on the NOP and opioid receptor agonist PWT2-[Dmt1]N/OFQ(1-13). European journal of pharmacology 23 27871910
2002 Increased duodenal DMT-1 expression and unchanged HFE mRNA levels in HFE-associated hereditary hemochromatosis and iron deficiency. Blood cells, molecules & diseases 23 12547214
2018 Genetic and transcriptional variations in NRAMP-2 and OPAQUE1 genes are associated with salt stress response in wheat. TAG. Theoretical and applied genetics. Theoretische und angewandte Genetik 21 30392081
2004 The mutation F227I increases the coupling of metal ion transport in DCT1. The Journal of biological chemistry 21 15475345
2000 Analysis of a positional candidate gene for inflammatory bowel disease: NRAMP2. Inflammatory bowel diseases 20 10833067
2024 Inorganic nitrogen inhibits symbiotic nitrogen fixation through blocking NRAMP2-mediated iron delivery in soybean nodules. Nature communications 19 39414817
2004 Differential expression of divalent metal transporter DMT1 (Slc11a2) in the spermatogenic epithelium of the developing and adult rat testis. American journal of physiology. Cell physiology 18 15355847
2002 Induction of Nramp2 in activated mouse macrophages is dissociated from regulation of the Nramp1, classical inflammatory genes, and genes involved in iron metabolism. Journal of leukocyte biology 18 11781385
2010 Suppression of SLC11A2 expression is essential to maintain duodenal integrity during dietary iron overload. The American journal of pathology 17 20558581
2008 Use of Nramp2-transfected Chinese hamster ovary cells and reticulocytes from mk/mk mice to study iron transport mechanisms. Experimental hematology 17 18722041
2002 Expression of ferritin, transferrin receptor, and non-specific resistance associated macrophage proteins 1 and 2 (Nramp1 and Nramp2) in the human rheumatoid synovium. Annals of the rheumatic diseases 17 12117685
2014 The influence of combined magnesium and vanadate administration on the level of some elements in selected rat organs: V-Mg interactions and the role of iron-essential protein (DMT-1) in the mechanism underlying altered tissues iron level. Metallomics : integrated biometal science 16 24549458
2012 Candidate gene sequencing of SLC11A2 and TMPRSS6 in a family with severe anaemia: common SNPs, rare haplotypes, no causative mutation. PloS one 16 22509377
2023 Promotive role of IRF7 in ferroptosis of colonic epithelial cells in ulcerative colitis by the miR-375-3p/SLC11A2 axis. Biomolecules & biomedicine 15 36336986
2020 Mechanistic Understanding of Peptide Analogues, DALDA, [Dmt1]DALDA, and KGOP01, Binding to the mu Opioid Receptor. Molecules (Basel, Switzerland) 15 32365707
2015 The bifunctional μ opioid agonist/antioxidant [Dmt(1)]DALDA is a superior analgesic in an animal model of complex regional pain syndrome-type i. ACS chemical neuroscience 15 26352668
2015 In silico analysis of consequences of non-synonymous SNPs of Slc11a2 gene in Indian bovines. Genomics data 15 26484229
2004 Quantitative analysis of [Dmt(1)]DALDA in ovine plasma by capillary liquid chromatography-nanospray ion-trap mass spectrometry. Journal of chromatography. B, Analytical technologies in the biomedical and life sciences 15 15026001
2000 Heterologous expression, functional characterization and localization of two isoforms of the monkey iron transporter Nramp2. The Biochemical journal 15 10861241
2014 Development and Validation of a Fast and Homogeneous Cell-Based Fluorescence Screening Assay for Divalent Metal Transporter 1 (DMT1/SLC11A2) Using the FLIPR Tetra. Journal of biomolecular screening 14 24505080
2014 [Dmt(1)]DALDA analogues with enhanced μ opioid agonist potency and with a mixed μ/κ opioid activity profile. Bioorganic & medicinal chemistry 14 24602401
2022 The Associations between Metalloestrogens, GSTP1, and SLC11A2 Polymorphism and the Risk of Endometrial Cancer. Nutrients 13 35893933
2018 Differences of Cd uptake and expression of MT family genes and NRAMP2 in two varieties of ryegrasses. Environmental science and pollution research international 12 29961908
2013 Characterization of chicken natural resistance-associated macrophage protein encoding genes (Nramp1 and Nramp2) and association with salmonellosis resistance. Genetics and molecular research : GMR 10 23408449
2009 Milk peptides increase iron dialyzability in water but do not affect DMT-1 expression in Caco-2 cells. Journal of agricultural and food chemistry 10 19183058
1998 Identification of Nramp2 as an iron transport protein: another piece of the intestinal iron absorption puzzle. Nutrition reviews 10 9564183
2023 Microglial-specific knockdown of iron import gene, Slc11a2, blunts LPS-induced neuroinflammatory responses in a sex-specific manner. Brain, behavior, and immunity 9 38141840
2014 In Vitro Membrane Permeation Studies and in Vivo Antinociception of Glycosylated Dmt1-DALDA Analogues. ACS medicinal chemistry letters 9 24839540
2008 The novel micro-opioid receptor antagonist, [N-allyl-Dmt(1)]endomorphin-2, attenuates the enhancement of GABAergic neurotransmission by ethanol. Alcohol and alcoholism (Oxford, Oxfordshire) 9 18971291
2025 The Potential Association of TFR1/SLC11A2/GPX4 with Ferroptosis in Mediating Lipid Metabolism Disorders in Atherosclerosis. Combinatorial chemistry & high throughput screening 8 38213145
2023 SLC11A2: a promising biomarker and therapeutic target in ovarian cancer. Scientific reports 8 36670142
2020 Simultaneous supplementation with iron and folic acid can affect Slc11a2 and Slc46a1 transcription and metabolite concentrations in rats. The British journal of nutrition 8 31656209
2018 Increased DMT-1 expression in placentas of women living in high-Cd-contaminated areas of Thailand. Environmental science and pollution research international 8 30387054
2007 Site-directed mutagenesis investigation of coupling properties of metal ion transport by DCT1. Biochimica et biophysica acta 8 17980698
2016 [Dmt(1)]DALDA analogues modified with tyrosine analogues at position 1. Bioorganic & medicinal chemistry letters 7 27301366
2011 Folding and assembly of TMD 6-related segments of DMT 1 in trifluoroethanol aqueous solution. Journal of peptide science : an official publication of the European Peptide Society 7 21674702
2008 LDL oxidation by THP-1 monocytes: implication of HNP-1, SgIII and DMT-1. Clinica chimica acta; international journal of clinical chemistry 7 19150442
2022 New Cases of Hypochromic Microcytic Anemia Due to Mutations in the SLC11A2 Gene and Functional Characterization of the G75R Mutation. International journal of molecular sciences 6 35457224
2020 Pyrazolyl-pyrimidones inhibit the function of human solute carrier protein SLC11A2 (hDMT1) by metal chelation. RSC medicinal chemistry 5 33479694
2024 Knockdown of microglial iron import gene, Slc11a2, worsens cognitive function and alters microglial transcriptional landscape in a sex-specific manner in the APP/PS1 model of Alzheimer's disease. Journal of neuroinflammation 4 39334471
2022 Regulation of Iron-Ion Transporter SLC11A2 by Three Identical miRNAs. Biological & pharmaceutical bulletin 4 36047197
2010 Rapid regulation of intestinal divalent metal (cation) transporter 1 (DMT1/DCT1) and ferritin mRNA expression in response to excess iron loading in iron-deficient rats. Bioscience, biotechnology, and biochemistry 4 20208373
2013 Chiral Effect of a Phe Residue in Position 3 of the Dmt1-L(or D)-Tic2 Analogues on Opioid Functional Activities. ACS medicinal chemistry letters 3 24648867
2002 Accurate microsatellite typing and inter-study comparison: pitfalls and solutions using interferon-gamma (IFNG) and natural resistance-associated macrophage protein 2 (NRAMP2) genes as examples. Clinical chemistry and laboratory medicine 3 12435110
2016 Molecular comparison of Slc11a1 and Slc11a2 genes of swamp- and riverine-type water buffaloes. International journal of immunogenetics 2 27091413
1999 Dinucleotide repeat polymorphism in the third intron of the NRAMP2/DMT1 gene. Journal of human genetics 2 10570921
2023 BMP4, SGSH, and SLC11A2 are Predicted to Be Biomarkers of Aging Associated with Programmed Cell Death. Journal of molecular neuroscience : MN 1 37632651
2000 Nramp2 analysis in hemochromatosis probands. Blood cells, molecules & diseases 1 11042033

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