SLC11A2

Summary

SLC11A2 (solute carrier family 11 member 2, HGNC:10908) is a protein-coding gene on chromosome 12q13.12, encoding Natural resistance-associated macrophage protein 2 (P49281). Proton-coupled metal ion symporter operating with a proton to metal ion stoichiometry of 1:1.

This gene encodes a member of the solute carrier family 11 protein family. The product of this gene transports divalent metals and is involved in iron absorption. Mutations in this gene are associated with hypochromic microcytic anemia with iron overload. A related solute carrier family 11 protein gene is located on chromosome 2. Multiple transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 4891 — RefSeq curated summary.

At a glance

• Gene–disease (curated): microcytic anemia with liver iron overload (Definitive, ClinGen)
• GWAS associations: 1
• Clinical variants (ClinVar): 176 total — 7 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 8
• Druggable target: yes
• MANE Select transcript: NM_000617

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10908
Approved symbol	SLC11A2
Name	solute carrier family 11 member 2
Location	12q13.12
Locus type	gene with protein product
Status	Approved
Aliases	DCT1, DMT1, DMT-1, FLJ37416
Ensembl gene	ENSG00000110911
Ensembl biotype	protein_coding
OMIM	600523
Entrez	4891

Gene structure

Transcript identifiers

Ensembl transcripts: 48 — 32 protein_coding, 7 nonsense_mediated_decay, 5 retained_intron, 4 protein_coding_CDS_not_defined

ENST00000262052, ENST00000394904, ENST00000541174, ENST00000545993, ENST00000546488, ENST00000546636, ENST00000546743, ENST00000547198, ENST00000547510, ENST00000547579, ENST00000547688, ENST00000547732, ENST00000548150, ENST00000548193, ENST00000548554, ENST00000549110, ENST00000549193, ENST00000549625, ENST00000550061, ENST00000550329, ENST00000550714, ENST00000550782, ENST00000550995, ENST00000551215, ENST00000551231, ENST00000642227, ENST00000643123, ENST00000643884, ENST00000644495, ENST00000646264, ENST00000646740, ENST00000646988, ENST00000681324, ENST00000866728, ENST00000866729, ENST00000866730, ENST00000866731, ENST00000866732, ENST00000914208, ENST00000914209, ENST00000914210, ENST00000914211, ENST00000965620, ENST00000965621, ENST00000965622, ENST00000965623, ENST00000965624, ENST00000965625

RefSeq mRNA: 18 — MANE Select: NM_000617 NM_000617, NM_001174125, NM_001174126, NM_001174127, NM_001174128, NM_001174129, NM_001174130, NM_001379446, NM_001379447, NM_001379448, NM_001379455, NM_001414744, NM_001414745, NM_001414746, NM_001414747, NM_001414748, NM_001414749, NM_001414750

CCDS: CCDS53791, CCDS53792, CCDS53793, CCDS8805, CCDS91695

Canonical transcript exons

ENST00000262052 — 16 exons

Exon	Start	End
ENSE00000743612	50995629	50995787
ENSE00000743615	50994544	50994630
ENSE00001317857	50985992	50988435
ENSE00002419618	51026310	51026384
ENSE00003469124	50992190	50992339
ENSE00003469681	50996817	50996972
ENSE00003487553	50999345	50999415
ENSE00003503108	50990795	50990948
ENSE00003532170	50999174	50999241
ENSE00003553887	51008476	51008624
ENSE00003568509	51010695	51010766
ENSE00003573707	50991599	50991672
ENSE00003647199	51000313	51000419
ENSE00003651435	51004788	51004907
ENSE00003668865	50992810	50992929
ENSE00003686838	51005311	51005436

Expression profiles

Bgee: expression breadth ubiquitous, 297 present calls, max score 96.24.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 20.8928 / max 269.4716, expressed in 1807 samples.

FANTOM5 promoters (9 alternative TSS)

Promoter ID	TPM avg	Samples expressed
130928	12.2601	1789
130922	5.1545	481
130929	1.2105	388
130927	0.9742	538
130923	0.6375	242
130921	0.3052	135
130926	0.2828	137
130924	0.0341	7
130930	0.0339	12

Top tissues by expression

299 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
inferior vagus X ganglion	UBERON:0005363	96.24	gold quality
buccal mucosa cell	CL:0002336	95.45	gold quality
caput epididymis	UBERON:0004358	95.19	gold quality
corpus callosum	UBERON:0002336	94.98	gold quality
cartilage tissue	UBERON:0002418	94.83	gold quality
oral cavity	UBERON:0000167	94.82	gold quality
minor salivary gland	UBERON:0001830	94.73	gold quality
superior vestibular nucleus	UBERON:0007227	94.70	gold quality
subthalamic nucleus	UBERON:0001906	94.69	gold quality
pons	UBERON:0000988	94.67	gold quality
saliva-secreting gland	UBERON:0001044	94.63	gold quality
ventral tegmental area	UBERON:0002691	94.46	gold quality
corpus epididymis	UBERON:0004359	94.33	gold quality
body of pancreas	UBERON:0001150	94.32	gold quality
parotid gland	UBERON:0001831	94.30	gold quality
medulla oblongata	UBERON:0001896	94.28	gold quality
mouth mucosa	UBERON:0003729	94.23	gold quality
pharyngeal mucosa	UBERON:0000355	94.18	gold quality
bronchial epithelial cell	CL:0002328	94.12	gold quality
penis	UBERON:0000989	94.10	gold quality
right lobe of thyroid gland	UBERON:0001119	94.01	gold quality
tongue squamous epithelium	UBERON:0006919	93.89	gold quality
left lobe of thyroid gland	UBERON:0001120	93.84	gold quality
thyroid gland	UBERON:0002046	93.76	gold quality
epithelium of bronchus	UBERON:0002031	93.75	gold quality
esophagus squamous epithelium	UBERON:0006920	93.70	gold quality
bronchus	UBERON:0002185	93.67	gold quality
right lung	UBERON:0002167	93.65	gold quality
dorsal plus ventral thalamus	UBERON:0001897	93.47	gold quality
spinal cord	UBERON:0002240	93.42	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	15.05

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): BMP6, DMRT1, EPAS1, HIF1A, SMAD4, SP1

miRNA regulators (miRDB)

125 targeting SLC11A2, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-223-3P	99.99	70.14	1140
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-367-3P	99.98	74.83	1819
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-545-3P	99.95	70.74	2783
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-141-3P	99.94	72.79	2421
HSA-MIR-200A-3P	99.94	72.68	2420
HSA-MIR-539-5P	99.93	70.30	2855
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-205-3P	99.92	69.92	3165
HSA-MIR-145-5P	99.92	71.13	1836
HSA-MIR-5195-3P	99.92	70.92	1877

Literature-anchored findings (GeneRIF, showing 40)

• location was observed on or near the cell surface suggesting it might participate in surface membrane transport of iron (PMID:11891802)
• expression levels of human DCT1 mRNA, and to a lesser extent IREG1 mRNA, are regulated in an iron-dependent manner (PMID:11897618)
• airway epithelial cells increase mRNA and expression of the Nramp2/DMT1/DCT1 without an IRE after exposure to iron. The increase results in an elevated transport of iron and its probable detoxification by these cells. (PMID:11943663)
• DMT1 is a transporter for lead (PMID:12127992)
• iron regulation of DMT1 involves the expression of a previously unrecognized upstream 5’ exon (exon 1A) of the human and murine DMT1 gene (PMID:12209011)
• Using the Xenopus oocyte expression system, human Nramp2, a human intestinal iron transporter, was shown to work as a cadmium transporter (PMID:12662899)
• These results demonstrate that DMT1 is a physiologically relevant Cu(1+) transporter in intestinal cells, indicating that intestinal absorption of copper and iron are intertwined. (PMID:12734107)
• in iron deficiency DMT-1 and mobilferrin concentrated in apical surface of duodenal villae; increase due to increased binding to mucin in vesicles near surfacel; localized in goblet cells and outside cell in luminal mucin (PMID:12949888)
• divalent metal ion transporter-1 may be of pivotal importance for the regulation of metal ion homeostasis within organs involved in absorption and excretion of ions (PMID:12973678)
• Increased expression of DMT1 may play an important role in the pathogenesis of cirrhosis-associated hepatic iron overload. (PMID:14768003)
• the G185R mutant DMT1 exhibits a new, constitutive Ca(2+) permeability (PMID:15024413)
• comparison of the regional distribution of SFT/UbcH5A and DMT1 mRNA in the adult brain (PMID:15139022)
• Mutation of DMT1 identified in a female with severe hypochromic microcytic anemia and iron overload. (PMID:15459009)
• Intracellular localization of SLC11A2 to endosomal/lysosomal compartment is regulated by iron. (PMID:15792797)
• Transferrin receptor (TfR) and hemochromatosis factor, as well as TfR and DMT1 interact in placental trophoblast cells (PMID:15880641)
• DMT1 isoforms are expressed in first trimester human placenta and embryonic tissues (PMID:16123094)
• DMT1 mutations are responsible for severe hypochromic microcytic anemia in humans. (PMID:16439678)
• Specific signals or cues to direct DMT1 to the appropriate subcellular compartments (e.g. in erythroid cells) or the plasma membrane (e.g. in intestine). (PMID:17109629)
• Modulation of DMT-1 function by L-type calcium channel blockers is a pharmacological therapy for the treatment of iron overload disorders. (PMID:17293870)
• two DMT1 intronic SNPs showed positive association with restless legs syndrome in patients with a history of anemia, when compared to RLS patients without anemia. (PMID:17510944)
• These results demonstrate the importance of these regions in coupling of metal ions and protons as well as the possible proximity of I144 and F227 in the folded structure of DCT1. (PMID:17980698)
• Increased DMT1+IRE expression in MES23.5 cells caused the increased intracellular iron accumulation. This resulted in the increased oxidative stress leading to ultimate cell apoptosis. (PMID:18082289)
• Correlation between the expression of DMT1 and the content of hypoxia-inducible factor-1 in hypoxic cells is reported. (PMID:18419598)
• DMT1 (NRAMP2/DCT1) genetic variability and resistance to recombinant human erythropoietin therapy in chronic kidney disease patients under haemodialysis. (PMID:18667808)
• These findings suggest both that DMT1 plays a critical role in ion-mediated neuropathogenesis in Alzheimer’s disease (AD) and that pharmacological blockage of DMT1 may provide novel therapeutic strategies against AD. (PMID:19679638)
• Suggest a novel mechanism of regulation of intestinal iron absorption based on inward and outward fluxes at both membrane domains, and repositioning of DMT1 and FPN between membrane and intracellular compartments as a function of iron supply. (PMID:20007457)
• Ca2+ is a low-affinity noncompetitive inhibitor–but not a transported substrate–of DMT1, explaining in part the effect of high dietary calcium on iron bioavailability. (PMID:20152801)
• Findings demonstrate that the retromer recognizes the recycling signal of DMT1-II and ensures its proper endosomal recycling. (PMID:20164305)
• Data suggest that miR-Let-7d participates in the finely tuned regulation of iron metabolism by targeting DMT1-IRE isoform in erythroid cells. (PMID:20410187)
• DMT1 is a hypoxia-inducible gene. (PMID:20945371)
• Data show that the peptide can bind to Mn2+ and Co2+ ions by the side chains of the negatively charged residues in the motif and the C-terminal part of DMT1-TMD1. (PMID:21074515)
• An acute increase in hepcidin concentration reduces intestinal iron absorption through ubiquitin-dependent proteasome degradation of DMT1 (PMID:21199652)
• Our findings support an implication for iron metabolism in amyotrophic lateral sclerosis and suggest that the genotype of the SLC11A2 gene could modulate the duration of the disease (PMID:21276595)
• CC haplotype in DMT1 gene is a possible risk factor for Parkinson disease in this Han Chinese population. (PMID:21777657)
• Variations in the ability of LAT1/DMT1/MTF1/MT1a to process and transport Hg may not play a significant role in the etiology of autism. (PMID:21798283)
• Our data confirm the major role of SLC11A2 in the maintenance of iron homeostasis in humans and demonstrate that the mutation contributes to the development of anemia and hepatic iron overload. (PMID:21871825)
• DMT1 is likely involved in endosomal iron transport in placental STB and placental DMT1 + IRE expression was primarily regulated by the IRE/IRP mechanism (PMID:21947861)
• Homology implies that inverted structural symmetry facilitates Slc11 H(+)-driven Me(2+) import and provides a 3D framework to test structure-activity relationships in macrophages and study functional evolution of MntH/Nramp (Slc11) carriers. (PMID:21948377)
• Data show that both shRNA-DMT1 and shRNA-hCTR1 cells had lower apical Fe uptake, Cu uptake, and Zn content compared to control cells. (PMID:22068728)
• Data suggest that DMT-1 in enterocytes is delocalized from plasma membrane upon iron or zinc depletion; apical abundance of DMT-1 increases with zinc supplementation. (PMID:22137264)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	slc11a2	ENSDARG00000024295
mus_musculus	Slc11a2	ENSMUSG00000023030
rattus_norvegicus	Slc11a2	ENSRNOG00000019550

Paralogs (1): SLC11A1 (ENSG00000018280)

Protein

Protein identifiers

Natural resistance-associated macrophage protein 2 — P49281 (reviewed: P49281)

Alternative names: Divalent cation transporter 1, Divalent metal transporter 1, Solute carrier family 11 member 2

All UniProt accessions (17): A0A0X8GKR4, A0A2R8Y4F9, A0A2R8Y5L1, A0A2R8Y5Q7, A0A2R8YD71, A0A2R8YDL2, A0A7P0T8E3, P49281, F8VR36, F8VRL7, F8VWB0, F8W154, F8W1C0, F8W1D8, F8W1F2, F8W1P7, H0YIV3

UniProt curated annotations — full annotation on UniProt →

Function. Proton-coupled metal ion symporter operating with a proton to metal ion stoichiometry of 1:1. Selectively transports various divalent metal cations, in decreasing affinity: Cd(2+) > Fe(2+) > Co(2+), Mn(2+) » Zn(2+), Ni(2+), VO(2+). Essential for maintenance of iron homeostasis by modulating intestinal absorption of dietary Fe(2+) and TF-associated endosomal Fe(2+) transport in erythroid precursors and other cells. Enables Fe(2+) and Mn(2+) ion entry into mitochondria, and is thus expected to promote mitochondrial heme synthesis, iron-sulfur cluster biogenesis and antioxidant defense. Can mediate uncoupled fluxes of either protons or metal ions.

Subunit / interactions. Forms a complex with NDFIP1 and NEDD4L, in cortical neurons, in response to iron and cobalt exposure; this interaction leads to SLC11A2 ubiquitination by NEDD4L and proteasome-dependent degradation. Interacts with NDFIP1, NDFIP2 and WWP2; this interaction leads to SLC11A2 ubiquitination by WWP2 and subsequent proteasome-dependent degradation. Interacts with COX2 and TOM6 at the outer mitochondrion membrane. Interacts with ARRDC1; this interaction regulates the incorporation of SLC11A2 into extracellular vesicles through an ubiquitination-dependent mechanism. Interacts with ARRDC4; controls the incorporation of SLC11A2 into extracellular vesicles through an ubiquitination-dependent mechanism.

Subcellular location. Early endosome membrane. Apical cell membrane Late endosome membrane. Lysosome membrane. Apical cell membrane. Cell membrane. Extracellular vesicle membrane Cell membrane Mitochondrion outer membrane. Golgi apparatus. trans-Golgi network membrane. Recycling endosome membrane.

Tissue specificity. Ubiquitously expressed. Expressed in erythroid progenitors.

Post-translational modifications. Ubiquitinated by WWP2. N-glycosylated.

Disease relevance. Anemia, hypochromic microcytic, with iron overload 1 (AHMIO1) [MIM:206100] A hematologic disease characterized by abnormal hemoglobin content in the erythrocytes which are reduced in size. The disorder is due to an error of iron metabolism that results in high serum iron, massive hepatic iron deposition, and absence of sideroblasts and stainable bone marrow iron store. Despite adequate transferrin-iron complex, delivery of iron to the erythroid bone marrow is apparently insufficient for the demands of hemoglobin synthesis. The disease is caused by variants affecting the gene represented in this entry.

Induction. Up-regulated under iron-depletion conditions. Down-regulated in response to high extracellular iron levels. Up-regulated under iron-depletion conditions. Down-regulated in response to high extracellular iron levels. Up-regulated under iron-depletion conditions. Down-regulated in response to high extracellular iron levels.

Miscellaneous. NRAMP2-mediated iron uptake is markedly stimulated by nifedipine in a concentration-dependent manner.

Similarity. Belongs to the NRAMP family.

Isoforms (5)

UniProt ID	Names	Canonical?
P49281-1	2, 1B-Non-IRE, DMT1B	yes
P49281-2	1, IB-IRE, DMT1A
P49281-3	3, 1A-IRE
P49281-4	4, 1A-Non-IRE
P49281-5	5

RefSeq proteins (18): NP_000608, NP_001167596, NP_001167597, NP_001167598, NP_001167599, NP_001167600, NP_001167601, NP_001366375, NP_001366376, NP_001366377, NP_001366384, NP_001401673, NP_001401674, NP_001401675, NP_001401676, NP_001401677, NP_001401678, NP_001401679 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001046	NRAMP_fam	Family

Pfam: PF01566

Catalyzed reactions (Rhea), 8 shown:

• Fe(2+)(in) = Fe(2+)(out) (RHEA:28486)
• Mn(2+)(in) + H(+)(in) = Mn(2+)(out) + H(+)(out) (RHEA:29007)
• Fe(2+)(in) + H(+)(in) = Fe(2+)(out) + H(+)(out) (RHEA:29579)
• H(+)(in) = H(+)(out) (RHEA:34979)
• Zn(2+)(out) + H(+)(out) = Zn(2+)(in) + H(+)(in) (RHEA:71195)
• Cd(2+)(out) + H(+)(out) = Cd(2+)(in) + H(+)(in) (RHEA:73031)
• Co(2+)(out) + H(+)(out) = Co(2+)(in) + H(+)(in) (RHEA:73035)
• Ni(2+)(out) + H(+)(out) = Ni(2+)(in) + H(+)(in) (RHEA:73039)

UniProt features (58 total): topological domain 13, transmembrane region 12, mutagenesis site 7, sequence conflict 7, sequence variant 6, splice variant 3, region of interest 2, compositionally biased region 2, modified residue 2, glycosylation site 2, chain 1, strand 1

Structure

Experimental structures (PDB)

7 structures.

PDB	Method	Resolution (Å)
5F0P	X-RAY DIFFRACTION	2.78
5F0M	X-RAY DIFFRACTION	3.1
5F0L	X-RAY DIFFRACTION	3.2
9F6N	ELECTRON MICROSCOPY	3.6
9F6O	ELECTRON MICROSCOPY	3.9
7BLQ	ELECTRON MICROSCOPY	9.2
7BLO	ELECTRON MICROSCOPY	9.5

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P49281-F1	80.83	0.47

Antibody-complex structures (SAbDab): 1 — 9F6O

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (2): 564, 567

Glycosylation sites (2): 336, 349

Mutagenesis-validated functional residues (7):

Position	Phenotype
86	abolishes metal ion transport.
89	decreases affinity for divalent metal cations. impairs metal ion transport.
265	abolishes metal ion transport.
338	abolishes n-glycosylation; when associated with a-351. does not affect endosome targeting; when associated with a-351. i
351	abolishes n-glycosylation; when associated with a-338. does not affect endosome targeting; when associated with a-338. i
555	abolishes localization at early endosomes and leads to localization at late endosomes and lysosomes.
557	abolishes localization at early endosomes and leads to localization at late endosomes and lysosomes.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-425410	Metal ion SLC transporters
R-HSA-5619048	Defective SLC11A2 causes hypochromic microcytic anemia, with iron overload 1 (AHMIO1)
R-HSA-917937	Iron uptake and transport

MSigDB gene sets: 487 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, GSE18804_SPLEEN_MACROPHAGE_VS_COLON_TUMORAL_MACROPHAGE_UP, GOBP_DENDRITE_DEVELOPMENT, GOBP_COGNITION, GOBP_BEHAVIOR, GOBP_MYELOID_CELL_HOMEOSTASIS, GOBP_MYELOID_CELL_DEVELOPMENT, MODULE_255, GOCC_VACUOLAR_MEMBRANE, GOBP_TRANSITION_METAL_ION_TRANSPORT, KAAB_HEART_ATRIUM_VS_VENTRICLE_UP, GOBP_ERYTHROCYTE_HOMEOSTASIS, GOBP_INTRACELLULAR_IRON_ION_HOMEOSTASIS, GAUSSMANN_MLL_AF4_FUSION_TARGETS_C_UP, MODULE_317

GO Biological Process (32): response to hypoxia (GO:0001666), detection of oxygen (GO:0003032), heme biosynthetic process (GO:0006783), cobalt ion transport (GO:0006824), copper ion transport (GO:0006825), iron ion transport (GO:0006826), manganese ion transport (GO:0006828), intracellular iron ion homeostasis (GO:0006879), learning or memory (GO:0007611), response to iron ion (GO:0010039), nickel cation transport (GO:0015675), vanadium ion transport (GO:0015676), lead ion transport (GO:0015692), intracellular manganese ion homeostasis (GO:0030026), iron import into cell (GO:0033212), cellular response to oxidative stress (GO:0034599), iron ion transmembrane transport (GO:0034755), dendrite morphogenesis (GO:0048813), erythrocyte development (GO:0048821), multicellular organismal-level iron ion homeostasis (GO:0060586), cadmium ion transmembrane transport (GO:0070574), porphyrin-containing compound metabolic process (GO:0006778), porphyrin-containing compound biosynthetic process (GO:0006779), monoatomic ion transport (GO:0006811), metal ion transport (GO:0030001), copper ion transmembrane transport (GO:0035434), nickel cation transmembrane transport (GO:0035444), establishment of localization in cell (GO:0051649), transmembrane transport (GO:0055085), manganese ion transmembrane transport (GO:0071421), zinc ion transmembrane transport (GO:0071577), proton transmembrane transport (GO:1902600)

GO Molecular Function (18): copper ion transmembrane transporter activity (GO:0005375), iron ion transmembrane transporter activity (GO:0005381), manganese ion transmembrane transporter activity (GO:0005384), zinc ion transmembrane transporter activity (GO:0005385), cadmium ion transmembrane transporter activity (GO:0015086), cobalt ion transmembrane transporter activity (GO:0015087), ferrous iron transmembrane transporter activity (GO:0015093), lead ion transmembrane transporter activity (GO:0015094), nickel cation transmembrane transporter activity (GO:0015099), vanadium ion transmembrane transporter activity (GO:0015100), solute:proton symporter activity (GO:0015295), obsolete inorganic cation transmembrane transporter activity (GO:0022890), cadmium ion binding (GO:0046870), transition metal ion transmembrane transporter activity (GO:0046915), retromer complex binding (GO:1905394), protein binding (GO:0005515), symporter activity (GO:0015293), metal ion transmembrane transporter activity (GO:0046873)

GO Cellular Component (28): nucleus (GO:0005634), cytoplasm (GO:0005737), mitochondrion (GO:0005739), mitochondrial outer membrane (GO:0005741), lysosome (GO:0005764), lysosomal membrane (GO:0005765), early endosome (GO:0005769), late endosome (GO:0005770), vacuole (GO:0005773), Golgi apparatus (GO:0005794), trans-Golgi network (GO:0005802), plasma membrane (GO:0005886), cell surface (GO:0009986), endosome membrane (GO:0010008), membrane (GO:0016020), apical plasma membrane (GO:0016324), cytoplasmic vesicle (GO:0031410), brush border membrane (GO:0031526), early endosome membrane (GO:0031901), late endosome membrane (GO:0031902), apical part of cell (GO:0045177), basal part of cell (GO:0045178), perinuclear region of cytoplasm (GO:0048471), recycling endosome (GO:0055037), recycling endosome membrane (GO:0055038), paraferritin complex (GO:0070826), extracellular vesicle (GO:1903561), endosome (GO:0005768)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
SLC-mediated transmembrane transport	1
SLC transporter disorders	1
Transport of small molecules	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
transition metal ion transmembrane transporter activity	8
transition metal ion transport	7
intracellular membrane-bounded organelle	4
cytoplasm	4
cellular anatomical structure	3
endosome	3
monoatomic cation transmembrane transport	2
intracellular monoatomic cation homeostasis	2
inorganic ion homeostasis	2
metal ion transport	2
iron ion transport	2
metal ion transmembrane transporter activity	2
endosome membrane	2
response to stress	1
response to decreased oxygen levels	1
detection of chemical stimulus	1
response to oxygen levels	1
porphyrin-containing compound biosynthetic process	1
heme metabolic process	1
pigment biosynthetic process	1
behavior	1
cognition	1
response to metal ion	1
manganese ion homeostasis	1
intracellular iron ion homeostasis	1
establishment of localization in cell	1
response to oxidative stress	1
cellular response to chemical stress	1
dendrite development	1
cell morphogenesis involved in neuron differentiation	1
neuron projection morphogenesis	1
erythrocyte differentiation	1
myeloid cell development	1
monoatomic cation homeostasis	1
multicellular organismal-level chemical homeostasis	1
copper ion transmembrane transport	1
iron ion transmembrane transport	1
manganese ion transmembrane transport	1
zinc ion transmembrane transport	1
cadmium ion transmembrane transport	1

Protein interactions and networks

STRING

1852 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SLC11A2	SLC40A1	Q9NP59	987
SLC11A2	CYBRD1	Q53TN4	966
SLC11A2	TFRC	P02786	957
SLC11A2	HAMP	P81172	942
SLC11A2	SLC39A14	Q15043	932
SLC11A2	ACO1	P21399	924
SLC11A2	IREB2	P48200	921
SLC11A2	HFE	Q30201	896
SLC11A2	FTL	P02792	883
SLC11A2	FTH1	P02794	850
SLC11A2	TFR2	Q9UP52	839
SLC11A2	SLC39A1	Q9NY26	836
SLC11A2	ACBD3	Q9H3P7	827
SLC11A2	HEPH	Q9BQS7	817
SLC11A2	HJV	Q6ZVN8	804
SLC11A2	STEAP3	Q658P3	804

IntAct

15 interactions, top by confidence:

A	B	Type	Score
SLC11A2	MT-CO2	psi-mi:“MI:0915”(physical association)	0.400
SLC11A2	NDFIP1	psi-mi:“MI:0915”(physical association)	0.400
SLC11A2	NEDD4L	psi-mi:“MI:0915”(physical association)	0.400
NDFIP1	SLC11A2	psi-mi:“MI:0915”(physical association)	0.400
SLC11A2		psi-mi:“MI:0915”(physical association)	0.400
SLC11A2	PMPCB	psi-mi:“MI:0915”(physical association)	0.400
	NPC1	psi-mi:“MI:0914”(association)	0.350
CANX	HLA-A	psi-mi:“MI:0914”(association)	0.350
SLC11A2	GPR89A	psi-mi:“MI:0914”(association)	0.350
SPPL2B	HAS3	psi-mi:“MI:0914”(association)	0.350
RHBG	PEDS1	psi-mi:“MI:0914”(association)	0.350
SLC11A2	UBXN8	psi-mi:“MI:0914”(association)	0.350
TCTN3	TMEM120B	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (122): SLC11A2 (Reconstituted Complex), SLC11A2 (Synthetic Lethality), SLC11A2 (Proximity Label-MS), SLC11A2 (Proximity Label-MS), SLC11A2 (Proximity Label-MS), SLC11A2 (Proximity Label-MS), SLC11A2 (Proximity Label-MS), PTPLB (Affinity Capture-MS), GPR89A (Affinity Capture-MS), LGALS3 (Affinity Capture-MS), ATP2B4 (Affinity Capture-MS), CYP20A1 (Affinity Capture-MS), ND1 (Affinity Capture-MS), PXMP2 (Affinity Capture-MS), RER1 (Affinity Capture-MS)

ESM2 similar proteins: A0A2K1ZPK4, A0A2K2AIF4, A0A2K2BF92, B9GNS0, B9H7I1, E7EXX2, O22881, O54902, O77741, P41251, P49279, P49280, P49281, P49282, P49283, P51027, P56436, P70553, Q0D7E4, Q21433, Q21434, Q27946, Q27981, Q4R335, Q5QN13, Q5ZHX6, Q6DFC0, Q6DIV6, Q6PF45, Q6YWQ4, Q6ZG85, Q7XIV8, Q869V1, Q8BGY9, Q8BYR8, Q8H3P9, Q8H4H5, Q8UWF0, Q8VDT1, Q8VXB5

Diamond homologs: A0A077Y877, O54902, P49281, P49282, Q8I3M7, A0A2K1ZPK4, A0A2K2AIF4, A0A2K2BF92, A0AIM7, A0KG66, A1JLC3, A4TMF6, A4WD10, A5IRZ2, A6QFW1, A6U0S3, A7FGC8, A7X111, B1JFZ6, B2K911, B3W6P3, B5XVU3, B8DE85, B9GNS0, B9H7I1, B9N9Y7, B9NAE4, C1L2Y0, C6D9J9, O77741, P41251, P49279, P49280, P49283, P51027, P56436, P65544, P65545, P70553, P96593

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
WWP2	“down-regulates quantity”	SLC11A2	ubiquitination

Disease & clinical

Clinical variants and AI predictions

ClinVar

176 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	7
Likely pathogenic	1
Uncertain significance	99
Likely benign	19
Benign	26

Top pathogenic / likely-pathogenic (8)

Variant ID	HGVS	Classification
2446381	NM_000617.3(SLC11A2):c.675+35A>G	Pathogenic
800819	NM_000617.3(SLC11A2):c.223G>A (p.Gly75Arg)	Pathogenic
9074	NM_000617.3(SLC11A2):c.1197G>C (p.Glu399Asp)	Pathogenic
9075	NM_000617.3(SLC11A2):c.310-5_310-3del	Pathogenic
9076	NM_000617.3(SLC11A2):c.1246C>T (p.Arg416Cys)	Pathogenic
9077	NM_000617.3(SLC11A2):c.341_343del (p.Val114del)	Pathogenic
9078	NM_000617.3(SLC11A2):c.635G>T (p.Gly212Val)	Pathogenic
2642996	NM_000617.3(SLC11A2):c.157G>T (p.Glu53Ter)	Likely pathogenic

SpliceAI

2649 predictions. Top by Δscore:

Variant	Effect	Δscore
12:50990788:GACTT:G	donor_loss	1.0000
12:50990789:ACTTA:A	donor_loss	1.0000
12:50990792:TAC:T	donor_loss	1.0000
12:50990793:A:AC	donor_gain	1.0000
12:50990793:ACCA:A	donor_loss	1.0000
12:50990794:C:CC	donor_gain	1.0000
12:50990947:CT:C	acceptor_gain	1.0000
12:50990949:C:CC	acceptor_gain	1.0000
12:50991597:A:AC	donor_gain	1.0000
12:50991597:ACAGT:A	donor_gain	1.0000
12:50991598:C:CC	donor_gain	1.0000
12:50991598:CAGT:C	donor_gain	1.0000
12:50991598:CAGTC:C	donor_gain	1.0000
12:50992184:CCTCA:C	donor_loss	1.0000
12:50992185:CTCAC:C	donor_loss	1.0000
12:50992186:TCA:T	donor_loss	1.0000
12:50992187:CA:C	donor_loss	1.0000
12:50992189:CCTGT:C	donor_loss	1.0000
12:50992226:C:A	donor_gain	1.0000
12:50992337:TCC:T	acceptor_gain	1.0000
12:50992338:CC:C	acceptor_gain	1.0000
12:50992338:CCC:C	acceptor_gain	1.0000
12:50992339:CC:C	acceptor_gain	1.0000
12:50992339:CCT:C	acceptor_loss	1.0000
12:50992340:C:CC	acceptor_gain	1.0000
12:50992340:CT:C	acceptor_loss	1.0000
12:50992926:CACC:C	acceptor_gain	1.0000
12:50992928:CC:C	acceptor_gain	1.0000
12:50992929:CC:C	acceptor_gain	1.0000
12:50994538:GCTTA:G	donor_loss	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000015684 (12:51011205 T>C), RS1000131350 (12:50975130 C>A,T), RS1000143184 (12:51021800 G>A), RS1000167726 (12:51008317 GTGTGTGTGTA>G), RS1000188243 (12:50955485 G>A), RS1000217598 (12:51000808 T>C), RS1000284362 (12:51022159 A>G), RS1000301668 (12:51015020 C>A,T), RS1000302643 (12:50955054 G>A,C), RS1000346845 (12:51005398 G>A), RS1000373864 (12:50989218 G>A), RS1000389699 (12:50962487 G>A,T), RS1000398972 (12:50961456 G>A), RS1000489314 (12:51017405 A>G), RS1000499560 (12:50956937 G>A)

Disease associations

OMIM: gene MIM:600523 | disease phenotypes: MIM:206100

GenCC curated gene-disease

Disease	Classification	Inheritance
microcytic anemia with liver iron overload	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
microcytic anemia with liver iron overload	Definitive	AR

Mondo (1): microcytic anemia with liver iron overload (MONDO:0008787)

Orphanet (1): Microcytic anemia with liver iron overload (Orphanet:83642)

HPO phenotypes

8 total (8 of 8 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0001903	Anemia
HP:0003452	Increased circulating iron concentration
HP:0003593	Infantile onset
HP:0012132	Erythroid hyperplasia
HP:0012465	Elevated hepatic iron concentration
HP:0025066	Decreased mean corpuscular volume
HP:0032231	Hypochromia

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST011369_35	Iron status biomarkers (ferritin levels)	1.000000e-24

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004459	ferritin measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL1932895 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: transporter — SLC11 family of proton-coupled metal ion transporters

Most potent curated ligand interactions (1 total), top 1:

Ligand	Action	Affinity	Parameter
compound 6b [PMID: 22749870]	Inhibition	7.1	pIC50

ChEMBL bioactivities

44 potent at pChembl≥5 of 45 total, top 44 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.22	IC50	60	nM	CHEMBL3145266
6.85	IC50	140	nM	CHEMBL2079088
6.82	IC50	150	nM	CHEMBL3145267
6.82	IC50	150	nM	CHEMBL1933782
6.77	IC50	170	nM	CHEMBL3145276
6.70	IC50	200	nM	CHEMBL3145277
6.68	IC50	210	nM	CHEMBL1933791
6.58	IC50	260	nM	CHEMBL3145278
6.58	IC50	260	nM	CHEMBL1933792
6.57	IC50	270	nM	CHEMBL1933793
6.54	IC50	290	nM	CHEMBL3145279
6.51	IC50	310	nM	CHEMBL1933794
6.50	IC50	320	nM	CHEMBL3145268
6.48	IC50	330	nM	CHEMBL1933783
6.46	IC50	350	nM	CHEMBL1197758
6.44	IC50	360	nM	CHEMBL3145265
6.41	IC50	390	nM	CHEMBL3145274
6.40	IC50	400	nM	CHEMBL1933784
6.39	IC50	410	nM	CHEMBL3145257
6.37	IC50	430	nM	CHEMBL1933774
6.28	IC50	520	nM	CHEMBL1933775
6.28	IC50	520	nM	CHEMBL1933795
6.25	IC50	560	nM	CHEMBL1933785
6.19	IC50	640	nM	CHEMBL3145246
6.18	IC50	660	nM	CHEMBL3145258
6.16	IC50	690	nM	CHEMBL3145259
6.15	IC50	710	nM	CHEMBL3145260
6.14	IC50	720	nM	CHEMBL1933786
6.11	IC50	770	nM	CHEMBL3145269
6.08	IC50	830	nM	CHEMBL1933787
6.04	IC50	910	nM	CHEMBL3145273
6.00	IC50	1000	nM	CHEMBL3145261
5.98	IC50	1040	nM	CHEMBL3145253
5.91	IC50	1220	nM	CHEMBL3145262
5.85	Ki	1400	nM	CHEMBL2079088
5.82	IC50	1530	nM	CHEMBL1933597
5.77	IC50	1700	nM	CHEMBL1933615
5.75	IC50	1760	nM	CHEMBL2079088
5.75	IC50	1760	nM	CHEMBL1933788
5.66	IC50	2190	nM	CHEMBL3145255
5.59	IC50	2570	nM	CHEMBL1548704
5.56	IC50	2770	nM	CHEMBL1933796
5.55	IC50	2820	nM	CHEMBL3145263
5.16	IC50	7000	nM	CHEMBL4783970

PubChem BioAssay actives

44 with measured affinity, of 70 total; 42 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
5-methyl-4-(4-nitrophenyl)-2-pyridin-2-yl-1H-pyrazol-3-one	637796: Inhibition of human DMT1 expressed in CHO cells assessed as blockage of ferrous influx after 20 mins by calcein fluorescence quenching method	ic50	0.0600	uM
[6-(carbamimidoylsulfanylmethyl)dibenzofuran-4-yl]methyl carbamimidothioate	1695426: Inhibition of human DMT1 expressed in Xenopus oocytes assessed as inhibition of channel currents at -50 mV holding potential by two-electrode voltage clamp assay	ic50	0.1400	uM
2-(6-methyl-1,3-benzothiazol-2-yl)-4,5-dihydro-3H-benzo[e]indazol-1-one	637796: Inhibition of human DMT1 expressed in CHO cells assessed as blockage of ferrous influx after 20 mins by calcein fluorescence quenching method	ic50	0.1500	uM
5-methyl-2-pyridin-2-yl-4-[4-(trifluoromethyl)phenyl]-1H-pyrazol-3-one	637796: Inhibition of human DMT1 expressed in CHO cells assessed as blockage of ferrous influx after 20 mins by calcein fluorescence quenching method	ic50	0.1500	uM
5-methyl-3-oxo-2-pyridin-2-yl-N-[3-(trifluoromethyl)phenyl]-1H-pyrazole-4-carboxamide	637796: Inhibition of human DMT1 expressed in CHO cells assessed as blockage of ferrous influx after 20 mins by calcein fluorescence quenching method	ic50	0.1700	uM
5-methyl-N-(4-nitrophenyl)-3-oxo-2-pyridin-2-yl-1H-pyrazole-4-carboxamide	637796: Inhibition of human DMT1 expressed in CHO cells assessed as blockage of ferrous influx after 20 mins by calcein fluorescence quenching method	ic50	0.2000	uM
7-(4-methoxyphenyl)-2-pyridin-2-yl-4,5-dihydro-3H-benzo[e]indazol-1-one	637796: Inhibition of human DMT1 expressed in CHO cells assessed as blockage of ferrous influx after 20 mins by calcein fluorescence quenching method	ic50	0.2100	uM
7-phenyl-2-pyridin-2-yl-4,5-dihydro-3H-benzo[e]indazol-1-one	637796: Inhibition of human DMT1 expressed in CHO cells assessed as blockage of ferrous influx after 20 mins by calcein fluorescence quenching method	ic50	0.2600	uM
N-(3-fluoro-4-methoxyphenyl)-5-methyl-3-oxo-2-pyridin-2-yl-1H-pyrazole-4-carboxamide	637796: Inhibition of human DMT1 expressed in CHO cells assessed as blockage of ferrous influx after 20 mins by calcein fluorescence quenching method	ic50	0.2600	uM
7-(4-methylphenyl)-2-pyridin-2-yl-4,5-dihydro-3H-benzo[e]indazol-1-one	637796: Inhibition of human DMT1 expressed in CHO cells assessed as blockage of ferrous influx after 20 mins by calcein fluorescence quenching method	ic50	0.2700	uM
5-methyl-3-oxo-2-pyridin-2-yl-N-[4-(trifluoromethyl)phenyl]-1H-pyrazole-4-carboxamide	637796: Inhibition of human DMT1 expressed in CHO cells assessed as blockage of ferrous influx after 20 mins by calcein fluorescence quenching method	ic50	0.2900	uM
7-bromo-2-pyridin-2-yl-4,5-dihydro-3H-benzo[e]indazol-1-one	637796: Inhibition of human DMT1 expressed in CHO cells assessed as blockage of ferrous influx after 20 mins by calcein fluorescence quenching method	ic50	0.3100	uM
5-methyl-2-pyridin-2-yl-4-[3-(trifluoromethyl)phenyl]-1H-pyrazol-3-one	637796: Inhibition of human DMT1 expressed in CHO cells assessed as blockage of ferrous influx after 20 mins by calcein fluorescence quenching method	ic50	0.3200	uM
2-(6-methoxy-1,3-benzothiazol-2-yl)-4,5-dihydro-3H-benzo[e]indazol-1-one	637796: Inhibition of human DMT1 expressed in CHO cells assessed as blockage of ferrous influx after 20 mins by calcein fluorescence quenching method	ic50	0.3300	uM
[3-(carbamimidoylsulfanylmethyl)-2,4,6-trimethylphenyl]methyl carbamimidothioate	1695435: Inhibition of human DMT1 expressed in HEK293T cells assessed as inhibition of radiolabeled 55Fe2+ uptake preincubated with compound for 5 mins followed by incubation with Fe2+ and radiolabeled 55Fe2+ for 15 mins at extracellular pH of 5.5 by scintillation counting analysis	ic50	0.3500	uM
4-(5-methyl-3-oxo-2-pyridin-2-yl-1H-pyrazol-4-yl)benzonitrile	637796: Inhibition of human DMT1 expressed in CHO cells assessed as blockage of ferrous influx after 20 mins by calcein fluorescence quenching method	ic50	0.3600	uM
2-(6-fluoro-1,3-benzothiazol-2-yl)-5-methyl-4-phenyl-1H-pyrazol-3-one	637796: Inhibition of human DMT1 expressed in CHO cells assessed as blockage of ferrous influx after 20 mins by calcein fluorescence quenching method	ic50	0.3900	uM
2-(6-fluoro-1,3-benzothiazol-2-yl)-4,5-dihydro-3H-benzo[e]indazol-1-one	637796: Inhibition of human DMT1 expressed in CHO cells assessed as blockage of ferrous influx after 20 mins by calcein fluorescence quenching method	ic50	0.4000	uM
5-methyl-N-(3-methylphenyl)-3-oxo-2-pyridin-2-yl-1H-pyrazole-4-carboxamide	637796: Inhibition of human DMT1 expressed in CHO cells assessed as blockage of ferrous influx after 20 mins by calcein fluorescence quenching method	ic50	0.4100	uM
2-(1,3-benzothiazol-2-yl)-5-methyl-4-phenyl-1H-pyrazol-3-one	637796: Inhibition of human DMT1 expressed in CHO cells assessed as blockage of ferrous influx after 20 mins by calcein fluorescence quenching method	ic50	0.4300	uM
1-oxo-2-pyridin-2-yl-4,5-dihydro-3H-benzo[e]indazole-7-carbonitrile	637796: Inhibition of human DMT1 expressed in CHO cells assessed as blockage of ferrous influx after 20 mins by calcein fluorescence quenching method	ic50	0.5200	uM
2-(1H-benzimidazol-2-yl)-5-methyl-4-phenyl-1H-pyrazol-3-one	637796: Inhibition of human DMT1 expressed in CHO cells assessed as blockage of ferrous influx after 20 mins by calcein fluorescence quenching method	ic50	0.5200	uM
2-(1-oxo-4,5-dihydro-3H-benzo[e]indazol-2-yl)-1,3-benzothiazole-6-carboxylic acid	637796: Inhibition of human DMT1 expressed in CHO cells assessed as blockage of ferrous influx after 20 mins by calcein fluorescence quenching method	ic50	0.5600	uM
5-methyl-3-oxo-N-phenyl-2-pyridin-2-yl-1H-pyrazole-4-carboxamide	637796: Inhibition of human DMT1 expressed in CHO cells assessed as blockage of ferrous influx after 20 mins by calcein fluorescence quenching method	ic50	0.6400	uM
N-(3-methoxyphenyl)-5-methyl-3-oxo-2-pyridin-2-yl-1H-pyrazole-4-carboxamide	637796: Inhibition of human DMT1 expressed in CHO cells assessed as blockage of ferrous influx after 20 mins by calcein fluorescence quenching method	ic50	0.6600	uM
5-methyl-N-(4-methylphenyl)-3-oxo-2-pyridin-2-yl-1H-pyrazole-4-carboxamide	637796: Inhibition of human DMT1 expressed in CHO cells assessed as blockage of ferrous influx after 20 mins by calcein fluorescence quenching method	ic50	0.6900	uM
5-methyl-N-(2-nitrophenyl)-3-oxo-2-pyridin-2-yl-1H-pyrazole-4-carboxamide	637796: Inhibition of human DMT1 expressed in CHO cells assessed as blockage of ferrous influx after 20 mins by calcein fluorescence quenching method	ic50	0.7100	uM
2-(1,3-benzothiazol-2-yl)-4,5-dihydro-3H-benzo[e]indazol-1-one	637796: Inhibition of human DMT1 expressed in CHO cells assessed as blockage of ferrous influx after 20 mins by calcein fluorescence quenching method	ic50	0.7200	uM
ethyl 4-(5-methyl-3-oxo-2-pyridin-2-yl-1H-pyrazol-4-yl)benzoate	637796: Inhibition of human DMT1 expressed in CHO cells assessed as blockage of ferrous influx after 20 mins by calcein fluorescence quenching method	ic50	0.7700	uM
2-pyridin-2-yl-4,5-dihydro-3H-benzo[e]indazol-1-one	637796: Inhibition of human DMT1 expressed in CHO cells assessed as blockage of ferrous influx after 20 mins by calcein fluorescence quenching method	ic50	0.8300	uM
4-(4-fluorophenyl)-5-methyl-2-pyridin-2-yl-1H-pyrazol-3-one	637796: Inhibition of human DMT1 expressed in CHO cells assessed as blockage of ferrous influx after 20 mins by calcein fluorescence quenching method	ic50	0.9100	uM
5-methyl-3-oxo-2-pyridin-2-yl-N-[2-(trifluoromethyl)phenyl]-1H-pyrazole-4-carboxamide	637796: Inhibition of human DMT1 expressed in CHO cells assessed as blockage of ferrous influx after 20 mins by calcein fluorescence quenching method	ic50	1.0000	uM
2-(6-methoxy-1,3-benzothiazol-2-yl)-5-methyl-4-phenyl-1H-pyrazol-3-one	637796: Inhibition of human DMT1 expressed in CHO cells assessed as blockage of ferrous influx after 20 mins by calcein fluorescence quenching method	ic50	1.0400	uM
N-(1,3-benzodioxol-5-yl)-5-methyl-3-oxo-2-pyridin-2-yl-1H-pyrazole-4-carboxamide	637796: Inhibition of human DMT1 expressed in CHO cells assessed as blockage of ferrous influx after 20 mins by calcein fluorescence quenching method	ic50	1.2200	uM
(4Z)-4-[[4-(diethylamino)phenyl]methylidene]-5-methyl-2-pyridin-2-ylpyrazol-3-one	637796: Inhibition of human DMT1 expressed in CHO cells assessed as blockage of ferrous influx after 20 mins by calcein fluorescence quenching method	ic50	1.5300	uM
5-methyl-4-phenyl-2-pyridin-2-yl-1H-pyrazol-3-one	637796: Inhibition of human DMT1 expressed in CHO cells assessed as blockage of ferrous influx after 20 mins by calcein fluorescence quenching method	ic50	1.7000	uM
2-(1H-benzimidazol-2-yl)-4,5-dihydro-3H-benzo[e]indazol-1-one	637796: Inhibition of human DMT1 expressed in CHO cells assessed as blockage of ferrous influx after 20 mins by calcein fluorescence quenching method	ic50	1.7600	uM
5-methyl-4-phenyl-2-(1,3-thiazol-2-yl)-1H-pyrazol-3-one	637796: Inhibition of human DMT1 expressed in CHO cells assessed as blockage of ferrous influx after 20 mins by calcein fluorescence quenching method	ic50	2.1900	uM
3-[(4Z)-4-[[4-(diethylamino)phenyl]methylidene]-3-methyl-5-oxopyrazol-1-yl]-6-methyl-4H-1,2,4-triazin-5-one	637796: Inhibition of human DMT1 expressed in CHO cells assessed as blockage of ferrous influx after 20 mins by calcein fluorescence quenching method	ic50	2.5700	uM
7-methoxy-2-pyridin-2-yl-4,5-dihydro-3H-benzo[e]indazol-1-one	637796: Inhibition of human DMT1 expressed in CHO cells assessed as blockage of ferrous influx after 20 mins by calcein fluorescence quenching method	ic50	2.7700	uM
4-(4-methoxyphenyl)-5-methyl-2-pyridin-2-yl-1H-pyrazol-3-one	637796: Inhibition of human DMT1 expressed in CHO cells assessed as blockage of ferrous influx after 20 mins by calcein fluorescence quenching method	ic50	2.8200	uM
[3-(carbamimidoylsulfanylmethyl)phenyl]methyl carbamimidothioate	1695434: Inhibition of human DMT1 expressed in HEK293 cells assessed as inhibition of radiolabeled 55Fe2+ uptake incubated for 1 hr by microplate scintillation counting analysis	ic50	7.0000	uM

CTD chemical–gene interactions

92 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Iron	decreases abundance, affects binding, decreases uptake, affects abundance, increases expression (+4 more)	10
Cadmium	decreases expression, increases abundance, increases expression, affects transport, affects reaction (+2 more)	7
Cadmium Chloride	affects reaction, increases transport, decreases expression, increases abundance, increases expression	5
Valproic Acid	affects expression, affects cotreatment, decreases expression	4
sodium arsenite	decreases expression, increases abundance, increases expression	3
ochratoxin A	decreases expression	3
Benzo(a)pyrene	decreases expression, decreases methylation	3
Copper	decreases reaction, affects expression, affects cotreatment, affects uptake, increases transport (+3 more)	3
Manganese	increases uptake, decreases reaction, increases transport, increases expression	3
Cyclosporine	decreases expression	3
manganese chloride	increases transport, increases expression	2
Arsenic	affects expression, decreases expression, increases abundance	2
Deferoxamine	increases expression, increases reaction, decreases abundance, increases uptake	2
Glucose	affects cotreatment, increases expression	2
Lead	affects abundance, increases transport	2
Zinc	increases expression, decreases reaction, increases transport, decreases uptake	2
Zinc Sulfate	decreases reaction, increases expression, increases uptake	2
Copper Sulfate	decreases expression	2
methylmercuric chloride	decreases expression	1
deoxynivalenol	decreases expression	1
trichostatin A	decreases expression	1
zinc chloride	increases transport	1
bathophenanthroline disulfonic acid	decreases reaction, increases expression, increases uptake	1
cobaltous chloride	increases expression	1
ferric nitrilotriacetate	decreases expression	1
ferrous sulfate	decreases expression	1
ferric chloride	decreases reaction, increases expression, increases uptake	1
cupric chloride	decreases reaction, increases uptake	1
nivalenol	decreases expression	1
isobutyl alcohol	increases abundance, affects cotreatment, decreases expression	1

ChEMBL screening assays

10 unique, capped per target: 10 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1936903	Binding	Inhibition of human DMT1 expressed in CHO cells assessed as blockage of ferrous influx after 20 mins by calcein fluorescence quenching method	Synthesis and biological evaluation of substituted pyrazoles as blockers of divalent metal transporter 1 (DMT1). — Bioorg Med Chem Lett

Cellosaurus cell lines

6 cell lines: 6 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B2FH	Abcam HeLa SLC11A2 KO	Cancer cell line	Female
CVCL_D4HJ	HCT116-SLC11A2-KO-c5	Cancer cell line	Male
CVCL_D4HK	HCT116-SLC11A2-KO-c6	Cancer cell line	Male
CVCL_TL44	HAP1 SLC11A2 (-) 1	Cancer cell line	Male
CVCL_TL45	HAP1 SLC11A2 (-) 2	Cancer cell line	Male
CVCL_TL46	HAP1 SLC11A2 (-) 3	Cancer cell line	Male

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.