Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTMEUHE8)

• DOT Name: Natural resistance-associated macrophage protein 2 (SLC11A2)
• Synonyms: NRAMP 2; Divalent cation transporter 1; Divalent metal transporter 1; DMT-1; Solute carrier family 11 member 2
• Gene Name: SLC11A2
• Related Disease: Microcytic anemia with liver iron overload
• UniProt ID: NRAM2_HUMAN
• PDB ID: 5F0L; 5F0M; 5F0P; 7BLO; 7BLQ
• Pfam ID: PF01566
• Sequence:
  MVLGPEQKMSDDSVSGDHGESASLGNINPAYSNPSLSQSPGDSEEYFATYFNEKISIPEE
  EYSCFSFRKLWAFTGPGFLMSIAYLDPGNIESDLQSGAVAGFKLLWILLLATLVGLLLQR
  LAARLGVVTGLHLAEVCHRQYPKVPRVILWLMVELAIIGSDMQEVIGSAIAINLLSVGRI
  PLWGGVLITIADTFVFLFLDKYGLRKLEAFFGFLITIMALTFGYEYVTVKPSQSQVLKGM
  FVPSCSGCRTPQIEQAVGIVGAVIMPHNMYLHSALVKSRQVNRNNKQEVREANKYFFIES
  CIALFVSFIINVFVVSVFAEAFFGKTNEQVVEVCTNTSSPHAGLFPKDNSTLAVDIYKGG
  VVLGCYFGPAALYIWAVGILAAGQSSTMTGTYSGQFVMEGFLNLKWSRFARVVLTRSIAI
  IPTLLVAVFQDVEHLTGMNDFLNVLQSLQLPFALIPILTFTSLRPVMSDFANGLGWRIAG
  GILVLIICSINMYFVVVYVRDLGHVALYVVAAVVSVAYLGFVFYLGWQCLIALGMSFLDC
  GHTCHLGLTAQPELYLLNTMDADSLVSR
• 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.
• Tissue Specificity: Ubiquitously expressed. Expressed in erythroid progenitors.
• KEGG Pathway:
  Lysosome (hsa04142)
  Ferroptosis (hsa04216)
  Mineral absorption (hsa04978)
  Alzheimer disease (hsa05010)
  Parkinson disease (hsa05012)
• Reactome Pathway:
  Defective SLC11A2 causes hypochromic microcytic anemia, with iron overload 1 (AHMIO1) (R-HSA-5619048)
  Iron uptake and transport (R-HSA-917937)
  Metal ion SLC transporters (R-HSA-425410)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Microcytic anemia with liver iron overload	DIS3WKE8	Strong	Autosomal recessive	[1]

19 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Natural resistance-associated macrophage protein 2 (SLC11A2).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Natural resistance-associated macrophage protein 2 (SLC11A2).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Natural resistance-associated macrophage protein 2 (SLC11A2).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Natural resistance-associated macrophage protein 2 (SLC11A2).	[5]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Natural resistance-associated macrophage protein 2 (SLC11A2).	[6]
Arsenic	DMTL2Y1	Approved	Arsenic affects the expression of Natural resistance-associated macrophage protein 2 (SLC11A2).	[7]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Natural resistance-associated macrophage protein 2 (SLC11A2).	[8]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of Natural resistance-associated macrophage protein 2 (SLC11A2).	[9]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Natural resistance-associated macrophage protein 2 (SLC11A2).	[10]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Natural resistance-associated macrophage protein 2 (SLC11A2).	[11]
Vitamin C	DMXJ7O8	Approved	Vitamin C decreases the expression of Natural resistance-associated macrophage protein 2 (SLC11A2).	[12]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Natural resistance-associated macrophage protein 2 (SLC11A2).	[13]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Natural resistance-associated macrophage protein 2 (SLC11A2).	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Natural resistance-associated macrophage protein 2 (SLC11A2).	[3]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Natural resistance-associated macrophage protein 2 (SLC11A2).	[15]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of Natural resistance-associated macrophage protein 2 (SLC11A2).	[16]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of Natural resistance-associated macrophage protein 2 (SLC11A2).	[17]
Manganese	DMKT129	Investigative	Manganese increases the expression of Natural resistance-associated macrophage protein 2 (SLC11A2).	[18]
PP-242	DM2348V	Investigative	PP-242 decreases the expression of Natural resistance-associated macrophage protein 2 (SLC11A2).	[19]

References

• [1] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [2] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [3] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [4] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [5] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] Influence of estrogens on copper indicators: in vivo and in vitro studies. Biol Trace Elem Res. 2010 Jun;134(3):252-64.
• [7] Drinking-water arsenic exposure modulates gene expression in human lymphocytes from a U.S. population. Environ Health Perspect. 2008 Apr;116(4):524-31. doi: 10.1289/ehp.10861.
• [8] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [9] Zinc inhibits oxidative stress-induced iron signaling and apoptosis in Caco-2 cells. Free Radic Biol Med. 2010 Apr 1;48(7):961-8. doi: 10.1016/j.freeradbiomed.2010.01.019. Epub 2010 Jan 20.
• [10] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [11] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [12] Ascorbic acid uptake affects ferritin, Dcytb and Nramp2 expression in Caco-2 cells. Eur J Nutr. 2008 Oct;47(7):401-8. doi: 10.1007/s00394-008-0741-8. Epub 2008 Sep 24.
• [13] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [14] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [15] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [16] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.
• [17] Ochratoxin a lowers mRNA levels of genes encoding for key proteins of liver cell metabolism. Cancer Genomics Proteomics. 2008 Nov-Dec;5(6):319-32.
• [18] Gene expression profiling of human primary astrocytes exposed to manganese chloride indicates selective effects on several functions of the cells. Neurotoxicology. 2007 May;28(3):478-89.
• [19] Marine biogenics in sea spray aerosols interact with the mTOR signaling pathway. Sci Rep. 2019 Jan 24;9(1):675.