Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTCN8N8B)

• DOT Name: Natural resistance-associated macrophage protein 1 (SLC11A1)
• Synonyms: NRAMP 1; Solute carrier family 11 member 1
• Gene Name: SLC11A1
• UniProt ID: NRAM1_HUMAN
• Pfam ID: PF01566
• Sequence:
  MTGDKGPQRLSGSSYGSISSPTSPTSPGPQQAPPRETYLSEKIPIPDTKPGTFSLRKLWA
  FTGPGFLMSIAFLDPGNIESDLQAGAVAGFKLLWVLLWATVLGLLCQRLAARLGVVTGKD
  LGEVCHLYYPKVPRTVLWLTIELAIVGSDMQEVIGTAIAFNLLSAGRIPLWGGVLITIVD
  TFFFLFLDNYGLRKLEAFFGLLITIMALTFGYEYVVARPEQGALLRGLFLPSCPGCGHPE
  LLQAVGIVGAIIMPHNIYLHSALVKSREIDRARRADIREANMYFLIEATIALSVSFIINL
  FVMAVFGQAFYQKTNQAAFNICANSSLHDYAKIFPMNNATVAVDIYQGGVILGCLFGPAA
  LYIWAIGLLAAGQSSTMTGTYAGQFVMEGFLRLRWSRFARVLLTRSCAILPTVLVAVFRD
  LRDLSGLNDLLNVLQSLLLPFAVLPILTFTSMPTLMQEFANGLLNKVVTSSIMVLVCAIN
  LYFVVSYLPSLPHPAYFGLAALLAAAYLGLSTYLVWTCCLAHGATFLAHSSHHHFLYGLL
  EEDQKGETSG
• Function: Macrophage-specific antiporter that fluxes metal ions in either direction against a proton gradient. Localized to late endosomal lysosomal membranes, delivers bivalent cations from the cytosol into these acidic compartments where they may directly affect antimicrobial activity. Involved in iron metabolism and host natural resistance to infection with intracellular parasites. Pathogen resistance involves sequestration of Fe(2+) and Mn(2+), cofactors of both prokaryotic and eukaryotic catalases and superoxide dismutases, not only to protect the macrophage against its own generation of reactive oxygen species, but to deny the cations to the pathogen for synthesis of its protective enzymes (Probable).
• Tissue Specificity: Macrophages; peripheral blood leukocytes, lung, spleen and liver.
• KEGG Pathway: Lysosome (hsa04142)
• Reactome Pathway:
  Metal ion SLC transporters (R-HSA-425410)
  Neutrophil degranulation (R-HSA-6798695)
  Ion influx/efflux at host-pathogen interface (R-HSA-6803544)
  ROS and RNS production in phagocytes (R-HSA-1222556)

Molecular Interaction Atlas (MIA) of This DOT

2 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the methylation of Natural resistance-associated macrophage protein 1 (SLC11A1).	[1]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Natural resistance-associated macrophage protein 1 (SLC11A1).	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Natural resistance-associated macrophage protein 1 (SLC11A1).	[2]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Natural resistance-associated macrophage protein 1 (SLC11A1).	[3]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Natural resistance-associated macrophage protein 1 (SLC11A1).	[4]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Natural resistance-associated macrophage protein 1 (SLC11A1).	[5]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Natural resistance-associated macrophage protein 1 (SLC11A1).	[7]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Natural resistance-associated macrophage protein 1 (SLC11A1).	[8]

References

• [1] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [2] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [3] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [4] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [5] The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
• [6] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [7] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [8] Involvement of the Endocrine-Disrupting Chemical Bisphenol A (BPA) in Human Placentation. J Clin Med. 2020 Feb 3;9(2):405. doi: 10.3390/jcm9020405.