Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTWB0BTO)

• DOT Name: Reduced folate transporter (SLC19A1)
• Synonyms: FOLT; Cyclic dinucleotide:anion antiporter SLC19A1; Folate:anion antiporter SLC19A1; Intestinal folate carrier 1; IFC-1; Placental folate transporter; Reduced folate carrier protein; RFC; hRFC; Reduced folate transporter 1; RFT-1; Solute carrier family 19 member 1; hSLC19A1
• Gene Name: SLC19A1
• UniProt ID: S19A1_HUMAN
• PDB ID: 7TX6; 7TX7; 7XPZ; 7XQ0; 7XQ1; 7XQ2; 7XTK; 8DEP; 8GOE; 8GOF; 8HII; 8HIJ; 8HIK
• Pfam ID: PF01770
• Sequence:
  MVPSSPAVEKQVPVEPGPDPELRSWRHLVCYLCFYGFMAQIRPGESFITPYLLGPDKNFT
  REQVTNEITPVLSYSYLAVLVPVFLLTDYLRYTPVLLLQGLSFVSVWLLLLLGHSVAHMQ
  LMELFYSVTMAARIAYSSYIFSLVRPARYQRVAGYSRAAVLLGVFTSSVLGQLLVTVGRV
  SFSTLNYISLAFLTFSVVLALFLKRPKRSLFFNRDDRGRCETSASELERMNPGPGGKLGH
  ALRVACGDSVLARMLRELGDSLRRPQLRLWSLWWVFNSAGYYLVVYYVHILWNEVDPTTN
  SARVYNGAADAASTLLGAITSFAAGFVKIRWARWSKLLIAGVTATQAGLVFLLAHTRHPS
  SIWLCYAAFVLFRGSYQFLVPIATFQIASSLSKELCALVFGVNTFFATIVKTIITFIVSD
  VRGLGLPVRKQFQLYSVYFLILSIIYFLGAMLDGLRHCQRGHHPRQPPAQGLRSAAEEKA
  AQALSVQDKGLGGLQPAQSPPLSPEDSLGAVGPASLEQRQSDPYLAQAPAPQAAEFLSPV
  TTPSPCTLCSAQASGPEAADETCPQLAVHPPGVSKLGLQCLPSDGVQNVNQ
• Function: Antiporter that mediates the import of reduced folates or a subset of cyclic dinucleotides, driven by the export of organic anions. Mechanistically, acts as a secondary active transporter, which exports intracellular organic anions down their concentration gradients to facilitate the uptake of its substrates. Has high affinity for N5-methyltetrahydrofolate, the predominant circulating form of folate. Also able to mediate the import of antifolate drug methotrexate. Also acts as an importer of immunoreactive cyclic dinucleotides, such as cyclic GMP-AMP (2'-3'-cGAMP), an immune messenger produced in response to DNA virus in the cytosol, and its linkage isomer 3'-3'-cGAMP, thus playing a role in triggering larger immune responses. 5-amino-4-imidazolecarboxamide riboside (AICAR), when phosphorylated to AICAR monophosphate, can serve as an organic anion for antiporter activity.
• Tissue Specificity: Placenta, liver, and to a much smaller extent, in lung.
• KEGG Pathway:
  Antifolate resistance (hsa01523)
  Vitamin digestion and absorption (hsa04977)
• Reactome Pathway: Metabolism of folate and pterines (R-HSA-196757)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 4 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Methotrexate	DM2TEOL	Approved	Reduced folate transporter (SLC19A1) decreases the response to substance of Methotrexate.	[24]
Pemetrexed	DMMX2E6	Approved	Reduced folate transporter (SLC19A1) increases the response to substance of Pemetrexed.	[24]
Raltitrexed	DMT9K8G	Approved	Reduced folate transporter (SLC19A1) decreases the response to substance of Raltitrexed.	[24]
Talotrexin	DM1AB4L	Phase 1/2	Reduced folate transporter (SLC19A1) decreases the response to substance of Talotrexin.	[24]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Reduced folate transporter (SLC19A1).	[1]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Reduced folate transporter (SLC19A1).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Reduced folate transporter (SLC19A1).	[18]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Reduced folate transporter (SLC19A1).	[20]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Reduced folate transporter (SLC19A1).	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Reduced folate transporter (SLC19A1).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Reduced folate transporter (SLC19A1).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Reduced folate transporter (SLC19A1).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Reduced folate transporter (SLC19A1).	[5]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Reduced folate transporter (SLC19A1).	[6]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Reduced folate transporter (SLC19A1).	[8]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Reduced folate transporter (SLC19A1).	[9]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Reduced folate transporter (SLC19A1).	[10]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Reduced folate transporter (SLC19A1).	[11]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Reduced folate transporter (SLC19A1).	[12]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Reduced folate transporter (SLC19A1).	[13]
Ethanol	DMDRQZU	Approved	Ethanol decreases the expression of Reduced folate transporter (SLC19A1).	[11]
Irinotecan	DMP6SC2	Approved	Irinotecan decreases the expression of Reduced folate transporter (SLC19A1).	[14]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of Reduced folate transporter (SLC19A1).	[9]
Nicotine	DMWX5CO	Approved	Nicotine decreases the expression of Reduced folate transporter (SLC19A1).	[11]
Atenolol	DMNKG1Z	Approved	Atenolol decreases the expression of Reduced folate transporter (SLC19A1).	[11]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Reduced folate transporter (SLC19A1).	[15]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Reduced folate transporter (SLC19A1).	[6]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Reduced folate transporter (SLC19A1).	[12]
GSK2110183	DMZHB37	Phase 2	GSK2110183 decreases the expression of Reduced folate transporter (SLC19A1).	[16]
OTX-015	DMI8RG1	Phase 1/2	OTX-015 decreases the expression of Reduced folate transporter (SLC19A1).	[17]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Reduced folate transporter (SLC19A1).	[19]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Reduced folate transporter (SLC19A1).	[21]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Reduced folate transporter (SLC19A1).	[22]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Reduced folate transporter (SLC19A1).	[23]

References

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• [12] 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.
• [13] The reduced folate carrier (RFC) is cytotoxic to cells under conditions of severe folate deprivationRFC as a double edged sword in folate homeostasis. J Biol Chem. 2008 Jul 25;283(30):20687-95.
• [14] Clinical determinants of response to irinotecan-based therapy derived from cell line models. Clin Cancer Res. 2008 Oct 15;14(20):6647-55.
• [15] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
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• [19] BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell. 2011 Sep 16;146(6):904-17.
• [20] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [21] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [22] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [23] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [24] The inverse relationship between reduced folate carrier function and pemetrexed activity in a human colon cancer cell line. Mol Cancer Ther. 2006 Feb;5(2):438-49. doi: 10.1158/1535-7163.MCT-05-0243.