Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT049V7Y)

• DOT Name: Proton-coupled folate transporter (SLC46A1)
• Synonyms: HsPCFT; hPCFT; Heme carrier protein 1; PCFT/HCP1; Solute carrier family 46 member 1
• Gene Name: SLC46A1
• Related Disease: Hereditary folate malabsorption
• UniProt ID: PCFT_HUMAN
• Pfam ID: PF07690
• Sequence:
  MEGSASPPEKPRARPAAAVLCRGPVEPLVFLANFALVLQGPLTTQYLWHRFSADLGYNGT
  RQRGGCSNRSADPTMQEVETLTSHWTLYMNVGGFLVGLFSSTLLGAWSDSVGRRPLLVLA
  SLGLLLQALVSVFVVQLQLHVGYFVLGRILCALLGDFGGLLAASFASVADVSSSRSRTFR
  MALLEASIGVAGMLASLLGGHWLRAQGYANPFWLALALLIAMTLYAAFCFGETLKEPKST
  RLFTFRHHRSIVQLYVAPAPEKSRKHLALYSLAIFVVITVHFGAQDILTLYELSTPLCWD
  SKLIGYGSAAQHLPYLTSLLALKLLQYCLADAWVAEIGLAFNILGMVVFAFATITPLMFT
  GYGLLFLSLVITPVIRAKLSKLVRETEQGALFSAVACVNSLAMLTASGIFNSLYPATLNF
  MKGFPFLLGAGLLLIPAVLIGMLEKADPHLEFQQFPQSP
• Function: Proton-coupled folate symporter that mediates folate absorption using an H(+) gradient as a driving force. Involved in the intestinal absorption of folates at the brush-border membrane of the proximal jejunum, and the transport from blood to cerebrospinal fluid across the choroid plexus. Functions at acidic pH via alternate outward- and inward-open conformation states. Protonation of residues in the outward open state primes the protein for transport. Binding of folate promotes breaking of salt bridge network and subsequent closure of the extracellular gate, leading to the inward-open state and release of protons and folate. Also able to transport antifolate drugs, such as methotrexate and pemetrexed, which are established treatments for cancer and autoimmune diseases. Involved in FOLR1-mediated endocytosis by serving as a route of export of folates from acidified endosomes. Also acts as a lower-affinity, pH-independent heme carrier protein and constitutes the main importer of heme in the intestine. Imports heme in the retina and retinal pigment epithelium, in neurons of the hippocampus, in hepatocytes and in the renal epithelial cells. Hence, participates in the trafficking of heme and increases intracellular iron content ; [Isoform 2]: Inactive isoform which is not able to mediate proton-coupled folate transport.
• Tissue Specificity: Expressed at highest level in the upper half of the small intestine (duodenum and jejunum), expression decreases downwardly in the subsequent quarter and is undetectable in the last quarter (the lowest ileum) . Also expressed in kidney, liver, placenta, spleen, retina and retinal pigment epithelium . Lower levels found in testis . Very low levels in brain, lung, stomach, heart and muscle .
• KEGG Pathway:
  Antifolate resistance (hsa01523)
  Vitamin digestion and absorption (hsa04977)
  Mineral absorption (hsa04978)
• Reactome Pathway:
  Iron uptake and transport (R-HSA-917937)
  Heme signaling (R-HSA-9707616)
  Metabolism of folate and pterines (R-HSA-196757)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hereditary folate malabsorption	DIS9XT7J	Definitive	Autosomal recessive	[1]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Methotrexate	DM2TEOL	Approved	Proton-coupled folate transporter (SLC46A1) increases the response to substance of Methotrexate.	[20]
Raltitrexed	DMT9K8G	Approved	Proton-coupled folate transporter (SLC46A1) increases the response to substance of Raltitrexed.	[14]

This DOT Affected the Regulation of Drug Effects of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
3-iodothyronamine	DM3L0F8	Investigative	Proton-coupled folate transporter (SLC46A1) affects the uptake of 3-iodothyronamine.	[21]
Heme	DMGC287	Investigative	Proton-coupled folate transporter (SLC46A1) increases the uptake of Heme.	[22]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Proton-coupled folate transporter (SLC46A1).	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Proton-coupled folate transporter (SLC46A1).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Proton-coupled folate transporter (SLC46A1).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Proton-coupled folate transporter (SLC46A1).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Proton-coupled folate transporter (SLC46A1).	[6]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Proton-coupled folate transporter (SLC46A1).	[7]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Proton-coupled folate transporter (SLC46A1).	[8]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Proton-coupled folate transporter (SLC46A1).	[9]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Proton-coupled folate transporter (SLC46A1).	[10]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Proton-coupled folate transporter (SLC46A1).	[11]
Cholecalciferol	DMGU74E	Approved	Cholecalciferol increases the expression of Proton-coupled folate transporter (SLC46A1).	[12]
Sulfasalazine	DMICA9H	Approved	Sulfasalazine decreases the activity of Proton-coupled folate transporter (SLC46A1).	[13]
Pemetrexed	DMMX2E6	Approved	Pemetrexed increases the activity of Proton-coupled folate transporter (SLC46A1).	[14]
Pyrimethamine	DM5X7VY	Approved	Pyrimethamine decreases the activity of Proton-coupled folate transporter (SLC46A1).	[15]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Proton-coupled folate transporter (SLC46A1).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Proton-coupled folate transporter (SLC46A1).	[17]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Proton-coupled folate transporter (SLC46A1).	[18]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Proton-coupled folate transporter (SLC46A1).	[19]
AM251	DMTAWHL	Investigative	AM251 increases the expression of Proton-coupled folate transporter (SLC46A1).	[10]
[3H]folinic acid	DME0XHN	Investigative	[3H]folinic acid decreases the activity of Proton-coupled folate transporter (SLC46A1).	[13]

References

• [1] A novel loss-of-function mutation in the proton-coupled folate transporter from a patient with hereditary folate malabsorption reveals that Arg 113 is crucial for function. Blood. 2008 Sep 1;112(5):2055-61. doi: 10.1182/blood-2008-04-150276. Epub 2008 Jun 17.
• [2] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [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] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [5] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [7] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [8] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [9] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [10] Effect of cannabinoids upon the uptake of folic acid by BeWo cells. Pharmacology. 2009;83(3):170-6. doi: 10.1159/000192587. Epub 2009 Jan 15.
• [11] The effect of folate status on the uptake of physiologically relevant compounds by Caco-2 cells. Eur J Pharmacol. 2010 Aug 25;640(1-3):29-37. doi: 10.1016/j.ejphar.2010.04.056. Epub 2010 May 11.
• [12] The SLCO1A2 gene, encoding human organic anion-transporting polypeptide 1A2, is transactivated by the vitamin D receptor. Mol Pharmacol. 2012 Jul;82(1):37-46. doi: 10.1124/mol.112.077909. Epub 2012 Apr 3.
• [13] Functional characterization of human proton-coupled folate transporter/heme carrier protein 1 heterologously expressed in mammalian cells as a folate transporter. J Pharmacol Exp Ther. 2007 Aug;322(2):469-76. doi: 10.1124/jpet.107.122606. Epub 2007 May 2.
• [14] Synthesis, biological, and antitumor activity of a highly potent 6-substituted pyrrolo[2,3-d]pyrimidine thienoyl antifolate inhibitor with proton-coupled folate transporter and folate receptor selectivity over the reduced folate carrier that inhibits -glycinamide ribonucleotide formyltransferase. J Med Chem. 2011 Oct 27;54(20):7150-64.
• [15] The human proton-coupled folate transporter (hPCFT): modulation of intestinal expression and function by drugs. Am J Physiol Gastrointest Liver Physiol. 2010 Feb;298(2):G248-54. doi: 10.1152/ajpgi.00224.2009. Epub 2009 Sep 17.
• [16] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [17] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [18] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [19] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [20] SLC19A1, SLC46A1 and SLCO1B1 polymorphisms as predictors of methotrexate-related toxicity in Portuguese rheumatoid arthritis patients. Toxicol Sci. 2014 Nov;142(1):196-209. doi: 10.1093/toxsci/kfu162. Epub 2014 Aug 14.
• [21] Identification and characterization of 3-iodothyronamine intracellular transport. Endocrinology. 2009 Apr;150(4):1991-9.
• [22] Haem carrier protein 1 (HCP1): Expression and functional studies in cultured cells. FEBS Lett. 2006 Dec 22;580(30):6865-70. doi: 10.1016/j.febslet.2006.11.048. Epub 2006 Nov 29.