Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT6E2DAX)

• DOT Name: Sodium-dependent phosphate transporter 2 (SLC20A2)
• Synonyms: Gibbon ape leukemia virus receptor 2; GLVR-2; Phosphate transporter 2; PiT-2; Pit2; hPit2; Solute carrier family 20 member 2
• Gene Name: SLC20A2
• Related Disease:
  Basal ganglia calcification, idiopathic, 1
  Bilateral striopallidodentate calcinosis
• UniProt ID: S20A2_HUMAN
• Pfam ID: PF01384
• Sequence:
  MAMDEYLWMVILGFIIAFILAFSVGANDVANSFGTAVGSGVVTLRQACILASIFETTGSV
  LLGAKVGETIRKGIIDVNLYNETVETLMAGEVSAMVGSAVWQLIASFLRLPISGTHCIVG
  STIGFSLVAIGTKGVQWMELVKIVASWFISPLLSGFMSGLLFVLIRIFILKKEDPVPNGL
  RALPVFYAATIAINVFSIMYTGAPVLGLVLPMWAIALISFGVALLFAFFVWLFVCPWMRR
  KITGKLQKEGALSRVSDESLSKVQEAESPVFKELPGAKANDDSTIPLTGAAGETLGTSEG
  TSAGSHPRAAYGRALSMTHGSVKSPISNGTFGFDGHTRSDGHVYHTVHKDSGLYKDLLHK
  IHIDRGPEEKPAQESNYRLLRRNNSYTCYTAAICGLPVHATFRAADSSAPEDSEKLVGDT
  VSYSKKRLRYDSYSSYCNAVAEAEIEAEEGGVEMKLASELADPDQPREDPAEEEKEEKDA
  PEVHLLFHFLQVLTACFGSFAHGGNDVSNAIGPLVALWLIYKQGGVTQEAATPVWLLFYG
  GVGICTGLWVWGRRVIQTMGKDLTPITPSSGFTIELASAFTVVIASNIGLPVSTTHCKVG
  SVVAVGWIRSRKAVDWRLFRNIFVAWFVTVPVAGLFSAAVMALLMYGILPYV
• Function: Sodium-phosphate symporter which preferentially transports the monovalent form of phosphate with a stoichiometry of two sodium ions per phosphate ion. Plays a critical role in the determination of bone quality and strength by providing phosphate for bone mineralization. Required to maintain normal cerebrospinal fluid phosphate levels. Mediates phosphate-induced calcification of vascular smooth muscle cells (VCMCs) and can functionally compensate for loss of SLC20A1 in VCMCs; (Microbial infection) Functions as a retroviral receptor and confers human cells susceptibility to infection to amphotropic murine leukemia virus (A-MuLV), 10A1 murine leukemia virus (10A1 MLV) and some feline leukemia virus subgroup B (FeLV-B) variants.
• Tissue Specificity: Ubiquitously expressed.
• Reactome Pathway:
  Defective SLC20A2 causes idiopathic basal ganglia calcification 1 (IBGC1) (R-HSA-5619111)
  Sodium-coupled phosphate cotransporters (R-HSA-427652)
• BioCyc Pathway: MetaCyc:ENSG00000168575-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Basal ganglia calcification, idiopathic, 1	DIS44NTG	Strong	Autosomal dominant	[1]
Bilateral striopallidodentate calcinosis	DISNZJTB	Supportive	Autosomal dominant	[2]

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 Sodium-dependent phosphate transporter 2 (SLC20A2).	[3]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Sodium-dependent phosphate transporter 2 (SLC20A2).	[7]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Sodium-dependent phosphate transporter 2 (SLC20A2).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Sodium-dependent phosphate transporter 2 (SLC20A2).	[19]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Sodium-dependent phosphate transporter 2 (SLC20A2).	[18]

13 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 Sodium-dependent phosphate transporter 2 (SLC20A2).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Sodium-dependent phosphate transporter 2 (SLC20A2).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Sodium-dependent phosphate transporter 2 (SLC20A2).	[6]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Sodium-dependent phosphate transporter 2 (SLC20A2).	[8]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Sodium-dependent phosphate transporter 2 (SLC20A2).	[9]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Sodium-dependent phosphate transporter 2 (SLC20A2).	[10]
Rifampicin	DM5DSFZ	Approved	Rifampicin decreases the expression of Sodium-dependent phosphate transporter 2 (SLC20A2).	[11]
Zidovudine	DM4KI7O	Approved	Zidovudine increases the expression of Sodium-dependent phosphate transporter 2 (SLC20A2).	[12]
Phosphate	DMUXQG7	Approved	Phosphate increases the expression of Sodium-dependent phosphate transporter 2 (SLC20A2).	[13]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Sodium-dependent phosphate transporter 2 (SLC20A2).	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Sodium-dependent phosphate transporter 2 (SLC20A2).	[15]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Sodium-dependent phosphate transporter 2 (SLC20A2).	[16]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Sodium-dependent phosphate transporter 2 (SLC20A2).	[17]

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] Mutations in SLC20A2 link familial idiopathic basal ganglia calcification with phosphate homeostasis. Nat Genet. 2012 Feb 12;44(3):254-6. doi: 10.1038/ng.1077.
• [3] 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.
• [4] 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.
• [5] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [8] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [9] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [10] 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.
• [11] Rifampin Regulation of Drug Transporters Gene Expression and the Association of MicroRNAs in Human Hepatocytes. Front Pharmacol. 2016 Apr 26;7:111.
• [12] Differential gene expression in human hepatocyte cell lines exposed to the antiretroviral agent zidovudine. Arch Toxicol. 2014 Mar;88(3):609-23. doi: 10.1007/s00204-013-1169-3. Epub 2013 Nov 30.
• [13] High expression of the Pi-transporter SLC20A1/Pit1 in calcific aortic valve disease promotes mineralization through regulation of Akt-1. PLoS One. 2013;8(1):e53393. doi: 10.1371/journal.pone.0053393. Epub 2013 Jan 4.
• [14] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [15] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [16] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [17] 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.
• [18] 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.
• [19] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.