Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTUAOB8T)

• DOT Name: Equilibrative nucleoside transporter 2 (SLC29A2)
• Synonyms: hENT2; 36 kDa nucleolar protein HNP36; Delayed-early response protein 12; Equilibrative nitrobenzylmercaptopurine riboside-insensitive nucleoside transporter; Equilibrative NBMPR-insensitive nucleoside transporter; Hydrophobic nucleolar protein, 36 kDa; Nucleoside transporter, ei-type; Solute carrier family 29 member 2
• Gene Name: SLC29A2
• UniProt ID: S29A2_HUMAN
• Pfam ID: PF01733
• Sequence:
  MARGDAPRDSYHLVGISFFILGLGTLLPWNFFITAIPYFQARLAGAGNSTARILSTNHTG
  PEDAFNFNNWVTLLSQLPLLLFTLLNSFLYQCVPETVRILGSLLAILLLFALTAALVKVD
  MSPGPFFSITMASVCFINSFSAVLQGSLFGQLGTMPSTYSTLFLSGQGLAGIFAALAMLL
  SMASGVDAETSALGYFITPCVGILMSIVCYLSLPHLKFARYYLANKSSQAQAQELETKAE
  LLQSDENGIPSSPQKVALTLDLDLEKEPESEPDEPQKPGKPSVFTVFQKIWLTALCLVLV
  FTVTLSVFPAITAMVTSSTSPGKWSQFFNPICCFLLFNIMDWLGRSLTSYFLWPDEDSRL
  LPLLVCLRFLFVPLFMLCHVPQRSRLPILFPQDAYFITFMLLFAVSNGYLVSLTMCLAPR
  QVLPHEREVAGALMTFFLALGLSCGASLSFLFKALL
• Function: Bidirectional uniporter involved in the facilitative transport of nucleosides and nucleobases, and contributes to maintaining their cellular homeostasis. Functions as a Na(+)-independent, passive transporter. Involved in the transport of nucleosides such as inosine, adenosine, uridine, thymidine, cytidine and guanosine. Also able to transport purine nucleobases (hypoxanthine, adenine, guanine) and pyrimidine nucleobases (thymine, uracil). Involved in nucleoside transport at basolateral membrane of kidney cells, allowing liver absorption of nucleoside metabolites. Mediates apical nucleoside uptake into Sertoli cells, thereby regulating the transport of nucleosides in testis across the blood-testis-barrier. Mediates both the influx and efflux of hypoxanthine in skeletal muscle microvascular endothelial cells to control the amount of intracellular hypoxanthine available for xanthine oxidase-mediated ROS production; [Isoform 3]: Non functional nucleoside transporter protein for adenosine or thymidine transport. Does not express on cell membrane.
• Tissue Specificity: Highly expressed in skeletal muscle . Expressed in liver, lung, placenta, brain, heart, kidney and ovarian tissues . Expressed in testis at the blood-brain-barrier .
• KEGG Pathway: Alcoholism (hsa05034)
• Reactome Pathway:
  Azathioprine ADME (R-HSA-9748787)
  Transport of nucleosides and free purine and pyrimidine bases across the plasma membrane (R-HSA-83936)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Regulation of Drug Effects of 3 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Adenosine	DMM2NSK	Approved	Equilibrative nucleoside transporter 2 (SLC29A2) increases the uptake of Adenosine.	[11]
Uridine	DMQTREB	Approved	Equilibrative nucleoside transporter 2 (SLC29A2) increases the uptake of Uridine.	[12]
3-iodothyronamine	DM3L0F8	Investigative	Equilibrative nucleoside transporter 2 (SLC29A2) affects the uptake of 3-iodothyronamine.	[13]

2 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 Equilibrative nucleoside transporter 2 (SLC29A2).	[1]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Equilibrative nucleoside transporter 2 (SLC29A2).	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Equilibrative nucleoside transporter 2 (SLC29A2).	[2]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Equilibrative nucleoside transporter 2 (SLC29A2).	[3]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Equilibrative nucleoside transporter 2 (SLC29A2).	[4]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Equilibrative nucleoside transporter 2 (SLC29A2).	[6]
Decitabine	DMQL8XJ	Approved	Decitabine decreases the expression of Equilibrative nucleoside transporter 2 (SLC29A2).	[7]
Azacitidine	DMTA5OE	Approved	Azacitidine decreases the expression of Equilibrative nucleoside transporter 2 (SLC29A2).	[7]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Equilibrative nucleoside transporter 2 (SLC29A2).	[8]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Equilibrative nucleoside transporter 2 (SLC29A2).	[9]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Equilibrative nucleoside transporter 2 (SLC29A2).	[10]

References

• [1] 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.
• [2] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [3] 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.
• [4] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [5] 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.
• [6] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [7] The DNA methyltransferase inhibitors azacitidine, decitabine and zebularine exert differential effects on cancer gene expression in acute myeloid leukemia cells. Leukemia. 2009 Jun;23(6):1019-28.
• [8] 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.
• [9] Bisphenol A and bisphenol S induce distinct transcriptional profiles in differentiating human primary preadipocytes. PLoS One. 2016 Sep 29;11(9):e0163318.
• [10] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [11] Molecular cloning and characterization of a nitrobenzylthioinosine-insensitive (ei) equilibrative nucleoside transporter from human placenta. Biochem J. 1997 Dec 15;328 ( Pt 3)(Pt 3):739-43. doi: 10.1042/bj3280739.
• [12] Nucleoside transport in human colonic epithelial cell lines: evidence for two Na+-independent transport systems in T84 and Caco-2 cells. Biochim Biophys Acta. 1999 Jun 9;1419(1):15-22. doi: 10.1016/s0005-2736(99)00045-0.
• [13] Identification and characterization of 3-iodothyronamine intracellular transport. Endocrinology. 2009 Apr;150(4):1991-9.