Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTGLX8XU)

• DOT Name: Equilibrative nucleoside transporter 3 (SLC29A3)
• Synonyms: hENT3; Solute carrier family 29 member 3
• Gene Name: SLC29A3
• Related Disease:
  H syndrome
  Dysosteosclerosis
• UniProt ID: S29A3_HUMAN
• Pfam ID: PF01733
• Sequence:
  MAVVSEDDFQHSSNSTYRTTSSSLRADQEALLEKLLDRPPPGLQRPEDRFCGTYIIFFSL
  GIGSLLPWNFFITAKEYWMFKLRNSSSPATGEDPEGSDILNYFESYLAVASTVPSMLCLV
  ANFLLVNRVAVHIRVLASLTVILAIFMVITALVKVDTSSWTRGFFAVTIVCMVILSGAST
  VFSSSIYGMTGSFPMRNSQALISGGAMGGTVSAVASLVDLAASSDVRNSALAFFLTATVF
  LVLCMGLYLLLSRLEYARYYMRPVLAAHVFSGEEELPQDSLSAPSVASRFIDSHTPPLRP
  ILKKTASLGFCVTYVFFITSLIYPAICTNIESLNKGSGSLWTTKFFIPLTTFLLYNFADL
  CGRQLTAWIQVPGPNSKALPGFVLLRTCLIPLFVLCNYQPRVHLKTVVFQSDVYPALLSS
  LLGLSNGYLSTLALLYGPKIVPRELAEATGVVMSFYVCLGLTLGSACSTLLVHLI
• Function: Uniporter that mediates the facilitative transport of nucleoside across lysosomal and mitochondrial membranes. Functions as a non-electrogenic Na(+)-independent transporter. Substrate transport is pH-dependent and enhanced under acidic condition, probably reflecting the location of the transporter in acidic intracellular compartments. Proton is not a cotransporting ion but most likely change the ionization state of the transporter which dictates transport-permissible/impermissible conformation for nucleoside translocation. May direct the nucleoside transport from lysosomes to cytosol or cytosol to mitochondria to facilitate the fundamental function of salvage synthesis of nucleic acids. Involved in the transport of nucleosides (adenosine, guanosine, uridine, thymidine, cytidine and inosine) and deoxynucleosides (deoxyadenosine, deoxycytidine). Also mediates transport of purine nucleobases (adenine, guanine) and pyrimidine nucleobases (uracil). Also able to transport monoamine neurotransmitters dopamine, serotonin, noradrenaline and tyramine. Capable of transporting ATP. Mediates nucleoside export from lysosomes in macrophages, which regulates macrophage functions and numbers.
• Tissue Specificity: Widely expressed in both adult and fetal tissues . Highest levels in placenta, uterus, ovary, spleen, lymph node and bone marrow . Expressed in liver . Lowest levels in brain and heart . Expressed in macrophages .
• KEGG Pathway: Alcoholism (hsa05034)
• Reactome Pathway:
  Transport of nucleosides and free purine and pyrimidine bases across the plasma membrane (R-HSA-83936)
  Ribavirin ADME (R-HSA-9755088)
  Defective SLC29A3 causes histiocytosis-lymphadenopathy plus syndrome (HLAS) (R-HSA-5619063)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
H syndrome	DISQ2RNS	Strong	Autosomal recessive	[1]
Dysosteosclerosis	DISYAE0Y	Supportive	Autosomal recessive	[2]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Equilibrative nucleoside transporter 3 (SLC29A3) affects the response to substance of Acetaminophen.	[14]

This DOT Affected the Regulation of Drug Effects of 8 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Gemcitabine	DMSE3I7	Approved	Equilibrative nucleoside transporter 3 (SLC29A3) affects the transport of Gemcitabine.	[15]
Adenosine	DMM2NSK	Approved	Equilibrative nucleoside transporter 3 (SLC29A3) affects the transport of Adenosine.	[15]
Zalcitabine	DMH7MUV	Approved	Equilibrative nucleoside transporter 3 (SLC29A3) affects the transport of Zalcitabine.	[15]
Stavudine	DM6DEK9	Approved	Equilibrative nucleoside transporter 3 (SLC29A3) affects the transport of Stavudine.	[15]
Didanosine	DMI2QPE	Approved	Equilibrative nucleoside transporter 3 (SLC29A3) affects the transport of Didanosine.	[15]
Fialuridine	DMCIGRB	Phase 2	Equilibrative nucleoside transporter 3 (SLC29A3) affects the transport of Fialuridine.	[15]
Ribavirin	DMEYLH9	Phase 1 Trial	Equilibrative nucleoside transporter 3 (SLC29A3) affects the transport of Ribavirin.	[15]
Guanosine	DM4T5LH	Phase 1	Equilibrative nucleoside transporter 3 (SLC29A3) affects the transport of Guanosine.	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Equilibrative nucleoside transporter 3 (SLC29A3).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Equilibrative nucleoside transporter 3 (SLC29A3).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Equilibrative nucleoside transporter 3 (SLC29A3).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Equilibrative nucleoside transporter 3 (SLC29A3).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Equilibrative nucleoside transporter 3 (SLC29A3).	[7]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Equilibrative nucleoside transporter 3 (SLC29A3).	[8]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Equilibrative nucleoside transporter 3 (SLC29A3).	[9]
Zidovudine	DM4KI7O	Approved	Zidovudine increases the expression of Equilibrative nucleoside transporter 3 (SLC29A3).	[10]
GSK2110183	DMZHB37	Phase 2	GSK2110183 increases the expression of Equilibrative nucleoside transporter 3 (SLC29A3).	[11]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Equilibrative nucleoside transporter 3 (SLC29A3).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Equilibrative nucleoside transporter 3 (SLC29A3).	[13]

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] Clinical Practice Guidelines for Rare Diseases: The Orphanet Database. PLoS One. 2017 Jan 18;12(1):e0170365. doi: 10.1371/journal.pone.0170365. eCollection 2017.
• [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] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [8] 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.
• [9] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [10] 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.
• [11] Novel ATP-competitive Akt inhibitor afuresertib suppresses the proliferation of malignant pleural mesothelioma cells. Cancer Med. 2017 Nov;6(11):2646-2659. doi: 10.1002/cam4.1179. Epub 2017 Sep 27.
• [12] 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.
• [13] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.
• [14] Interindividual variation in gene expression responses and metabolite formation in acetaminophen-exposed primary human hepatocytes. Arch Toxicol. 2016 May;90(5):1103-15. doi: 10.1007/s00204-015-1545-2. Epub 2015 Jun 24.
• [15] Facilitated mitochondrial import of antiviral and anticancer nucleoside drugs by human equilibrative nucleoside transporter-3. Am J Physiol Gastrointest Liver Physiol. 2009 Apr;296(4):G910-22. doi: 10.1152/ajpgi.90672.2008. Epub 2009 Jan 22.