Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTF951ZS)

• DOT Name: Voltage-gated purine nucleotide uniporter SLC17A9 (SLC17A9)
• Synonyms: Solute carrier family 17 member 9; Vesicular nucleotide transporter; VNUT
• Gene Name: SLC17A9
• Related Disease:
  Disseminated superficial actinic porokeratosis
  Porokeratosis 8, disseminated superficial actinic type
• UniProt ID: S17A9_HUMAN
• Pfam ID: PF07690
• Sequence:
  MQPPPDEARRDMAGDTQWSRPECQAWTGTLLLGTCLLYCARSSMPICTVSMSQDFGWNKK
  EAGIVLSSFFWGYCLTQVVGGHLGDRIGGEKVILLSASAWGSITAVTPLLAHLSSAHLAF
  MTFSRILMGLLQGVYFPALTSLLSQKVRESERAFTYSIVGAGSQFGTLLTGAVGSLLLEW
  YGWQSIFYFSGGLTLLWVWYVYRYLLSEKDLILALGVLAQSRPVSRHNRVPWRRLFRKPA
  VWAAVVSQLSAACSFFILLSWLPTFFEETFPDAKGWIFNVVPWLVAIPASLFSGFLSDHL
  INQGYRAITVRKLMQGMGLGLSSVFALCLGHTSSFCESVVFASASIGLQTFNHSGISVNI
  QDLAPSCAGFLFGVANTAGALAGVVGVCLGGYLMETTGSWTCLFNLVAIISNLGLCTFLV
  FGQAQRVDLSSTHEDL
• Function: Voltage-gated ATP nucleotide uniporter that can also transport the purine nucleotides ADP and GTP. Uses the membrane potential as the driving force to control ATP accumulation in lysosomes and secretory vesicles. By controlling ATP storage in lysosomes, regulates ATP-dependent proteins of these organelles. Also indirectly regulates the exocytosis of ATP through its import into lysosomes in astrocytes and secretory vesicles such as adrenal chromaffin granules, mucin granules and synaptic vesicles.
• Tissue Specificity: Widely expressed, but more predominantly in adrenal gland, brain and thyroid.

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Disseminated superficial actinic porokeratosis	DISELZ77	Supportive	Autosomal dominant	[1]
Porokeratosis 8, disseminated superficial actinic type	DIS044JP	Limited	Autosomal dominant	[1]

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 Voltage-gated purine nucleotide uniporter SLC17A9 (SLC17A9).	[2]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate increases the methylation of Voltage-gated purine nucleotide uniporter SLC17A9 (SLC17A9).	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Voltage-gated purine nucleotide uniporter SLC17A9 (SLC17A9).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Voltage-gated purine nucleotide uniporter SLC17A9 (SLC17A9).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Voltage-gated purine nucleotide uniporter SLC17A9 (SLC17A9).	[5]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Voltage-gated purine nucleotide uniporter SLC17A9 (SLC17A9).	[6]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Voltage-gated purine nucleotide uniporter SLC17A9 (SLC17A9).	[7]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Voltage-gated purine nucleotide uniporter SLC17A9 (SLC17A9).	[8]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Voltage-gated purine nucleotide uniporter SLC17A9 (SLC17A9).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Voltage-gated purine nucleotide uniporter SLC17A9 (SLC17A9).	[3]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Voltage-gated purine nucleotide uniporter SLC17A9 (SLC17A9).	[10]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Voltage-gated purine nucleotide uniporter SLC17A9 (SLC17A9).	[11]

References

• [1] Exome sequencing identifies SLC17A9 pathogenic gene in two Chinese pedigrees with disseminated superficial actinic porokeratosis. J Med Genet. 2014 Oct;51(10):699-704. doi: 10.1136/jmedgenet-2014-102486. Epub 2014 Sep 1.
• [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] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [5] 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.
• [6] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [7] 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.
• [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] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [10] 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.
• [11] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [12] Pregnancy exposure to synthetic phenols and placental DNA methylation - An epigenome-wide association study in male infants from the EDEN cohort. Environ Pollut. 2021 Dec 1;290:118024. doi: 10.1016/j.envpol.2021.118024. Epub 2021 Aug 21.