Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTENU71Z)

• DOT Name: Solute carrier family 2, facilitated glucose transporter member 9 (SLC2A9)
• Synonyms: Glucose transporter type 9; GLUT-9; Urate transporter
• Gene Name: SLC2A9
• Related Disease:
  Hypouricemia, renal, 2
  Hereditary renal hypouricemia
• UniProt ID: GTR9_HUMAN
• Pfam ID: PF00083
• Sequence:
  MARKQNRNSKELGLVPLTDDTSHAGPPGPGRALLECDHLRSGVPGGRRRKDWSCSLLVAS
  LAGAFGSSFLYGYNLSVVNAPTPYIKAFYNESWERRHGRPIDPDTLTLLWSVTVSIFAIG
  GLVGTLIVKMIGKVLGRKHTLLANNGFAISAALLMACSLQAGAFEMLIVGRFIMGIDGGV
  ALSVLPMYLSEISPKEIRGSLGQVTAIFICIGVFTGQLLGLPELLGKESTWPYLFGVIVV
  PAVVQLLSLPFLPDSPRYLLLEKHNEARAVKAFQTFLGKADVSQEVEEVLAESRVQRSIR
  LVSVLELLRAPYVRWQVVTVIVTMACYQLCGLNAIWFYTNSIFGKAGIPPAKIPYVTLST
  GGIETLAAVFSGLVIEHLGRRPLLIGGFGLMGLFFGTLTITLTLQDHAPWVPYLSIVGIL
  AIIASFCSGPGGIPFILTGEFFQQSQRPAAFIIAGTVNWLSNFAVGLLFPFIQKSLDTYC
  FLVFATICITGAIYLYFVLPETKNRTYAEISQAFSKRNKAYPPEEKIDSAVTDGKINGRP
• Function: High-capacity urate transporter, which may play a role in the urate reabsorption by proximal tubules. May have a residual high-affinity, low-capacity glucose and fructose transporter activity. Transports urate at rates 45- to 60-fold faster than glucose. Does not transport galactose. May mediate small uptake of adenine but not of other nucleobases.
• Tissue Specificity: .Most strongly expressed in basolateral membranes of proximal renal tubular cells, liver and placenta. Also detected in lung, blood leukocytes, heart skeletal muscle and chondrocytes from articular cartilage. Detected in kidney membrane (at protein level).; [Isoform 2]: Only detected in the apical membranes of polarized renal tubular cells and placenta. Detected in kidney membrane (at protein level).
• Reactome Pathway:
  Defective SLC2A9 causes hypouricemia renal 2 (RHUC2) (R-HSA-5619047)
  Cellular hexose transport (R-HSA-189200)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hypouricemia, renal, 2	DISUTG8K	Strong	Autosomal recessive	[1]
Hereditary renal hypouricemia	DISURZ91	Supportive	Autosomal recessive	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fructose	DM43AN2	Approved	Solute carrier family 2, facilitated glucose transporter member 9 (SLC2A9) increases the transport of Fructose.	[13]
D-glucose	DMMG2TO	Investigative	Solute carrier family 2, facilitated glucose transporter member 9 (SLC2A9) increases the transport of D-glucose.	[13]
Uric acid	DMA1MKT	Investigative	Solute carrier family 2, facilitated glucose transporter member 9 (SLC2A9) increases the transport of Uric acid.	[14]

4 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 Solute carrier family 2, facilitated glucose transporter member 9 (SLC2A9).	[3]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Solute carrier family 2, facilitated glucose transporter member 9 (SLC2A9).	[6]
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Solute carrier family 2, facilitated glucose transporter member 9 (SLC2A9).	[10]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Solute carrier family 2, facilitated glucose transporter member 9 (SLC2A9).	[10]

7 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 Solute carrier family 2, facilitated glucose transporter member 9 (SLC2A9).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Solute carrier family 2, facilitated glucose transporter member 9 (SLC2A9).	[5]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Solute carrier family 2, facilitated glucose transporter member 9 (SLC2A9).	[7]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Solute carrier family 2, facilitated glucose transporter member 9 (SLC2A9).	[8]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Solute carrier family 2, facilitated glucose transporter member 9 (SLC2A9).	[9]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Solute carrier family 2, facilitated glucose transporter member 9 (SLC2A9).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Solute carrier family 2, facilitated glucose transporter member 9 (SLC2A9).	[12]

References

• [1] Glut9 is a major regulator of urate homeostasis and its genetic inactivation induces hyperuricosuria and urate nephropathy. Proc Natl Acad Sci U S A. 2009 Sep 8;106(36):15501-6. doi: 10.1073/pnas.0904411106. Epub 2009 Aug 21.
• [2] Homozygous SLC2A9 mutations cause severe renal hypouricemia. J Am Soc Nephrol. 2010 Jan;21(1):64-72. doi: 10.1681/ASN.2009040406. Epub 2009 Nov 19.
• [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] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [5] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] 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.
• [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] Vitamin D3 transactivates the zinc and manganese transporter SLC30A10 via the Vitamin D receptor. J Steroid Biochem Mol Biol. 2016 Oct;163:77-87.
• [9] 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.
• [10] 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.
• [11] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [12] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [13] A highly conserved hydrophobic motif in the exofacial vestibule of fructose transporting SLC2A proteins acts as a critical determinant of their substrate selectivity. Mol Membr Biol. 2007 Sep-Dec;24(5-6):455-63. doi: 10.1080/09687680701298143.
• [14] SLC2A9 is a high-capacity urate transporter in humans. PLoS Med. 2008 Oct 7;5(10):e197. doi: 10.1371/journal.pmed.0050197.