Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTYI6SX1)

• DOT Name: Urea transporter 2 (SLC14A2)
• Synonyms: Solute carrier family 14 member 2; Urea transporter, kidney
• Gene Name: SLC14A2
• UniProt ID: UT2_HUMAN
• PDB ID: 8BLO
• Pfam ID: PF03253
• Sequence:
  MSDPHSSPLLPEPLSSRYKLYEAEFTSPSWPSTSPDTHPALPLLEMPEEKDLRSSNEDSH
  IVKIEKLNERSKRKDDGVAHRDSAGQRCICLSKAVGYLTGDMKEYRIWLKDKHLALQFID
  WVLRGTAQVMFINNPLSGLIIFIGLLIQNPWWTITGGLGTVVSTLTALALGQDRSAIASG
  LHGYNGMLVGLLMAVFSEKLDYYWWLLFPVTFTAMSCPVLSSALNSIFSKWDLPVFTLPF
  NIAVTLYLAATGHYNLFFPTTLVEPVSSVPNITWTEMEMPLLLQAIPVGVGQVYGCDNPW
  TGGVFLVALFISSPLICLHAAIGSIVGLLAALSVATPFETIYTGLWSYNCVLSCIAIGGM
  FYALTWQTHLLALICALFCAYMEAAISNIMSVVGVPPGTWAFCLATIIFLLLTTNNPAIF
  RLPLSKVTYPEANRIYYLTVKSGEEEKAPSGGGGEHPPTAGPKVEEGSEAVLSKHRSVFH
  IEWSSIRRRSKVFGKGEHQERQNKDPFPYRYRKPTVELLDLDTMEESSEIKVETNISKTS
  WIRSSMAASGKRVSKALSYITGEMKECGEGLKDKSPVFQFFDWVLRGTSQVMFVNNPLSG
  ILIILGLFIQNPWWAISGCLGTIMSTLTALILSQDKSAIAAGFHGYNGVLVGLLMAVFSD
  KGDYYWWLLLPVIIMSMSCPILSSALGTIFSKWDLPVFTLPFNITVTLYLAATGHYNLFF
  PTTLLQPASAMPNITWSEVQVPLLLRAIPVGIGQVYGCDNPWTGGIFLIALFISSPLICL
  HAAIGSTMGMLAALTIATPFDSIYFGLCGFNSTLACIAIGGMFYVITWQTHLLAIACALF
  AAYLGAALANMLSVFGLPPCTWPFCLSALTFLLLTTNNPAIYKLPLSKVTYPEANRIYYL
  SQERNRRASIITKYQAYDVS
• Function: [Isoform 1]: Mediates the transport of urea driven by a concentration gradient across the cell membrane of the renal inner medullary collecting duct which is critical to the urinary concentrating mechanism; [Isoform 2]: Mediates the transport of urea driven by a concentration gradient across the cell membrane of the kidney inner medullary collecting duct which is critical to the urinary concentrating mechanism.
• Tissue Specificity: .Epressed in the inner medulla of the kidney (at protein level).; [Isoform 2]: Expressed in the kidney.
• Reactome Pathway: Transport of bile salts and organic acids, metal ions and amine compounds (R-HSA-425366)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Regulation of Drug Effects of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Hydroxyurea	DMOQVU9	Approved	Urea transporter 2 (SLC14A2) increases the uptake of Hydroxyurea.	[6]

3 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 Urea transporter 2 (SLC14A2).	[1]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Urea transporter 2 (SLC14A2).	[4]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Urea transporter 2 (SLC14A2).	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Urea transporter 2 (SLC14A2).	[2]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Urea transporter 2 (SLC14A2).	[3]

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] Arsenic suppresses gene expression in promyelocytic leukemia cells partly through Sp1 oxidation. Blood. 2005 Jul 1;106(1):304-10.
• [3] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [4] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [5] 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.
• [6] Transcellular movement of hydroxyurea is mediated by specific solute carrier transporters. Exp Hematol. 2011 Apr;39(4):446-56.