Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTBO2WXH)

• DOT Name: Zinc transporter ZIP5 (SLC39A5)
• Synonyms: Solute carrier family 39 member 5; Zrt- and Irt-like protein 5; ZIP-5
• Gene Name: SLC39A5
• Related Disease: Myopia 24, autosomal dominant
• UniProt ID: S39A5_HUMAN
• PDB ID: 7Y9C; 7YF2; 7YF4
• Pfam ID: PF02535
• Sequence:
  MMGSPVSHLLAGFCVWVVLGWVGGSVPNLGPAEQEQNHYLAQLFGLYGENGTLTAGGLAR
  LLHSLGLGRVQGLRLGQHGPLTGRAASPAADNSTHRPQNPELSVDVWAGMPLGPSGWGDL
  EESKAPHLPRGPAPSGLDLLHRLLLLDHSLADHLNEDCLNGSQLLVNFGLSPAAPLTPRQ
  FALLCPALLYQIDSRVCIGAPAPAPPGDLLSALLQSALAVLLLSLPSPLSLLLLRLLGPR
  LLRPLLGFLGALAVGTLCGDALLHLLPHAQEGRHAGPGGLPEKDLGPGLSVLGGLFLLFV
  LENMLGLLRHRGLRPRCCRRKRRNLETRNLDPENGSGMALQPLQAAPEPGAQGQREKNSQ
  HPPALAPPGHQGHSHGHQGGTDITWMVLLGDGLHNLTDGLAIGAAFSDGFSSGLSTTLAV
  FCHELPHELGDFAMLLQSGLSFRRLLLLSLVSGALGLGGAVLGVGLSLGPVPLTPWVFGV
  TAGVFLYVALVDMLPALLRPPEPLPTPHVLLQGLGLLLGGGLMLAITLLEERLLPVTTEG
• Function: Uniporter that transports zinc(2+) into polarized cells of enterocytes, pancreatic acinar and endoderm cells across the basolateral membrane and participates, notably, in zinc excretion from the intestine by the uptake of zinc from the blood into the intestine. The transport mechanism is temperature- and concentration-dependent and saturable. In addition, is also a high affinity copper transporter in vitro. Also may regulate glucose-stimulated insulin secretion (GSIS) in islets primarily through the zinc-activated SIRT1-PPARGC1A axis. Could regulate the BMP/TGF-beta (bone morphogenetic protein/transforming growth factor-beta) signaling pathway and modulates extracellular matrix (ECM) proteins of the sclera. Plays a role in eye development.
• Tissue Specificity: Expressed in liver, kidney, pancreas, small intestine, colon, spleen, fetal liver and fetal kidney.
• KEGG Pathway:
  Alzheimer disease (hsa05010)
  Parkinson disease (hsa05012)
• Reactome Pathway: Zinc influx into cells by the SLC39 gene family (R-HSA-442380)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Myopia 24, autosomal dominant	DISWLJZJ	Strong	Autosomal dominant	[1]

9 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 Zinc transporter ZIP5 (SLC39A5).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Zinc transporter ZIP5 (SLC39A5).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Zinc transporter ZIP5 (SLC39A5).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Zinc transporter ZIP5 (SLC39A5).	[5]
Quercetin	DM3NC4M	Approved	Quercetin affects the expression of Zinc transporter ZIP5 (SLC39A5).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Zinc transporter ZIP5 (SLC39A5).	[7]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Zinc transporter ZIP5 (SLC39A5).	[8]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Zinc transporter ZIP5 (SLC39A5).	[9]
Octanal	DMTN0OK	Investigative	Octanal decreases the expression of Zinc transporter ZIP5 (SLC39A5).	[10]

References

• [1] Mutational screening of SLC39A5, LEPREL1 and LRPAP1 in a cohort of 187 high myopia patients. Sci Rep. 2017 Apr 25;7(1):1120. doi: 10.1038/s41598-017-01285-3.
• [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] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [4] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [5] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] 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.
• [7] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [8] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [9] 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.
• [10] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.