Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTYMA1VB)

• DOT Name: Zinc transporter SLC39A7 (SLC39A7)
• Synonyms: Histidine-rich membrane protein Ke4; Really interesting new gene 5 protein; Solute carrier family 39 member 7; Zrt-, Irt-like protein 7; ZIP7
• Gene Name: SLC39A7
• Related Disease:
  Agammaglobulinemia 9, autosomal recessive
  Agammaglobulinemia
• UniProt ID: S39A7_HUMAN
• PDB ID: 8GZE
• Pfam ID: PF02535
• Sequence:
  MARGLGAPHWVAVGLLTWATLGLLVAGLGGHDDLHDDLQEDFHGHSHRHSHEDFHHGHSH
  AHGHGHTHESIWHGHTHDHDHGHSHEDLHHGHSHGYSHESLYHRGHGHDHEHSHGGYGES
  GAPGIKQDLDAVTLWAYALGATVLISAAPFFVLFLIPVESNSPRHRSLLQILLSFASGGL
  LGDAFLHLIPHALEPHSHHTLEQPGHGHSHSGQGPILSVGLWVLSGIVAFLVVEKFVRHV
  KGGHGHSHGHGHAHSHTRGSHGHGRQERSTKEKQSSEEEEKETRGVQKRRGGSTVPKDGP
  VRPQNAEEEKRGLDLRVSGYLNLAADLAHNFTDGLAIGASFRGGRGLGILTTMTVLLHEV
  PHEVGDFAILVQSGCSKKQAMRLQLLTAVGALAGTACALLTEGGAVGSEIAGGAGPGWVL
  PFTAGGFIYVATVSVLPELLREASPLQSLLEVLGLLGGVIMMVLIAHLE
• Function: Transports Zn(2+) from the endoplasmic reticulum (ER)/Golgi apparatus to the cytosol, playing an essential role in the regulation of cytosolic zinc levels. Acts as a gatekeeper of zinc release from intracellular stores, requiring post-translational activation by phosphorylation, resulting in activation of multiple downstream pathways leading to cell growth and proliferation. Has an essential role in B cell development and is required for proper B cell receptor signaling. Plays an important role in maintaining intestinal epithelial homeostasis and skin dermis development by regulating ER function. Controls cell signaling pathways involved in glucose metabolism in skeletal muscle. Has a protective role against ER stress in different biological contexts. Mediates Zn(2+)-induced ferroptosis.
• Tissue Specificity: Widely expressed.
• 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

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Agammaglobulinemia 9, autosomal recessive	DIS7VQTQ	Strong	Autosomal recessive	[1]
Agammaglobulinemia	DISXMS80	Moderate	Autosomal recessive	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Zinc transporter SLC39A7 (SLC39A7) affects the response to substance of Cisplatin.	[13]

9 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 Zinc transporter SLC39A7 (SLC39A7).	[3]
Selenium	DM25CGV	Approved	Selenium increases the expression of Zinc transporter SLC39A7 (SLC39A7).	[4]
Cannabidiol	DM0659E	Approved	Cannabidiol increases the expression of Zinc transporter SLC39A7 (SLC39A7).	[5]
Amphotericin B	DMTAJQE	Approved	Amphotericin B decreases the expression of Zinc transporter SLC39A7 (SLC39A7).	[6]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Zinc transporter SLC39A7 (SLC39A7).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Zinc transporter SLC39A7 (SLC39A7).	[8]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Zinc transporter SLC39A7 (SLC39A7).	[9]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Zinc transporter SLC39A7 (SLC39A7).	[10]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of Zinc transporter SLC39A7 (SLC39A7).	[12]

1 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Zinc transporter SLC39A7 (SLC39A7).	[11]

References

• [1] Nephropathy and renal colic in patients treated with indinavir, ritonavir plus indinavir or ritonavir plus saquinavir. AIDS. 1999 Oct 22;13(15):2173-4. doi: 10.1097/00002030-199910220-00025.
• [2] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [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] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [5] Cannabidiol induces antioxidant pathways in keratinocytes by targeting BACH1. Redox Biol. 2020 Jan;28:101321. doi: 10.1016/j.redox.2019.101321. Epub 2019 Sep 5.
• [6] Differential expression of microRNAs and their predicted targets in renal cells exposed to amphotericin B and its complex with copper (II) ions. Toxicol Mech Methods. 2017 Sep;27(7):537-543. doi: 10.1080/15376516.2017.1333554. Epub 2017 Jun 8.
• [7] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [8] 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.
• [9] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.
• [10] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [11] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [12] Intracellular zinc stores protect the intestinal epithelium from Ochratoxin A toxicity. Toxicol In Vitro. 2009 Dec;23(8):1516-21.
• [13] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.