Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTOWD75R)

• DOT Name: Proton-coupled zinc antiporter SLC30A5 (SLC30A5)
• Synonyms: Solute carrier family 30 member 5; Zinc transporter 5; ZnT-5; ZnT-like transporter 1; hZTL1
• Gene Name: SLC30A5
• UniProt ID: ZNT5_HUMAN
• Pfam ID: PF01545
• Sequence:
  MEEKYGGDVLAGPGGGGGLGPVDVPSARLTKYIVLLCFTKFLKAVGLFESYDLLKAVHIV
  QFIFILKLGTAFFMVLFQKPFSSGKTITKHQWIKIFKHAVAGCIISLLWFFGLTLCGPLR
  TLLLFEHSDIVVISLLSVLFTSSGGGPAKTRGAAFFIIAVICLLLFDNDDLMAKMAEHPE
  GHHDSALTHMLYTAIAFLGVADHKGGVLLLVLALCCKVGFHTASRKLSVDVGGAKRLQAL
  SHLVSVLLLCPWVIVLSVTTESKVESWFSLIMPFATVIFFVMILDFYVDSICSVKMEVSK
  CARYGSFPIFISALLFGNFWTHPITDQLRAMNKAAHQESTEHVLSGGVVVSAIFFILSAN
  ILSSPSKRGQKGTLIGYSPEGTPLYNFMGDAFQHSSQSIPRFIKESLKQILEESDSRQIF
  YFLCLNLLFTFVELFYGVLTNSLGLISDGFHMLFDCSALVMGLFAALMSRWKATRIFSYG
  YGRIEILSGFINGLFLIVIAFFVFMESVARLIDPPELDTHMLTPVSVGGLIVNLIGICAF
  SHAHSHAHGASQGSCHSSDHSHSHHMHGHSDHGHGHSHGSAGGGMNANMRGVFLHVLADT
  LGSIGVIVSTVLIEQFGWFIADPLCSLFIAILIFLSVVPLIKDACQVLLLRLPPEYEKEL
  HIALEKIQKIEGLISYRDPHFWRHSASIVAGTIHIQVTSDVLEQRIVQQVTGILKDAGVN
  NLTIQVEKEAYFQHMSGLSTGFHDVLAMTKQMESMKYCKDGTYIM
• Function: Together with SLC30A6 forms a functional proton-coupled zinc ion antiporter mediating zinc entry into the lumen of organelles along the secretory pathway. By contributing to zinc ion homeostasis within the early secretory pathway, regulates the activation and folding of enzymes like alkaline phosphatases and enzymes involved in phosphatidylinositol glycan anchor biosynthesis. Through the transport of zinc into secretory granules of pancreatic beta-cells, plays an important role in the storage and secretion of insulin ; [Isoform 2]: Zinc ion:proton antiporter mediating influx and efflux of zinc at the plasma membrane.
• Tissue Specificity: Ubiquitously expressed . Highly expressed in pancreas, liver and kidney . Expressed abundantly in insulin-containing beta cells, undetectable in other endocrine cell types including glucagon-secreting alpha cells and most acinar cells (at protein level) .
• Reactome Pathway:
  Zinc efflux and compartmentalization by the SLC30 family (R-HSA-435368)
  Insulin processing (R-HSA-264876)

Molecular Interaction Atlas (MIA) of This DOT

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 Proton-coupled zinc antiporter SLC30A5 (SLC30A5).	[1]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Proton-coupled zinc antiporter SLC30A5 (SLC30A5).	[5]

8 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 Proton-coupled zinc antiporter SLC30A5 (SLC30A5).	[2]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Proton-coupled zinc antiporter SLC30A5 (SLC30A5).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Proton-coupled zinc antiporter SLC30A5 (SLC30A5).	[4]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Proton-coupled zinc antiporter SLC30A5 (SLC30A5).	[6]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Proton-coupled zinc antiporter SLC30A5 (SLC30A5).	[7]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Proton-coupled zinc antiporter SLC30A5 (SLC30A5).	[8]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Proton-coupled zinc antiporter SLC30A5 (SLC30A5).	[9]
AHPN	DM8G6O4	Investigative	AHPN decreases the expression of Proton-coupled zinc antiporter SLC30A5 (SLC30A5).	[10]

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] 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.
• [3] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [4] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [5] 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.
• [6] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [7] Cellular zinc homeostasis is a regulator in monocyte differentiation of HL-60 cells by 1 alpha,25-dihydroxyvitamin D3. J Leukoc Biol. 2010 May;87(5):833-44. doi: 10.1189/jlb.0409241. Epub 2010 Jan 20.
• [8] 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.
• [9] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [10] ST1926, a novel and orally active retinoid-related molecule inducing apoptosis in myeloid leukemia cells: modulation of intracellular calcium homeostasis. Blood. 2004 Jan 1;103(1):194-207.