Details of Drug Off-Target (DOT)

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

• DOT Name: Selenide, water dikinase 2 (SEPHS2)
• Synonyms: EC 2.7.9.3; Selenium donor protein 2; Selenophosphate synthase 2
• Gene Name: SEPHS2
• Related Disease:
  Lung adenocarcinoma
  Breast cancer
  Breast carcinoma
  Triple negative breast cancer
• UniProt ID: SPS2_HUMAN
• EC Number: 2.7.9.3
• Pfam ID: PF00586 ; PF02769
• Sequence:
  MAEASATGACGEAMAAAEGSSGPAGLTLGRSFSNYRPFEPQALGLSPSWRLTGFSGMKGU
  GCKVPQEALLKLLAGLTRPDVRPPLGRGLVGGQEEASQEAGLPAGAGPSPTFPALGIGMD
  SCVIPLRHGGLSLVQTTDFFYPLVEDPYMMGRIACANVLSDLYAMGITECDNMLMLLSVS
  QSMSEEEREKVTPLMVKGFRDAAEEGGTAVTGGQTVVNPWIIIGGVATVVCQPNEFIMPD
  SAVVGDVLVLTKPLGTQVAVNAHQWLDNPERWNKVKMVVSREEVELAYQEAMFNMATLNR
  TAAGLMHTFNAHAATDITGFGILGHSQNLAKQQRNEVSFVIHNLPIIAKMAAVSKASGRF
  GLLQGTSAETSGGLLICLPREQAARFCSEIKSSKYGEGHQAWIVGIVEKGNRTARIIDKP
  RVIEVLPRGATAAVLAPDSSNASSEPSS
• Function: Synthesizes selenophosphate from selenide and ATP.
• KEGG Pathway:
  Selenocompound metabolism (hsa00450)
  Metabolic pathways (hsa01100)
• Reactome Pathway: Selenocysteine synthesis (R-HSA-2408557)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Lung adenocarcinoma	DISD51WR	Definitive	Biomarker	[1]
Breast cancer	DIS7DPX1	Strong	Biomarker	[2]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[2]
Triple negative breast cancer	DISAMG6N	Strong	Altered Expression	[2]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic trioxide	DM61TA4	Approved	Selenide, water dikinase 2 (SEPHS2) decreases the response to substance of Arsenic trioxide.	[15]
Fluorouracil	DMUM7HZ	Approved	Selenide, water dikinase 2 (SEPHS2) affects the response to substance of Fluorouracil.	[16]

3 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 Selenide, water dikinase 2 (SEPHS2).	[3]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Selenide, water dikinase 2 (SEPHS2).	[10]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Selenide, water dikinase 2 (SEPHS2).	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Selenide, water dikinase 2 (SEPHS2).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Selenide, water dikinase 2 (SEPHS2).	[5]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Selenide, water dikinase 2 (SEPHS2).	[6]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Selenide, water dikinase 2 (SEPHS2).	[7]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Selenide, water dikinase 2 (SEPHS2).	[6]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Selenide, water dikinase 2 (SEPHS2).	[8]
Phenol	DM1QSM3	Phase 2/3	Phenol decreases the expression of Selenide, water dikinase 2 (SEPHS2).	[9]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Selenide, water dikinase 2 (SEPHS2).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Selenide, water dikinase 2 (SEPHS2).	[13]
Deguelin	DMXT7WG	Investigative	Deguelin increases the expression of Selenide, water dikinase 2 (SEPHS2).	[14]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride decreases the expression of Selenide, water dikinase 2 (SEPHS2).	[9]

References

• [1] Selenophosphate synthetase genes from lung adenocarcinoma cells: Sps1 for recycling L-selenocysteine and Sps2 for selenite assimilation.Proc Natl Acad Sci U S A. 2004 Nov 16;101(46):16162-7. doi: 10.1073/pnas.0406313101. Epub 2004 Nov 8.
• [2] Structural analysis of human SEPHS2 protein, a selenocysteine machinery component, over-expressed in triple negative breast cancer.Sci Rep. 2019 Nov 6;9(1):16131. doi: 10.1038/s41598-019-52718-0.
• [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] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [5] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [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] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [8] Resveratrol modulates mRNA transcripts of genes related to redox metabolism and cell proliferation in non-small-cell lung carcinoma cells. Biol Chem. 2007 Feb;388(2):207-19.
• [9] Classification of heavy-metal toxicity by human DNA microarray analysis. Environ Sci Technol. 2007 May 15;41(10):3769-74.
• [10] 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.
• [11] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [12] 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.
• [13] 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.
• [14] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.
• [15] Functional Profiling Identifies Determinants of Arsenic Trioxide Cellular Toxicity. Toxicol Sci. 2019 May 1;169(1):108-121. doi: 10.1093/toxsci/kfz024.
• [16] 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.