Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT5DMKFX)

• DOT Name: Thiosulfate:glutathione sulfurtransferase (TSTD1)
• Synonyms: TST; EC 2.8.1.-
• Gene Name: TSTD1
• Related Disease:
  Acute myelogenous leukaemia
  Advanced cancer
  Carcinoma
  Colon cancer
  Colon carcinoma
  Schizophrenia
  Thyroid gland undifferentiated (anaplastic) carcinoma
• UniProt ID: TSTD1_HUMAN
• PDB ID: 6BEV
• EC Number: 2.8.1.-
• Pfam ID: PF00581
• Sequence:
  MAGAPTVSLPELRSLLASGRARLFDVRSREEAAAGTIPGALNIPVSELESALQMEPAAFQ
  ALYSAEKPKLEDEHLVFFCQMGKRGLQATQLARSLGYTGARNYAGAYREWLEKES
• Function: Thiosulfate:glutathione sulfurtransferase (TST) required to produce S-sulfanylglutathione (GSS(-)), a central intermediate in hydrogen sulfide metabolism. Provides the link between the first step in mammalian H(2)S metabolism performed by the sulfide:quinone oxidoreductase (SQOR) which catalyzes the conversion of H(2)S to thiosulfate, and the sulfur dioxygenase (SDO) which uses GSS(-) as substrate. The thermodynamic coupling of the irreversible SDO and reversible TST reactions provides a model for the physiologically relevant reaction with thiosulfate as the sulfane donor.
• Tissue Specificity: Highly expressed in kidney, liver and skeletal muscle. Lower levels of expression in heart, colon, thymus, spleen, placenta and lung. Weakly expressed in brain, small intestine and peripheral blood leukocytes. Expressed at high levels in the breast carcinoma cell lines MCF-7 and MDA-MB-468 and at a lower level in the breast carcinoma cell line MDA-MB-231, the colon carcinoma call line LoVo and the lung carcinoma cell line A-549. No expression in the cell lines EFO-27 and HeLa, or the normal breast tissue cell lines MCF-10A and H184A1. Detected in invasive ductal carcinoma, but not in the adjacent tissues.
• Reactome Pathway: Sulfide oxidation to sulfate (R-HSA-1614517)
• BioCyc Pathway: MetaCyc:MONOMER-20304

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute myelogenous leukaemia	DISCSPTN	Strong	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Carcinoma	DISH9F1N	Strong	Genetic Variation	[3]
Colon cancer	DISVC52G	Strong	Biomarker	[4]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[4]
Schizophrenia	DISSRV2N	Strong	Altered Expression	[5]
Thyroid gland undifferentiated (anaplastic) carcinoma	DISYBB1W	Strong	Genetic Variation	[6]

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 Thiosulfate:glutathione sulfurtransferase (TSTD1).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Thiosulfate:glutathione sulfurtransferase (TSTD1).	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Thiosulfate:glutathione sulfurtransferase (TSTD1).	[8]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Thiosulfate:glutathione sulfurtransferase (TSTD1).	[9]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Thiosulfate:glutathione sulfurtransferase (TSTD1).	[10]
Berberine	DMC5Q8X	Phase 4	Berberine increases the expression of Thiosulfate:glutathione sulfurtransferase (TSTD1).	[11]

References

• [1] Panobinostat for the treatment of acute myelogenous leukemia.Expert Opin Investig Drugs. 2016 Sep;25(9):1117-31. doi: 10.1080/13543784.2016.1216971. Epub 2016 Aug 8.
• [2] Targeting cancer using KAT inhibitors to mimic lethal knockouts.Biochem Soc Trans. 2016 Aug 15;44(4):979-86. doi: 10.1042/BST20160081.
• [3] Somatostatin receptor subtype expression in human thyroid and thyroid carcinoma cell lines.J Clin Endocrinol Metab. 1997 Jun;82(6):1857-62. doi: 10.1210/jcem.82.6.4013.
• [4] KAT3B-p300 and H3AcK18/H3AcK14 levels are prognostic markers for kidney ccRCC tumor aggressiveness and target of KAT inhibitor CPTH2.Clin Epigenetics. 2018 Apr 4;10:44. doi: 10.1186/s13148-018-0473-4. eCollection 2018.
• [5] Dysregulation of kynurenine metabolism is related to proinflammatory cytokines, attention, and prefrontal cortex volume in schizophrenia.Mol Psychiatry. 2020 Nov;25(11):2860-2872. doi: 10.1038/s41380-019-0401-9. Epub 2019 Apr 3.
• [6] Mutant p53 (G199V) gains antiapoptotic function through signal transducer and activator of transcription 3 in anaplastic thyroid cancer cells.Mol Cancer Res. 2009 Oct;7(10):1645-54. doi: 10.1158/1541-7786.MCR-09-0117. Epub 2009 Oct 13.
• [7] 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.
• [8] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [9] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [10] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [11] Berberine acts as a putative epigenetic modulator by affecting the histone code. Toxicol In Vitro. 2016 Oct;36:10-17. doi: 10.1016/j.tiv.2016.06.004. Epub 2016 Jun 13.
• [12] 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.