Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTP9A2BQ)

• DOT Name: Persulfide dioxygenase ETHE1, mitochondrial (ETHE1)
• Synonyms: EC 1.13.11.18; Ethylmalonic encephalopathy protein 1; Hepatoma subtracted clone one protein; Sulfur dioxygenase ETHE1
• Gene Name: ETHE1
• Related Disease:
  Ethylmalonic encephalopathy
  Leigh syndrome
  Colorectal carcinoma
  Cytochrome-c oxidase deficiency disease
  Gastric cancer
  Hepatocellular carcinoma
  Metabolic disorder
  Stomach cancer
  Lung cancer
  Lung carcinoma
• UniProt ID: ETHE1_HUMAN
• PDB ID: 4CHL
• EC Number: 1.13.11.18
• Pfam ID: PF00753
• Sequence:
  MAEAVLRVARRQLSQRGGSGAPILLRQMFEPVSCTFTYLLGDRESREAVLIDPVLETAPR
  DAQLIKELGLRLLYAVNTHCHADHITGSGLLRSLLPGCQSVISRLSGAQADLHIEDGDSI
  RFGRFALETRASPGHTPGCVTFVLNDHSMAFTGDALLIRGCGRTDFQQGCAKTLYHSVHE
  KIFTLPGDCLIYPAHDYHGFTVSTVEEERTLNPRLTLSCEEFVKIMGNLNLPKPQQIDFA
  VPANMRCGVQTPTA
• Function: Sulfur dioxygenase that plays an essential role in hydrogen sulfide catabolism in the mitochondrial matrix. Hydrogen sulfide (H(2)S) is first oxidized by SQRDL, giving rise to cysteine persulfide residues. ETHE1 consumes molecular oxygen to catalyze the oxidation of the persulfide, once it has been transferred to a thiophilic acceptor, such as glutathione (R-SSH). Plays an important role in metabolic homeostasis in mitochondria by metabolizing hydrogen sulfide and preventing the accumulation of supraphysiological H(2)S levels that have toxic effects, due to the inhibition of cytochrome c oxidase. First described as a protein that can shuttle between the nucleus and the cytoplasm and suppress p53-induced apoptosis by sequestering the transcription factor RELA/NFKB3 in the cytoplasm and preventing its accumulation in the nucleus.
• Tissue Specificity: Ubiquitously expressed.
• KEGG Pathway:
  Sulfur metabolism (hsa00920)
  Metabolic pathways (hsa01100)
• Reactome Pathway: Sulfide oxidation to sulfate (R-HSA-1614517)
• BioCyc Pathway: MetaCyc:ENSG00000105755-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Ethylmalonic encephalopathy	DISH7SB9	Definitive	Autosomal recessive	[1]
Leigh syndrome	DISWQU45	Definitive	Autosomal recessive	[2]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[3]
Cytochrome-c oxidase deficiency disease	DISK7N3G	Strong	Biomarker	[4]
Gastric cancer	DISXGOUK	Strong	Altered Expression	[5]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[1]
Metabolic disorder	DIS71G5H	Strong	Biomarker	[6]
Stomach cancer	DISKIJSX	Strong	Altered Expression	[5]
Lung cancer	DISCM4YA	Limited	Biomarker	[7]
Lung carcinoma	DISTR26C	Limited	Biomarker	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Persulfide dioxygenase ETHE1, mitochondrial (ETHE1).	[8]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Persulfide dioxygenase ETHE1, mitochondrial (ETHE1).	[9]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Persulfide dioxygenase ETHE1, mitochondrial (ETHE1).	[10]
Acetaminophen	DMUIE76	Approved	Acetaminophen affects the expression of Persulfide dioxygenase ETHE1, mitochondrial (ETHE1).	[11]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Persulfide dioxygenase ETHE1, mitochondrial (ETHE1).	[12]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Persulfide dioxygenase ETHE1, mitochondrial (ETHE1).	[13]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Persulfide dioxygenase ETHE1, mitochondrial (ETHE1).	[14]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Persulfide dioxygenase ETHE1, mitochondrial (ETHE1).	[15]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Persulfide dioxygenase ETHE1, mitochondrial (ETHE1).	[16]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Persulfide dioxygenase ETHE1, mitochondrial (ETHE1).	[17]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Persulfide dioxygenase ETHE1, mitochondrial (ETHE1).	[18]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Persulfide dioxygenase ETHE1, mitochondrial (ETHE1).	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Persulfide dioxygenase ETHE1, mitochondrial (ETHE1).	[19]

References

• [1] Ethylmalonic encephalopathy is caused by mutations in ETHE1, a gene encoding a mitochondrial matrix protein. Am J Hum Genet. 2004 Feb;74(2):239-52. doi: 10.1086/381653. Epub 2004 Jan 19.
• [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] ETHE1 overexpression promotes SIRT1 and PGC1 mediated aerobic glycolysis, oxidative phosphorylation, mitochondrial biogenesis and colorectal cancer.Oncotarget. 2019 Jun 18;10(40):4004-4017. doi: 10.18632/oncotarget.26958. eCollection 2019 Jun 18.
• [4] Chronic exposure to sulfide causes accelerated degradation of cytochrome c oxidase in ethylmalonic encephalopathy.Antioxid Redox Signal. 2011 Jul 15;15(2):353-62. doi: 10.1089/ars.2010.3520. Epub 2011 Feb 25.
• [5] Search for new biomarkers of gastric cancer through serial analysis of gene expression and its clinical implications. Cancer Sci. 2004 May;95(5):385-92.
• [6] Deficiency of the mitochondrial sulfide regulator ETHE1 disturbs cell growth, glutathione level and causes proteome alterations outside mitochondria.Biochim Biophys Acta Mol Basis Dis. 2019 Jan;1865(1):126-135. doi: 10.1016/j.bbadis.2018.10.035. Epub 2018 Nov 2.
• [7] Identification of Serological Biomarkers for Early Diagnosis of Lung Cancer Using a Protein Array-Based Approach.Mol Cell Proteomics. 2017 Dec;16(12):2069-2078. doi: 10.1074/mcp.RA117.000212. Epub 2017 Oct 11.
• [8] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [9] 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.
• [10] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [11] Increased mitochondrial ROS formation by acetaminophen in human hepatic cells is associated with gene expression changes suggesting disruption of the mitochondrial electron transport chain. Toxicol Lett. 2015 Apr 16;234(2):139-50.
• [12] 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.
• [13] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [14] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [15] 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.
• [16] Gene expression profile induced by arsenic trioxide in chronic lymphocytic leukemia cells reveals a central role for heme oxygenase-1 in apoptosis and regulation of matrix metalloproteinase-9. Oncotarget. 2016 Dec 13;7(50):83359-83377.
• [17] 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.
• [18] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [19] 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.
• [20] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.