Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT2TP4IX)

• DOT Name: Enoyl-CoA delta isomerase 2 (ECI2)
• Synonyms: EC 5.3.3.8; DRS-1; Delta(3),delta(2)-enoyl-CoA isomerase; D3,D2-enoyl-CoA isomerase; Diazepam-binding inhibitor-related protein 1; DBI-related protein 1; Dodecenoyl-CoA isomerase; Hepatocellular carcinoma-associated antigen 88; Peroxisomal 3,2-trans-enoyl-CoA isomerase; pECI; Renal carcinoma antigen NY-REN-1
• Gene Name: ECI2
• Related Disease:
  Acquired aplastic anemia
  Aplastic anemia
  Myelodysplastic syndrome
  Paroxysmal nocturnal haemoglobinuria
  Prostate cancer
  Prostate carcinoma
• UniProt ID: ECI2_HUMAN
• PDB ID: 2CQU; 2F6Q; 4U18; 4U19; 4U1A
• EC Number: 5.3.3.8
• Pfam ID: PF00887 ; PF00378
• Sequence:
  MAMAYLAWRLARRSCPSSLQVTSFPVVQLHMNRTAMRASQKDFENSMNQVKLLKKDPGNE
  VKLKLYALYKQATEGPCNMPKPGVFDLINKAKWDAWNALGSLPKEAARQNYVDLVSSLSP
  SLESSSQVEPGTDRKSTGFETLVVTSEDGITKIMFNRPKKKNAINTEMYHEIMRALKAAS
  KDDSIITVLTGNGDYYSSGNDLTNFTDIPPGGVEEKAKNNAVLLREFVGCFIDFPKPLIA
  VVNGPAVGISVTLLGLFDAVYASDRATFHTPFSHLGQSPEGCSSYTFPKIMSPAKATEML
  IFGKKLTAGEACAQGLVTEVFPDSTFQKEVWTRLKAFAKLPPNALRISKEVIRKREREKL
  HAVNAEECNVLQGRWLSDECTNAVVNFLSRKSKL
• Function: Able to isomerize both 3-cis and 3-trans double bonds into the 2-trans form in a range of enoyl-CoA species. Has a preference for 3-trans substrates.
• Tissue Specificity: Abundant in heart, skeletal muscle and liver. Expressed in CD34(+) T-cells and CD34(+) bone marrow cells.
• KEGG Pathway:
  Fatty acid degradation (hsa00071)
  Peroxisome (hsa04146)
• BioCyc Pathway: MetaCyc:HS03615-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acquired aplastic anemia	DISCMKMX	Strong	Biomarker	[1]
Aplastic anemia	DISJRSC0	Strong	Biomarker	[1]
Myelodysplastic syndrome	DISYHNUI	Strong	Biomarker	[1]
Paroxysmal nocturnal haemoglobinuria	DISBHMYH	Strong	Biomarker	[1]
Prostate cancer	DISF190Y	Strong	Altered Expression	[2]
Prostate carcinoma	DISMJPLE	Strong	Altered Expression	[2]

17 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 Enoyl-CoA delta isomerase 2 (ECI2).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Enoyl-CoA delta isomerase 2 (ECI2).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Enoyl-CoA delta isomerase 2 (ECI2).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Enoyl-CoA delta isomerase 2 (ECI2).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin affects the expression of Enoyl-CoA delta isomerase 2 (ECI2).	[7]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Enoyl-CoA delta isomerase 2 (ECI2).	[8]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Enoyl-CoA delta isomerase 2 (ECI2).	[9]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of Enoyl-CoA delta isomerase 2 (ECI2).	[10]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Enoyl-CoA delta isomerase 2 (ECI2).	[11]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Enoyl-CoA delta isomerase 2 (ECI2).	[12]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Enoyl-CoA delta isomerase 2 (ECI2).	[13]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Enoyl-CoA delta isomerase 2 (ECI2).	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Enoyl-CoA delta isomerase 2 (ECI2).	[15]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Enoyl-CoA delta isomerase 2 (ECI2).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Enoyl-CoA delta isomerase 2 (ECI2).	[18]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Enoyl-CoA delta isomerase 2 (ECI2).	[19]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Enoyl-CoA delta isomerase 2 (ECI2).	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Enoyl-CoA delta isomerase 2 (ECI2).	[17]

References

• [1] Diazepam-binding inhibitor-related protein 1: a candidate autoantigen in acquired aplastic anemia patients harboring a minor population of paroxysmal nocturnal hemoglobinuria-type cells.Blood. 2004 Oct 15;104(8):2425-31. doi: 10.1182/blood-2004-05-1839. Epub 2004 Jun 24.
• [2] HNF1B expression regulates ECI2 gene expression, potentially serving a role in prostate cancer progression.Oncol Lett. 2019 Jan;17(1):1094-1100. doi: 10.3892/ol.2018.9677. Epub 2018 Nov 8.
• [3] The neuroprotective action of the mood stabilizing drugs lithium chloride and sodium valproate is mediated through the up-regulation of the homeodomain protein Six1. Toxicol Appl Pharmacol. 2009 Feb 15;235(1):124-34.
• [4] 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.
• [5] Benzodithiophenes potentiate differentiation of acute promyelocytic leukemia cells by lowering the threshold for ligand-mediated corepressor/coactivator exchange with retinoic acid receptor alpha and enhancing changes in all-trans-retinoic acid-regulated gene expression. Cancer Res. 2005 Sep 1;65(17):7856-65. doi: 10.1158/0008-5472.CAN-05-1056.
• [6] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [7] 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.
• [8] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [9] 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.
• [10] Identification of novel low-dose bisphenol a targets in human foreskin fibroblast cells derived from hypospadias patients. PLoS One. 2012;7(5):e36711. doi: 10.1371/journal.pone.0036711. Epub 2012 May 4.
• [11] 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.
• [12] 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.
• [13] 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.
• [14] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [15] Label-free quantitative proteomic analysis identifies the oncogenic role of FOXA1 in BaP-transformed 16HBE cells. Toxicol Appl Pharmacol. 2020 Sep 15;403:115160. doi: 10.1016/j.taap.2020.115160. Epub 2020 Jul 25.
• [16] 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.
• [17] 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.
• [18] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [19] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [20] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.