Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT5MS8EM)

• DOT Name: Peroxisomal trans-2-enoyl-CoA reductase (PECR)
• Synonyms: TERP; EC 1.3.1.38; 2,4-dienoyl-CoA reductase-related protein; DCR-RP; HPDHase; Short chain dehydrogenase/reductase family 29C member 1; pVI-ARL
• Gene Name: PECR
• Related Disease:
  Alcohol dependence
  Intellectual disability
  Alcohol-induced disorders
  Alcohol-related disorders
• UniProt ID: PECR_HUMAN
• PDB ID: 1YXM
• EC Number: 1.3.1.38
• Pfam ID: PF13561
• Sequence:
  MASWAKGRSYLAPGLLQGQVAIVTGGATGIGKAIVKELLELGSNVVIASRKLERLKSAAD
  ELQANLPPTKQARVIPIQCNIRNEEEVNNLVKSTLDTFGKINFLVNNGGGQFLSPAEHIS
  SKGWHAVLETNLTGTFYMCKAVYSSWMKEHGGSIVNIIVPTKAGFPLAVHSGAARAGVYN
  LTKSLALEWACSGIRINCVAPGVIYSQTAVENYGSWGQSFFEGSFQKIPAKRIGVPEEVS
  SVVCFLLSPAASFITGQSVDVDGGRSLYTHSYEVPDHDNWPKGAGDLSVVKKMKETFKEK
  AKL
• Function: Participates in chain elongation of fatty acids. Catalyzes the reduction of trans-2-enoyl-CoAs of varying chain lengths from 6:1 to 16:1, having maximum activity with 10:1 CoA. Has no 2,4-dienoyl-CoA reductase activity.
• KEGG Pathway: Peroxisome (hsa04146)
• Reactome Pathway:
  Peroxisomal protein import (R-HSA-9033241)
  Alpha-oxidation of phytanate (R-HSA-389599)
• BioCyc Pathway: MetaCyc:HS03889-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alcohol dependence	DIS4ZSCO	Strong	Biomarker	[1]
Intellectual disability	DISMBNXP	Strong	Biomarker	[2]
Alcohol-induced disorders	DIS3SFYT	moderate	Genetic Variation	[3]
Alcohol-related disorders	DIS3K4KK	moderate	Genetic Variation	[3]

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 Peroxisomal trans-2-enoyl-CoA reductase (PECR).	[4]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Peroxisomal trans-2-enoyl-CoA reductase (PECR).	[5]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Peroxisomal trans-2-enoyl-CoA reductase (PECR).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Peroxisomal trans-2-enoyl-CoA reductase (PECR).	[7]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Peroxisomal trans-2-enoyl-CoA reductase (PECR).	[8]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Peroxisomal trans-2-enoyl-CoA reductase (PECR).	[9]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Peroxisomal trans-2-enoyl-CoA reductase (PECR).	[10]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Peroxisomal trans-2-enoyl-CoA reductase (PECR).	[11]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Peroxisomal trans-2-enoyl-CoA reductase (PECR).	[12]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Peroxisomal trans-2-enoyl-CoA reductase (PECR).	[13]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Peroxisomal trans-2-enoyl-CoA reductase (PECR).	[14]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Peroxisomal trans-2-enoyl-CoA reductase (PECR).	[15]
Bicalutamide	DMZMSPF	Approved	Bicalutamide increases the expression of Peroxisomal trans-2-enoyl-CoA reductase (PECR).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Peroxisomal trans-2-enoyl-CoA reductase (PECR).	[5]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Peroxisomal trans-2-enoyl-CoA reductase (PECR).	[17]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of Peroxisomal trans-2-enoyl-CoA reductase (PECR).	[20]
Oleic acid	DM54O1Z	Investigative	Oleic acid decreases the expression of Peroxisomal trans-2-enoyl-CoA reductase (PECR).	[21]

2 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 Peroxisomal trans-2-enoyl-CoA reductase (PECR).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Peroxisomal trans-2-enoyl-CoA reductase (PECR).	[19]

References

• [1] Genome-wide association discoveries of alcohol dependence.Am J Addict. 2014 Nov-Dec;23(6):526-39. doi: 10.1111/j.1521-0391.2014.12147.x.
• [2] Deep sequencing reveals 50 novel genes for recessive cognitive disorders. Nature. 2011 Sep 21;478(7367):57-63. doi: 10.1038/nature10423.
• [3] Genome-wide association study of alcohol dependence.Arch Gen Psychiatry. 2009 Jul;66(7):773-84. doi: 10.1001/archgenpsychiatry.2009.83.
• [4] Stem cell transcriptome responses and corresponding biomarkers that indicate the transition from adaptive responses to cytotoxicity. Chem Res Toxicol. 2017 Apr 17;30(4):905-922.
• [5] 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.
• [6] 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.
• [7] 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.
• [8] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [9] Characterisation of cisplatin-induced transcriptomics responses in primary mouse hepatocytes, HepG2 cells and mouse embryonic stem cells shows conservation of regulating transcription factor networks. Mutagenesis. 2014 Jan;29(1):17-26.
• [10] 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.
• [11] 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.
• [12] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [13] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [14] The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
• [15] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [16] Microarray analysis of bicalutamide action on telomerase activity, p53 pathway and viability of prostate carcinoma cell lines. J Pharm Pharmacol. 2005 Jan;57(1):83-92.
• [17] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [18] 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.
• [19] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [20] Ochratoxin a lowers mRNA levels of genes encoding for key proteins of liver cell metabolism. Cancer Genomics Proteomics. 2008 Nov-Dec;5(6):319-32.
• [21] Farnesol induces fatty acid oxidation and decreases triglyceride accumulation in steatotic HepaRG cells. Toxicol Appl Pharmacol. 2019 Feb 15;365:61-70.