Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT8JFXUQ)

• DOT Name: Isovaleryl-CoA dehydrogenase, mitochondrial (IVD)
• Synonyms: IVD; EC 1.3.8.4; Butyryl-CoA dehydrogenase; EC 1.3.8.1
• Gene Name: IVD
• Related Disease:
  Isovaleric acidemia
  Metabolic disorder
  Advanced cancer
  Arteriosclerosis
  Atherosclerosis
  Giardiasis
  Intervertebral disc degeneration
  Myocardial infarction
  Pulmonary fibrosis
  Vaginitis
  Bacterial vaginosis
  Colorectal carcinoma
• UniProt ID: IVD_HUMAN
• PDB ID: 1IVH
• EC Number: 1.3.8.1; 1.3.8.4
• Pfam ID: PF00441 ; PF02770 ; PF02771
• Sequence:
  MAEMATATRLLGWRVASWRLRPPLAGFVSQRAHSLLPVDDAINGLSEEQRQLRQTMAKFL
  QEHLAPKAQEIDRSNEFKNLREFWKQLGNLGVLGITAPVQYGGSGLGYLEHVLVMEEISR
  ASGAVGLSYGAHSNLCINQLVRNGNEAQKEKYLPKLISGEYIGALAMSEPNAGSDVVSMK
  LKAEKKGNHYILNGNKFWITNGPDADVLIVYAKTDLAAVPASRGITAFIVEKGMPGFSTS
  KKLDKLGMRGSNTCELIFEDCKIPAANILGHENKGVYVLMSGLDLERLVLAGGPLGLMQA
  VLDHTIPYLHVREAFGQKIGHFQLMQGKMADMYTRLMACRQYVYNVAKACDEGHCTAKDC
  AGVILYSAECATQVALDGIQCFGGNGYINDFPMGRFLRDAKLYEIGAGTSEVRRLVIGRA
  FNADFH
• Function: Catalyzes the conversion of isovaleryl-CoA/3-methylbutanoyl-CoA to 3-methylbut-2-enoyl-CoA as an intermediate step in the leucine (Leu) catabolic pathway. To a lesser extent, is also able to catalyze the oxidation of other saturated short-chain acyl-CoA thioesters as pentanoyl-CoA, hexenoyl-CoA and butenoyl-CoA.
• KEGG Pathway:
  Valine, leucine and isoleucine degradation (hsa00280)
  Metabolic pathways (hsa01100)
• Reactome Pathway: Branched-chain amino acid catabolism (R-HSA-70895)

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Isovaleric acidemia	DIS3ETX9	Definitive	Autosomal recessive	[1]
Metabolic disorder	DIS71G5H	Definitive	Genetic Variation	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[4]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[4]
Giardiasis	DISWUNWK	Strong	Biomarker	[5]
Intervertebral disc degeneration	DISG3AIM	Strong	Biomarker	[6]
Myocardial infarction	DIS655KI	Strong	Genetic Variation	[7]
Pulmonary fibrosis	DISQKVLA	Strong	Genetic Variation	[8]
Vaginitis	DISCYOMR	Strong	Biomarker	[9]
Bacterial vaginosis	DISK2MZ2	Limited	Genetic Variation	[10]
Colorectal carcinoma	DIS5PYL0	Limited	Biomarker	[11]

2 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 Isovaleryl-CoA dehydrogenase, mitochondrial (IVD).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Isovaleryl-CoA dehydrogenase, mitochondrial (IVD).	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Isovaleryl-CoA dehydrogenase, mitochondrial (IVD).	[13]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Isovaleryl-CoA dehydrogenase, mitochondrial (IVD).	[14]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Isovaleryl-CoA dehydrogenase, mitochondrial (IVD).	[15]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Isovaleryl-CoA dehydrogenase, mitochondrial (IVD).	[16]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Isovaleryl-CoA dehydrogenase, mitochondrial (IVD).	[17]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Isovaleryl-CoA dehydrogenase, mitochondrial (IVD).	[18]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Isovaleryl-CoA dehydrogenase, mitochondrial (IVD).	[20]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Isovaleryl-CoA dehydrogenase, mitochondrial (IVD).	[21]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Isovaleryl-CoA dehydrogenase, mitochondrial (IVD).	[22]

References

• [1] 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.
• [2] Two novel isovaleryl-CoA dehydrogenase gene mutations in a Chinese infant.Gene. 2013 Jul 25;524(2):396-400. doi: 10.1016/j.gene.2013.03.139. Epub 2013 Apr 12.
• [3] Epigenetic IVD Tests for Personalized Precision Medicine in Cancer.Front Genet. 2019 Jun 28;10:621. doi: 10.3389/fgene.2019.00621. eCollection 2019.
• [4] APOE-knockout in rabbits causes loss of cells in nucleus pulposus and enhances the levels of inflammatory catabolic cytokines damaging the intervertebral disc matrix.PLoS One. 2019 Nov 21;14(11):e0225527. doi: 10.1371/journal.pone.0225527. eCollection 2019.
• [5] Evaluation of a new multiplex PCR assay (ParaGENIE G-Amoeba Real-Time PCR kit) targeting Giardia intestinalis, Entamoeba histolytica and Entamoeba dispar/Entamoeba moshkovskii from stool specimens: evidence for the limited performances of microscopy-based approach for amoeba species identification.Clin Microbiol Infect. 2018 Nov;24(11):1205-1209. doi: 10.1016/j.cmi.2018.02.007. Epub 2018 Feb 15.
• [6] Diabetes mellitus as a risk factor for intervertebral disc degeneration: a critical review.Eur Spine J. 2019 Sep;28(9):2129-2144. doi: 10.1007/s00586-019-06029-7. Epub 2019 Jun 14.
• [7] Association of a polymorphism of BTN2A1 with myocardial infarction in East Asian populations.Atherosclerosis. 2011 Mar;215(1):145-52. doi: 10.1016/j.atherosclerosis.2010.12.005. Epub 2010 Dec 15.
• [8] The MUC5B promoter polymorphism is associated with idiopathic pulmonary fibrosis in a Mexican cohort but is rare among Asian ancestries.Chest. 2015 Feb;147(2):460-464. doi: 10.1378/chest.14-0867.
• [9] Clinical Validation of the Aptima Bacterial Vaginosis and Aptima Candida/Trichomonas Vaginitis Assays: Results from a Prospective Multicenter Clinical Study.J Clin Microbiol. 2020 Jan 28;58(2):e01643-19. doi: 10.1128/JCM.01643-19. Print 2020 Jan 28.
• [10] Increased richness and diversity of the vaginal microbiota and spontaneous preterm birth.Microbiome. 2018 Jun 28;6(1):117. doi: 10.1186/s40168-018-0502-8.
• [11] KRAS analysis in colorectal carcinoma: analytical aspects of Pyrosequencing and allele-specific PCR in clinical practice.BMC Cancer. 2010 Dec 1;10:660. doi: 10.1186/1471-2407-10-660.
• [12] Integrated 'omics analysis reveals new drug-induced mitochondrial perturbations in human hepatocytes. Toxicol Lett. 2018 Jun 1;289:1-13.
• [13] 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.
• [14] 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.
• [15] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [16] 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.
• [17] Minimal peroxide exposure of neuronal cells induces multifaceted adaptive responses. PLoS One. 2010 Dec 17;5(12):e14352. doi: 10.1371/journal.pone.0014352.
• [18] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [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] 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.
• [21] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.
• [22] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.