Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTU2VHWR)

• DOT Name: 3-hydroxyisobutyryl-CoA hydrolase, mitochondrial (HIBCH)
• Synonyms: EC 3.1.2.4; 3-hydroxyisobutyryl-coenzyme A hydrolase; HIB-CoA hydrolase; HIBYL-CoA-H
• Gene Name: HIBCH
• Related Disease:
  3-hydroxyisobutyryl-CoA hydrolase deficiency
  Leigh syndrome
  Colorectal carcinoma
  Dystonia
  Inborn error of metabolism
  Neoplasm
  Osteoarthritis
• UniProt ID: HIBCH_HUMAN
• PDB ID: 3BPT
• EC Number: 3.1.2.4
• Pfam ID: PF16113
• Sequence:
  MGQREMWRLMSRFNAFKRTNTILHHLRMSKHTDAAEEVLLEKKGCTGVITLNRPKFLNAL
  TLNMIRQIYPQLKKWEQDPETFLIIIKGAGGKAFCAGGDIRVISEAEKAKQKIAPVFFRE
  EYMLNNAVGSCQKPYVALIHGITMGGGVGLSVHGQFRVATEKCLFAMPETAIGLFPDVGG
  GYFLPRLQGKLGYFLALTGFRLKGRDVYRAGIATHFVDSEKLAMLEEDLLALKSPSKENI
  ASVLENYHTESKIDRDKSFILEEHMDKINSCFSANTVEEIIENLQQDGSSFALEQLKVIN
  KMSPTSLKITLRQLMEGSSKTLQEVLTMEYRLSQACMRGHDFHEGVRAVLIDKDQSPKWK
  PADLKEVTEEDLNNHFKSLGSSDLKF
• Function: Hydrolyzes 3-hydroxyisobutyryl-CoA (HIBYL-CoA), a saline catabolite. Has high activity toward isobutyryl-CoA. Could be an isobutyryl-CoA dehydrogenase that functions in valine catabolism. Also hydrolyzes 3-hydroxypropanoyl-CoA.
• Tissue Specificity: Highly expressed in liver and kidney, also detected in heart, muscle and brain (at protein level). Not detected in lung.
• KEGG Pathway:
  Valine, leucine and isoleucine degradation (hsa00280)
  beta-Alanine metabolism (hsa00410)
  Propanoate metabolism (hsa00640)
  Metabolic pathways (hsa01100)
  Carbon metabolism (hsa01200)
• Reactome Pathway: Branched-chain amino acid catabolism (R-HSA-70895)

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
3-hydroxyisobutyryl-CoA hydrolase deficiency	DISB4WD7	Definitive	Autosomal recessive	[1]
Leigh syndrome	DISWQU45	Definitive	Autosomal recessive	[1]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[2]
Dystonia	DISJLFGW	Strong	Genetic Variation	[3]
Inborn error of metabolism	DISO5FAY	Strong	Genetic Variation	[4]
Neoplasm	DISZKGEW	Strong	Altered Expression	[5]
Osteoarthritis	DIS05URM	Limited	Biomarker	[6]

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 3-hydroxyisobutyryl-CoA hydrolase, mitochondrial (HIBCH).	[7]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of 3-hydroxyisobutyryl-CoA hydrolase, mitochondrial (HIBCH).	[8]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of 3-hydroxyisobutyryl-CoA hydrolase, mitochondrial (HIBCH).	[9]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of 3-hydroxyisobutyryl-CoA hydrolase, mitochondrial (HIBCH).	[10]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of 3-hydroxyisobutyryl-CoA hydrolase, mitochondrial (HIBCH).	[11]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of 3-hydroxyisobutyryl-CoA hydrolase, mitochondrial (HIBCH).	[12]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of 3-hydroxyisobutyryl-CoA hydrolase, mitochondrial (HIBCH).	[13]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of 3-hydroxyisobutyryl-CoA hydrolase, mitochondrial (HIBCH).	[14]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of 3-hydroxyisobutyryl-CoA hydrolase, mitochondrial (HIBCH).	[15]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of 3-hydroxyisobutyryl-CoA hydrolase, mitochondrial (HIBCH).	[14]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of 3-hydroxyisobutyryl-CoA hydrolase, mitochondrial (HIBCH).	[16]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of 3-hydroxyisobutyryl-CoA hydrolase, mitochondrial (HIBCH).	[17]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of 3-hydroxyisobutyryl-CoA hydrolase, mitochondrial (HIBCH).	[18]
Isoflavone	DM7U58J	Phase 4	Isoflavone increases the expression of 3-hydroxyisobutyryl-CoA hydrolase, mitochondrial (HIBCH).	[19]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of 3-hydroxyisobutyryl-CoA hydrolase, mitochondrial (HIBCH).	[21]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of 3-hydroxyisobutyryl-CoA hydrolase, mitochondrial (HIBCH).	[22]
KOJIC ACID	DMP84CS	Investigative	KOJIC ACID decreases the expression of 3-hydroxyisobutyryl-CoA hydrolase, mitochondrial (HIBCH).	[24]

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 decreases the methylation of 3-hydroxyisobutyryl-CoA hydrolase, mitochondrial (HIBCH).	[20]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
D-glucose	DMMG2TO	Investigative	D-glucose decreases the secretion of 3-hydroxyisobutyryl-CoA hydrolase, mitochondrial (HIBCH).	[23]

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] Targeting HIBCH to reprogram valine metabolism for the treatment of colorectal cancer.Cell Death Dis. 2019 Aug 13;10(8):618. doi: 10.1038/s41419-019-1832-6.
• [3] A therapeutic regimen for 3-hydroxyisobutyryl-CoA hydrolase deficiency with exercise-induced dystonia.Eur J Paediatr Neurol. 2019 Sep;23(5):755-759. doi: 10.1016/j.ejpn.2017.11.004. Epub 2017 Nov 23.
• [4] HIBCH deficiency in a patient with phenotypic characteristics of mitochondrial disorders.Am J Med Genet A. 2014 Dec;164A(12):3162-9. doi: 10.1002/ajmg.a.36766. Epub 2014 Sep 23.
• [5] Proteomic Analysis of the Breast Cancer Brain Metastasis Microenvironment.Int J Mol Sci. 2019 May 22;20(10):2524. doi: 10.3390/ijms20102524.
• [6] Mitochondrial dysregulation of osteoarthritic human articular chondrocytes analyzed by proteomics: a decrease in mitochondrial superoxide dismutase points to a redox imbalance.Mol Cell Proteomics. 2009 Jan;8(1):172-89. doi: 10.1074/mcp.M800292-MCP200. Epub 2008 Sep 9.
• [7] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [8] 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.
• [9] 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.
• [10] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [11] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [12] 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.
• [13] 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.
• [14] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [15] 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.
• [16] The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
• [17] 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.
• [18] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [19] Soy isoflavones exert differential effects on androgen responsive genes in LNCaP human prostate cancer cells. J Nutr. 2007 Apr;137(4):964-72.
• [20] 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.
• [21] 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.
• [22] 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.
• [23] Calorie restriction-induced changes in the secretome of human adipocytes, comparison with resveratrol-induced secretome effects. Biochim Biophys Acta. 2014 Sep;1844(9):1511-22. doi: 10.1016/j.bbapap.2014.04.023. Epub 2014 May 5.
• [24] Toxicogenomics of kojic acid on gene expression profiling of a375 human malignant melanoma cells. Biol Pharm Bull. 2006 Apr;29(4):655-69.