Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTR89YF5)

• DOT Name: Isocitrate dehydrogenase subunit beta, mitochondrial (IDH3B)
• Synonyms: Isocitric dehydrogenase subunit beta; NAD(+)-specific ICDH subunit beta
• Gene Name: IDH3B
• Related Disease:
  Gastric cancer
  Gastric neoplasm
  Hereditary diffuse gastric adenocarcinoma
  Hidradenitis suppurativa
  Inherited retinal dystrophy
  Retinitis pigmentosa 46
  IDH3B-related retinopathy
  Retinitis pigmentosa
• UniProt ID: IDH3B_HUMAN
• PDB ID: 6KDE; 6KDF; 6KDY; 6KE3; 7CE3; 8GRB; 8GRD; 8GRU; 8GS5
• Pfam ID: PF00180
• Sequence:
  MAALSGVRWLTRALVSAGNPGAWRGLSTSAAAHAASRSQAEDVRVEGSFPVTMLPGDGVG
  PELMHAVKEVFKAAAVPVEFQEHHLSEVQNMASEEKLEQVLSSMKENKVAIIGKIHTPME
  YKGELASYDMRLRRKLDLFANVVHVKSLPGYMTRHNNLDLVIIREQTEGEYSSLEHESAR
  GVIECLKIVTRAKSQRIAKFAFDYATKKGRGKVTAVHKANIMKLGDGLFLQCCEEVAELY
  PKIKFETMIIDNCCMQLVQNPYQFDVLVMPNLYGNIIDNLAAGLVGGAGVVPGESYSAEY
  AVFETGARHPFAQAVGRNIANPTAMLLSASNMLRHLNLEYHSSMIADAVKKVIKVGKVRT
  RDMGGYSTTTDFIKSVIGHLQTKGS
• Function: Plays a structural role to facilitate the assembly and ensure the full activity of the enzyme catalyzing the decarboxylation of isocitrate (ICT) into alpha-ketoglutarate. The heterodimer composed of the alpha (IDH3A) and beta (IDH3B) subunits and the heterodimer composed of the alpha (IDH3A) and gamma (IDH3G) subunits, have considerable basal activity but the full activity of the heterotetramer (containing two subunits of IDH3A, one of IDH3B and one of IDH3G) requires the assembly and cooperative function of both heterodimers.
• KEGG Pathway:
  Citrate cycle (TCA cycle) (hsa00020)
  Metabolic pathways (hsa01100)
  Carbon metabolism (hsa01200)
  2-Oxocarboxylic acid metabolism (hsa01210)
  Biosynthesis of amino acids (hsa01230)
• Reactome Pathway: Citric acid cycle (TCA cycle) (R-HSA-71403)
• BioCyc Pathway: MetaCyc:ENSG00000101365-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Gastric cancer	DISXGOUK	Strong	Biomarker	[1]
Gastric neoplasm	DISOKN4Y	Strong	Biomarker	[1]
Hereditary diffuse gastric adenocarcinoma	DISUIBYS	Strong	Biomarker	[1]
Hidradenitis suppurativa	DIS3ZNAK	Strong	Biomarker	[2]
Inherited retinal dystrophy	DISGGL77	Strong	Genetic Variation	[3]
Retinitis pigmentosa 46	DISAIJ7C	Strong	Autosomal recessive	[4]
IDH3B-related retinopathy	DIS8Y13I	Moderate	Autosomal recessive	[5]
Retinitis pigmentosa	DISCGPY8	Supportive	Autosomal dominant	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Isocitrate dehydrogenase subunit beta, mitochondrial (IDH3B).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Isocitrate dehydrogenase subunit beta, mitochondrial (IDH3B).	[8]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Isocitrate dehydrogenase subunit beta, mitochondrial (IDH3B).	[9]
Selenium	DM25CGV	Approved	Selenium increases the expression of Isocitrate dehydrogenase subunit beta, mitochondrial (IDH3B).	[10]
Fenofibrate	DMFKXDY	Approved	Fenofibrate increases the expression of Isocitrate dehydrogenase subunit beta, mitochondrial (IDH3B).	[11]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Isocitrate dehydrogenase subunit beta, mitochondrial (IDH3B).	[10]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Isocitrate dehydrogenase subunit beta, mitochondrial (IDH3B).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Isocitrate dehydrogenase subunit beta, mitochondrial (IDH3B).	[14]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of Isocitrate dehydrogenase subunit beta, mitochondrial (IDH3B).	[15]

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 Isocitrate dehydrogenase subunit beta, mitochondrial (IDH3B).	[12]

References

• [1] A gene expression signature of acquired chemoresistance to cisplatin and fluorouracil combination chemotherapy in gastric cancer patients.PLoS One. 2011 Feb 18;6(2):e16694. doi: 10.1371/journal.pone.0016694.
• [2] Reduced ten-eleven translocation and isocitrate dehydrogenase expression in inflammatory hidradenitis suppurativa lesions.Eur J Dermatol. 2018 Aug 1;28(4):449-456. doi: 10.1684/ejd.2018.3369.
• [3] Extensive genic and allelic heterogeneity underlying inherited retinal dystrophies in Mexican patients molecularly analyzed by next-generation sequencing.Mol Genet Genomic Med. 2020 Jan;8(1):10.1002/mgg3.1044. doi: 10.1002/mgg3.1044. Epub 2019 Nov 17.
• [4] Insights from retinitis pigmentosa into the roles of isocitrate dehydrogenases in the Krebs cycle. Nat Genet. 2008 Oct;40(10):1230-4. doi: 10.1038/ng.223. Epub 2008 Sep 21.
• [5] 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.
• [6] Nonsyndromic Retinitis Pigmentosa Overview. 2000 Aug 4 [updated 2023 Apr 6]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(?) [Internet]. Seattle (WA): University of Washington, Seattle; 1993C2024.
• [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] 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.
• [9] Identification of biomarkers for the initiation of apoptosis in human preneoplastic colonocytes by proteome analysis. Int J Cancer. 2004 Mar 20;109(2):220-9. doi: 10.1002/ijc.11692.
• [10] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [11] Linalool is a PPARalpha ligand that reduces plasma TG levels and rewires the hepatic transcriptome and plasma metabolome. J Lipid Res. 2014 Jun;55(6):1098-110.
• [12] 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.
• [13] 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.
• [14] 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.
• [15] 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.