Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT2FWPSE)

• DOT Name: Isocitrate dehydrogenase subunit gamma, mitochondrial (IDH3G)
• Synonyms: Isocitric dehydrogenase subunit gamma; NAD(+)-specific ICDH subunit gamma
• Gene Name: IDH3G
• UniProt ID: IDH3G_HUMAN
• PDB ID: 5GRE; 5GRF; 5GRH; 5GRI; 5GRL; 5YVT; 6L57; 6L59; 7CE3; 8GRG; 8GRH; 8GS5
• Pfam ID: PF00180
• Sequence:
  MALKVATVAGSAAKAVLGPALLCRPWEVLGAHEVPSRNIFSEQTIPPSAKYGGRHTVTMI
  PGDGIGPELMLHVKSVFRHACVPVDFEEVHVSSNADEEDIRNAIMAIRRNRVALKGNIET
  NHNLPPSHKSRNNILRTSLDLYANVIHCKSLPGVVTRHKDIDILIVRENTEGEYSSLEHE
  SVAGVVESLKIITKAKSLRIAEYAFKLAQESGRKKVTAVHKANIMKLGDGLFLQCCREVA
  ARYPQITFENMIVDNTTMQLVSRPQQFDVMVMPNLYGNIVNNVCAGLVGGPGLVAGANYG
  HVYAVFETATRNTGKSIANKNIANPTATLLASCMMLDHLKLHSYATSIRKAVLASMDNEN
  MHTPDIGGQGTTSEAIQDVIRHIRVINGRAVEA
• Function: Regulatory subunit which plays a role in the allosteric regulation 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)
  Mitochondrial protein import (R-HSA-1268020)
• BioCyc Pathway: MetaCyc:ENSG00000067829-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Isocitrate dehydrogenase subunit gamma, mitochondrial (IDH3G).	[1]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Isocitrate dehydrogenase subunit gamma, mitochondrial (IDH3G).	[2]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Isocitrate dehydrogenase subunit gamma, mitochondrial (IDH3G).	[3]
Selenium	DM25CGV	Approved	Selenium increases the expression of Isocitrate dehydrogenase subunit gamma, mitochondrial (IDH3G).	[4]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Isocitrate dehydrogenase subunit gamma, mitochondrial (IDH3G).	[5]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Isocitrate dehydrogenase subunit gamma, mitochondrial (IDH3G).	[4]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Isocitrate dehydrogenase subunit gamma, mitochondrial (IDH3G).	[7]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Isocitrate dehydrogenase subunit gamma, mitochondrial (IDH3G).	[8]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Isocitrate dehydrogenase subunit gamma, mitochondrial (IDH3G).	[9]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of Isocitrate dehydrogenase subunit gamma, mitochondrial (IDH3G).	[10]
CH-223191	DMMJZYC	Investigative	CH-223191 decreases the expression of Isocitrate dehydrogenase subunit gamma, mitochondrial (IDH3G).	[12]

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 gamma, mitochondrial (IDH3G).	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Manganese	DMKT129	Investigative	Manganese affects the binding of Isocitrate dehydrogenase subunit gamma, mitochondrial (IDH3G).	[11]

References

• [1] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [2] 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.
• [3] 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.
• [4] 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.
• [5] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [6] 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.
• [7] 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.
• [8] 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.
• [9] Low-dose Bisphenol A exposure alters the functionality and cellular environment in a human cardiomyocyte model. Environ Pollut. 2023 Oct 15;335:122359. doi: 10.1016/j.envpol.2023.122359. Epub 2023 Aug 9.
• [10] 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.
• [11] Identification of Mn2+-binding aspartates from alpha, beta, and gamma subunits of human NAD-dependent isocitrate dehydrogenase. J Biol Chem. 2006 Jul 28;281(30):21073-21081. doi: 10.1074/jbc.M602956200. Epub 2006 May 31.
• [12] Adaptive changes in global gene expression profile of lung carcinoma A549 cells acutely exposed to distinct types of AhR ligands. Toxicol Lett. 2018 Aug;292:162-174.