Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT5QQB5L)

• DOT Name: Isocitrate dehydrogenase subunit alpha, mitochondrial (IDH3A)
• Synonyms: EC 1.1.1.41; Isocitric dehydrogenase subunit alpha; NAD(+)-specific ICDH subunit alpha
• Gene Name: IDH3A
• Related Disease:
  OPTN-related open angle glaucoma
  Bipolar disorder
  Lung adenocarcinoma
  Retinitis pigmentosa
  Retinitis pigmentosa 90
  Nervous system disease
  Osteoarthritis
• UniProt ID: IDH3A_HUMAN
• PDB ID: 5GRE; 5GRF; 5GRH; 5GRI; 5GRL; 5YVT; 6KDE; 6KDF; 6KDY; 6KE3; 6L57; 6L59; 7CE3; 8GRB; 8GRD; 8GRG; 8GRH; 8GRU; 8GS5
• EC Number: 1.1.1.41
• Pfam ID: PF00180
• Sequence:
  MAGPAWISKVSRLLGAFHNPKQVTRGFTGGVQTVTLIPGDGIGPEISAAVMKIFDAAKAP
  IQWEERNVTAIQGPGGKWMIPSEAKESMDKNKMGLKGPLKTPIAAGHPSMNLLLRKTFDL
  YANVRPCVSIEGYKTPYTDVNIVTIRENTEGEYSGIEHVIVDGVVQSIKLITEGASKRIA
  EFAFEYARNNHRSNVTAVHKANIMRMSDGLFLQKCREVAESCKDIKFNEMYLDTVCLNMV
  QDPSQFDVLVMPNLYGDILSDLCAGLIGGLGVTPSGNIGANGVAIFESVHGTAPDIAGKD
  MANPTALLLSAVMMLRHMGLFDHAARIEAACFATIKDGKSLTKDLGGNAKCSDFTEEICR
  RVKDLD
• Function: Catalytic subunit of the enzyme which catalyzes 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:ENSG00000166411-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
OPTN-related open angle glaucoma	DISDR98A	Definitive	Biomarker	[1]
Bipolar disorder	DISAM7J2	Strong	Biomarker	[2]
Lung adenocarcinoma	DISD51WR	Strong	Biomarker	[3]
Retinitis pigmentosa	DISCGPY8	Strong	Biomarker	[4]
Retinitis pigmentosa 90	DISGIC3X	Strong	Autosomal recessive	[5]
Nervous system disease	DISJ7GGT	Disputed	Biomarker	[6]
Osteoarthritis	DIS05URM	Limited	Biomarker	[7]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Mitoxantrone	DMM39BF	Approved	Isocitrate dehydrogenase subunit alpha, mitochondrial (IDH3A) affects the response to substance of Mitoxantrone.	[31]

28 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 Isocitrate dehydrogenase subunit alpha, mitochondrial (IDH3A).	[8]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Isocitrate dehydrogenase subunit alpha, mitochondrial (IDH3A).	[9]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Isocitrate dehydrogenase subunit alpha, mitochondrial (IDH3A).	[10]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Isocitrate dehydrogenase subunit alpha, mitochondrial (IDH3A).	[11]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Isocitrate dehydrogenase subunit alpha, mitochondrial (IDH3A).	[12]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of Isocitrate dehydrogenase subunit alpha, mitochondrial (IDH3A).	[14]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Isocitrate dehydrogenase subunit alpha, mitochondrial (IDH3A).	[15]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Isocitrate dehydrogenase subunit alpha, mitochondrial (IDH3A).	[16]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Isocitrate dehydrogenase subunit alpha, mitochondrial (IDH3A).	[17]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Isocitrate dehydrogenase subunit alpha, mitochondrial (IDH3A).	[18]
Cannabidiol	DM0659E	Approved	Cannabidiol increases the expression of Isocitrate dehydrogenase subunit alpha, mitochondrial (IDH3A).	[19]
Bortezomib	DMNO38U	Approved	Bortezomib decreases the expression of Isocitrate dehydrogenase subunit alpha, mitochondrial (IDH3A).	[20]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of Isocitrate dehydrogenase subunit alpha, mitochondrial (IDH3A).	[21]
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate decreases the expression of Isocitrate dehydrogenase subunit alpha, mitochondrial (IDH3A).	[22]
Artemisinin	DMOY7W3	Approved	Artemisinin decreases the expression of Isocitrate dehydrogenase subunit alpha, mitochondrial (IDH3A).	[20]
Berberine	DMC5Q8X	Phase 4	Berberine decreases the expression of Isocitrate dehydrogenase subunit alpha, mitochondrial (IDH3A).	[20]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Isocitrate dehydrogenase subunit alpha, mitochondrial (IDH3A).	[18]
Belinostat	DM6OC53	Phase 2	Belinostat increases the expression of Isocitrate dehydrogenase subunit alpha, mitochondrial (IDH3A).	[18]
Metoprine	DM5GQD7	Phase 2	Metoprine decreases the expression of Isocitrate dehydrogenase subunit alpha, mitochondrial (IDH3A).	[20]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the mutagenesis of Isocitrate dehydrogenase subunit alpha, mitochondrial (IDH3A).	[23]
Acriflavine	DMKVE8X	Phase 1	Acriflavine decreases the expression of Isocitrate dehydrogenase subunit alpha, mitochondrial (IDH3A).	[20]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Isocitrate dehydrogenase subunit alpha, mitochondrial (IDH3A).	[24]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Isocitrate dehydrogenase subunit alpha, mitochondrial (IDH3A).	[25]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Isocitrate dehydrogenase subunit alpha, mitochondrial (IDH3A).	[26]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Isocitrate dehydrogenase subunit alpha, mitochondrial (IDH3A).	[27]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Isocitrate dehydrogenase subunit alpha, mitochondrial (IDH3A).	[28]
Deguelin	DMXT7WG	Investigative	Deguelin increases the expression of Isocitrate dehydrogenase subunit alpha, mitochondrial (IDH3A).	[29]
XCT790	DMZ7N8D	Investigative	XCT790 decreases the expression of Isocitrate dehydrogenase subunit alpha, mitochondrial (IDH3A).	[20]

1 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Isocitrate dehydrogenase subunit alpha, mitochondrial (IDH3A).	[13]

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 alpha, mitochondrial (IDH3A).	[30]

References

• [1] Proteomic Alterations in Aqueous Humor From Patients With Primary Open Angle Glaucoma.Invest Ophthalmol Vis Sci. 2018 May 1;59(6):2635-2643. doi: 10.1167/iovs.17-23434.
• [2] Cerebrospinal fluid metabolomics identifies a key role of isocitrate dehydrogenase in bipolar disorder: evidence in support of mitochondrial dysfunction hypothesis.Mol Psychiatry. 2016 Nov;21(11):1504-1510. doi: 10.1038/mp.2015.217. Epub 2016 Jan 19.
• [3] Effect of IDH3a on glucose uptake in lung adenocarcinoma: A pilot study based on [(18) F]FDG.Cancer Med. 2019 Sep;8(11):5341-5351. doi: 10.1002/cam4.2421. Epub 2019 Jul 29.
• [4] Mouse Idh3a mutations cause retinal degeneration and reduced mitochondrial function.Dis Model Mech. 2018 Dec 18;11(12):dmm036426. doi: 10.1242/dmm.036426.
• [5] Knockdown of both mitochondrial isocitrate dehydrogenase enzymes in pancreatic beta cells inhibits insulin secretion. Biochim Biophys Acta. 2013 Nov;1830(11):5104-11. doi: 10.1016/j.bbagen.2013.07.013. Epub 2013 Jul 20.
• [6] Homozygous mutation, p.Pro304His, in IDH3A, encoding isocitrate dehydrogenase subunit is associated with severe encephalopathy in infancy.Neurogenetics. 2017 Jan;18(1):57-61. doi: 10.1007/s10048-016-0507-z. Epub 2017 Jan 5.
• [7] 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.
• [8] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [9] 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.
• [10] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [11] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [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] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [14] The role of NAD(+)-dependent isocitrate dehydrogenase 3 subunit in AFB1 induced liver lesion. Toxicol Lett. 2014 Jan 30;224(3):371-9. doi: 10.1016/j.toxlet.2013.10.037. Epub 2013 Nov 5.
• [15] Proteomic analysis of liver cancer cells treated with suberonylanilide hydroxamic acid. Cancer Chemother Pharmacol. 2008 Apr;61(5):791-802.
• [16] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [17] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [18] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [19] Gingival Stromal Cells as an In Vitro Model: Cannabidiol Modulates Genes Linked With Amyotrophic Lateral Sclerosis. J Cell Biochem. 2017 Apr;118(4):819-828. doi: 10.1002/jcb.25757. Epub 2016 Nov 28.
• [20] Identification of Compounds That Inhibit Estrogen-Related Receptor Alpha Signaling Using High-Throughput Screening Assays. Molecules. 2019 Feb 27;24(5):841. doi: 10.3390/molecules24050841.
• [21] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [22] Identification of potential biomarkers for predicting acute dermal irritation by proteomic analysis. J Appl Toxicol. 2011 Nov;31(8):762-72.
• [23] Exome-wide mutation profile in benzo[a]pyrene-derived post-stasis and immortal human mammary epithelial cells. Mutat Res Genet Toxicol Environ Mutagen. 2014 Dec;775-776:48-54. doi: 10.1016/j.mrgentox.2014.10.011. Epub 2014 Nov 4.
• [24] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [25] Environmental pollutant induced cellular injury is reflected in exosomes from placental explants. Placenta. 2020 Jan 1;89:42-49. doi: 10.1016/j.placenta.2019.10.008. Epub 2019 Oct 17.
• [26] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [27] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [28] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [29] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.
• [30] 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.
• [31] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.