Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT4DLHC8)

• DOT Name: Isocitrate dehydrogenase cytoplasmic (IDH1)
• Synonyms: IDH; IDH1; EC 1.1.1.42; Cytosolic NADP-isocitrate dehydrogenase; IDPc; NADP(+)-specific ICDH; Oxalosuccinate decarboxylase
• Gene Name: IDH1
• UniProt ID: IDHC_HUMAN
• PDB ID: 1T09 ; 1T0L ; 3INM ; 3MAP ; 3MAR ; 3MAS ; 4I3K ; 4I3L ; 4KZO ; 4L03 ; 4L04 ; 4L06 ; 4UMX ; 4UMY ; 4XRX ; 4XS3 ; 5DE1 ; 5GIR ; 5K10 ; 5K11 ; 5L57 ; 5L58 ; 5LGE ; 5SUN ; 5SVF ; 5TQH ; 5YFM ; 5YFN ; 6ADG ; 6B0Z ; 6BKX ; 6BKY ; 6BKZ ; 6BL0 ; 6BL1 ; 6BL2 ; 6IO0 ; 6O2Y ; 6O2Z ; 6PAY ; 6Q6F ; 6U4J ; 6VEI ; 6VG0 ; 7PJM ; 7PJN ; 8BAY ; 8HB9
• EC Number: 1.1.1.42
• Pfam ID: PF00180
• Sequence:
  MSKKISGGSVVEMQGDEMTRIIWELIKEKLIFPYVELDLHSYDLGIENRDATNDQVTKDA
  AEAIKKHNVGVKCATITPDEKRVEEFKLKQMWKSPNGTIRNILGGTVFREAIICKNIPRL
  VSGWVKPIIIGRHAYGDQYRATDFVVPGPGKVEITYTPSDGTQKVTYLVHNFEEGGGVAM
  GMYNQDKSIEDFAHSSFQMALSKGWPLYLSTKNTILKKYDGRFKDIFQEIYDKQYKSQFE
  AQKIWYEHRLIDDMVAQAMKSEGGFIWACKNYDGDVQSDSVAQGYGSLGMMTSVLVCPDG
  KTVEAEAAHGTVTRHYRMYQKGQETSTNPIASIFAWTRGLAHRAKLDNNKELAFFANALE
  EVSIETIEAGFMTKDLAACIKGLPNVQRSDYLNTFEFMDKLGENLKIKLAQAKL
• Function: Catalyzes the NADP(+)-dependent oxidative decarboxylation of isocitrate (D-threo-isocitrate) to 2-ketoglutarate (2-oxoglutarate), which is required by other enzymes such as the phytanoyl-CoA dioxygenase. Plays a critical role in the generation of NADPH, an important cofactor in many biosynthesis pathways. May act as a corneal epithelial crystallin and may be involved in maintaining corneal epithelial transparency.
• KEGG Pathway:
  Citrate cycle (TCA cycle) (hsa00020)
  Glutathione metabolism (hsa00480)
  Metabolic pathways (hsa01100)
  Carbon metabolism (hsa01200)
  2-Oxocarboxylic acid metabolism (hsa01210)
  Biosynthesis of amino acids (hsa01230)
  Peroxisome (hsa04146)
  Central carbon metabolism in cancer (hsa05230)
• Reactome Pathway:
  NADPH regeneration (R-HSA-389542)
  Neutrophil degranulation (R-HSA-6798695)
  Peroxisomal protein import (R-HSA-9033241)
  NFE2L2 regulating TCA cycle genes (R-HSA-9818025)
  Abnormal conversion of 2-oxoglutarate to 2-hydroxyglutarate (R-HSA-2978092)
• BioCyc Pathway: MetaCyc:HS06502-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

20 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 Isocitrate dehydrogenase cytoplasmic (IDH1).	[1]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Isocitrate dehydrogenase cytoplasmic (IDH1).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Isocitrate dehydrogenase cytoplasmic (IDH1).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Isocitrate dehydrogenase cytoplasmic (IDH1).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Isocitrate dehydrogenase cytoplasmic (IDH1).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Isocitrate dehydrogenase cytoplasmic (IDH1).	[6]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Isocitrate dehydrogenase cytoplasmic (IDH1).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Isocitrate dehydrogenase cytoplasmic (IDH1).	[8]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Isocitrate dehydrogenase cytoplasmic (IDH1).	[10]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Isocitrate dehydrogenase cytoplasmic (IDH1).	[11]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Isocitrate dehydrogenase cytoplasmic (IDH1).	[12]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Isocitrate dehydrogenase cytoplasmic (IDH1).	[13]
Azathioprine	DMMZSXQ	Approved	Azathioprine decreases the expression of Isocitrate dehydrogenase cytoplasmic (IDH1).	[14]
Fenretinide	DMRD5SP	Phase 3	Fenretinide affects the expression of Isocitrate dehydrogenase cytoplasmic (IDH1).	[15]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Isocitrate dehydrogenase cytoplasmic (IDH1).	[10]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Isocitrate dehydrogenase cytoplasmic (IDH1).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Isocitrate dehydrogenase cytoplasmic (IDH1).	[17]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of Isocitrate dehydrogenase cytoplasmic (IDH1).	[18]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate increases the expression of Isocitrate dehydrogenase cytoplasmic (IDH1).	[19]
[3H]methyltrienolone	DMTSGOW	Investigative	[3H]methyltrienolone increases the expression of Isocitrate dehydrogenase cytoplasmic (IDH1).	[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 cytoplasmic (IDH1).	[9]

References

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• [2] Retinoic acid receptor alpha amplifications and retinoic acid sensitivity in breast cancers. Clin Breast Cancer. 2013 Oct;13(5):401-8.
• [3] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [4] 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.
• [5] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [7] 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.
• [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] 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.
• [10] 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.
• [11] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [12] Coordinate up-regulation of TMEM97 and cholesterol biosynthesis genes in normal ovarian surface epithelial cells treated with progesterone: implications for pathogenesis of ovarian cancer. BMC Cancer. 2007 Dec 11;7:223.
• [13] 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.
• [14] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [15] 4-HPR modulates gene expression in ovarian cells. Int J Cancer. 2006 Sep 1;119(5):1005-13. doi: 10.1002/ijc.21797.
• [16] 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.
• [17] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [18] Ochratoxin A induces reprogramming of glucose metabolism by switching energy metabolism from oxidative phosphorylation to glycolysis in human gastric epithelium GES-1 cells in vitro. Toxicol Lett. 2020 Oct 15;333:232-241. doi: 10.1016/j.toxlet.2020.08.008. Epub 2020 Aug 22.
• [19] Transcriptome dynamics of alternative splicing events revealed early phase of apoptosis induced by methylparaben in H1299 human lung carcinoma cells. Arch Toxicol. 2020 Jan;94(1):127-140. doi: 10.1007/s00204-019-02629-w. Epub 2019 Nov 20.
• [20] Evaluation of an in vitro model of androgen ablation and identification of the androgen responsive proteome in LNCaP cells. Proteomics. 2007 Jan;7(1):47-63.