Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT4LIRBC)

• DOT Name: Glutaredoxin-2, mitochondrial (GLRX2)
• Gene Name: GLRX2
• UniProt ID: GLRX2_HUMAN
• PDB ID: 2CQ9; 2FLS; 2HT9
• Pfam ID: PF00462
• Sequence:
  MIWRRAALAGTRLVWSRSGSAGWLDRAAGAAGAAAAAASGMESNTSSSLENLATAPVNQI
  QETISDNCVVIFSKTSCSYCTMAKKLFHDMNVNYKVVELDLLEYGNQFQDALYKMTGERT
  VPRIFVNGTFIGGATDTHRLHKEGKLLPLVHQCYLKKSKRKEFQ
• Function: Glutathione-dependent oxidoreductase that facilitates the maintenance of mitochondrial redox homeostasis upon induction of apoptosis by oxidative stress. Involved in response to hydrogen peroxide and regulation of apoptosis caused by oxidative stress. Acts as a very efficient catalyst of monothiol reactions because of its high affinity for protein glutathione-mixed disulfides. Can receive electrons not only from glutathione (GSH), but also from thioredoxin reductase supporting both monothiol and dithiol reactions. Efficiently catalyzes both glutathionylation and deglutathionylation of mitochondrial complex I, which in turn regulates the superoxide production by the complex. Overexpression decreases the susceptibility to apoptosis and prevents loss of cardiolipin and cytochrome c release.
• Tissue Specificity: Widely expressed. Expressed in brain, heart, skeletal muscle, colon, thymus, spleen, kidney, liver, small intestine, placenta and lung. Not expressed in peripheral blood leukocytes.

Molecular Interaction Atlas (MIA) of This DOT

15 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 Glutaredoxin-2, mitochondrial (GLRX2).	[1]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Glutaredoxin-2, mitochondrial (GLRX2).	[2]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Glutaredoxin-2, mitochondrial (GLRX2).	[3]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Glutaredoxin-2, mitochondrial (GLRX2).	[4]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Glutaredoxin-2, mitochondrial (GLRX2).	[5]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Glutaredoxin-2, mitochondrial (GLRX2).	[6]
Cannabidiol	DM0659E	Approved	Cannabidiol increases the expression of Glutaredoxin-2, mitochondrial (GLRX2).	[7]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Glutaredoxin-2, mitochondrial (GLRX2).	[8]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Glutaredoxin-2, mitochondrial (GLRX2).	[9]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Glutaredoxin-2, mitochondrial (GLRX2).	[10]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Glutaredoxin-2, mitochondrial (GLRX2).	[10]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Glutaredoxin-2, mitochondrial (GLRX2).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Glutaredoxin-2, mitochondrial (GLRX2).	[10]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Glutaredoxin-2, mitochondrial (GLRX2).	[13]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Glutaredoxin-2, mitochondrial (GLRX2).	[14]

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 Glutaredoxin-2, mitochondrial (GLRX2).	[11]

References

• [1] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [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] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [4] 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.
• [5] 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.
• [6] 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.
• [7] 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.
• [8] 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.
• [9] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [10] Gene expression profiling in Ishikawa cells: a fingerprint for estrogen active compounds. Toxicol Appl Pharmacol. 2009 Apr 1;236(1):85-96.
• [11] 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.
• [12] 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.
• [13] 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.
• [14] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.