Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTE3L48D)

• DOT Name: Glutaredoxin-related protein 5, mitochondrial (GLRX5)
• Synonyms: Monothiol glutaredoxin-5
• Gene Name: GLRX5
• Related Disease:
  Friedreich's ataxia
  Hepatocellular carcinoma
  Inherited sideroblastic anemia
  Myopathy
  Sideroblastic anemia 2
  Sideroblastic anemia 3
  Spasticity-ataxia-gait anomalies syndrome
  X-linked sideroblastic anemia 1
  Anemia
  Bacteremia
  Methicillin-resistant staphylococci infection
  Glycine encephalopathy
  Sideroblastic anemia
  Type-1/2 diabetes
• UniProt ID: GLRX5_HUMAN
• PDB ID: 2MMZ; 2WUL
• Pfam ID: PF00462
• Sequence:
  MSGSLGRAAAALLRWGRGAGGGGLWGPGVRAAGSGAGGGGSAEQLDALVKKDKVVVFLKG
  TPEQPQCGFSNAVVQILRLHGVRDYAAYNVLDDPELRQGIKDYSNWPTIPQVYLNGEFVG
  GCDILLQMHQNGDLVEELKKLGIHSALLDEKKDQDSK
• Function: Monothiol glutaredoxin involved in mitochondrial iron-sulfur (Fe/S) cluster transfer. Receives 2Fe/2S clusters from scaffold protein ISCU and mediates their transfer to apoproteins, to the 4Fe/FS cluster biosynthesis machinery, or export from mitochondrion. Required for normal regulation of hemoglobin synthesis by the iron-sulfur protein ACO1.
• Reactome Pathway: Mitochondrial iron-sulfur cluster biogenesis (R-HSA-1362409)

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Friedreich's ataxia	DIS5DV35	Strong	Biomarker	[1]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[2]
Inherited sideroblastic anemia	DISLT2PU	Strong	Genetic Variation	[3]
Myopathy	DISOWG27	Strong	Biomarker	[1]
Sideroblastic anemia 2	DIS3T984	Strong	Biomarker	[4]
Sideroblastic anemia 3	DIS0LANJ	Strong	Autosomal recessive	[5]
Spasticity-ataxia-gait anomalies syndrome	DISD9OYI	Strong	Autosomal recessive	[5]
X-linked sideroblastic anemia 1	DISWBQC7	Strong	Genetic Variation	[6]
Anemia	DISTVL0C	moderate	Genetic Variation	[7]
Bacteremia	DIS6N9RZ	moderate	Biomarker	[8]
Methicillin-resistant staphylococci infection	DIS6DRDZ	moderate	Biomarker	[8]
Glycine encephalopathy	DISI2XE5	Disputed	Genetic Variation	[9]
Sideroblastic anemia	DIS4F3X1	Limited	Biomarker	[10]
Type-1/2 diabetes	DISIUHAP	Limited	Biomarker	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Glutaredoxin-related protein 5, mitochondrial (GLRX5).	[12]

8 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 Glutaredoxin-related protein 5, mitochondrial (GLRX5).	[13]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Glutaredoxin-related protein 5, mitochondrial (GLRX5).	[14]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Glutaredoxin-related protein 5, mitochondrial (GLRX5).	[15]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Glutaredoxin-related protein 5, mitochondrial (GLRX5).	[16]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Glutaredoxin-related protein 5, mitochondrial (GLRX5).	[17]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Glutaredoxin-related protein 5, mitochondrial (GLRX5).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Glutaredoxin-related protein 5, mitochondrial (GLRX5).	[19]
chloropicrin	DMSGBQA	Investigative	chloropicrin decreases the expression of Glutaredoxin-related protein 5, mitochondrial (GLRX5).	[20]

References

• [1] Iron-sulfur cluster biogenesis and human disease.Trends Genet. 2008 Aug;24(8):398-407. doi: 10.1016/j.tig.2008.05.008. Epub 2008 Jul 5.
• [2] Expression of thioredoxins and glutaredoxins in human hepatocellular carcinoma: correlation to cell proliferation, tumor size and metabolic syndrome.Int J Immunopathol Pharmacol. 2014 Apr-Jun;27(2):169-83. doi: 10.1177/039463201402700204.
• [3] GLRX5 mutations impair heme biosynthetic enzymes ALA synthase 2 and ferrochelatase in Human congenital sideroblastic anemia.Mol Genet Metab. 2019 Nov;128(3):342-351. doi: 10.1016/j.ymgme.2018.12.012. Epub 2019 Jan 7.
• [4] Advantages and pitfalls of an extended gene panel for investigating complex neurometabolic phenotypes.Brain. 2016 Nov 1;139(11):2844-2854. doi: 10.1093/brain/aww221.
• [5] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [6] Regulation and tissue-specific expression of -aminolevulinic acid synthases in non-syndromic sideroblastic anemias and porphyrias.Mol Genet Metab. 2019 Nov;128(3):190-197. doi: 10.1016/j.ymgme.2019.01.015. Epub 2019 Jan 23.
• [7] The human counterpart of zebrafish shiraz shows sideroblastic-like microcytic anemia and iron overload. Blood. 2007 Aug 15;110(4):1353-8. doi: 10.1182/blood-2007-02-072520. Epub 2007 May 7.
• [8] Trends in incidence and resistance patterns of Staphylococcus aureus bacteremia().Infect Dis (Lond). 2018 Jan;50(1):52-58. doi: 10.1080/23744235.2017.1405276. Epub 2017 Nov 21.
• [9] Brain imaging and genetic risk in the pediatric population, part 1: inherited metabolic diseases.Neuroimaging Clin N Am. 2015 Feb;25(1):31-51. doi: 10.1016/j.nic.2014.09.004.
• [10] TLR-activated repression of Fe-S cluster biogenesis drives a metabolic shift and alters histone and tubulin acetylation.Blood Adv. 2018 May 22;2(10):1146-1156. doi: 10.1182/bloodadvances.2018015669.
• [11] Distinct Shift in Beta-Cell Glutaredoxin 5 Expression Is Mediated by Hypoxia and Lipotoxicity Both In Vivo and In Vitro.Front Endocrinol (Lausanne). 2018 Mar 12;9:84. doi: 10.3389/fendo.2018.00084. eCollection 2018.
• [12] 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.
• [13] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [14] 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.
• [15] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [16] 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.
• [17] 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.
• [18] New insights into BaP-induced toxicity: role of major metabolites in transcriptomics and contribution to hepatocarcinogenesis. Arch Toxicol. 2016 Jun;90(6):1449-58.
• [19] 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.
• [20] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.