Details of Drug Off-Target (DOT)

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

• DOT Name: EKC/KEOPS complex subunit LAGE3 (LAGE3)
• Synonyms: L antigen family member 3; Protein ESO-3; Protein ITBA2
• Gene Name: LAGE3
• Related Disease:
  Galloway-Mowat syndrome 2, X-linked
  Isolated congenital microcephaly
  Methicillin-resistant staphylococci infection
  Steroid-resistant nephrotic syndrome
  Galloway-Mowat syndrome
• UniProt ID: LAGE3_HUMAN
• PDB ID: 6GWJ
• Pfam ID: PF09341
• Sequence:
  MRDADADAGGGADGGDGRGGHSCRGGVDTAAAPAGGAPPAHAPGPGRDAASAARGSRMRP
  HIFTLSVPFPTPLEAEIAHGSLAPDAEPHQRVVGKDLTVSGRILVVRWKAEDCRLLRISV
  INFLDQLSLVVRTMQRFGPPVSR
• Function: Component of the EKC/KEOPS complex that is required for the formation of a threonylcarbamoyl group on adenosine at position 37 (t(6)A37) in tRNAs that read codons beginning with adenine. The complex is probably involved in the transfer of the threonylcarbamoyl moiety of threonylcarbamoyl-AMP (TC-AMP) to the N6 group of A37. LAGE3 functions as a dimerization module for the complex.
• Tissue Specificity: Ubiquitous.
• Reactome Pathway: tRNA modification in the nucleus and cytosol (R-HSA-6782315)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Galloway-Mowat syndrome 2, X-linked	DISNMJOL	Strong	X-linked	[1]
Isolated congenital microcephaly	DISUXHZ6	moderate	Genetic Variation	[2]
Methicillin-resistant staphylococci infection	DIS6DRDZ	moderate	Genetic Variation	[3]
Steroid-resistant nephrotic syndrome	DISVEBC9	moderate	Genetic Variation	[2]
Galloway-Mowat syndrome	DISVB7IM	Supportive	Autosomal recessive	[4]

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 EKC/KEOPS complex subunit LAGE3 (LAGE3).	[5]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of EKC/KEOPS complex subunit LAGE3 (LAGE3).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of EKC/KEOPS complex subunit LAGE3 (LAGE3).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of EKC/KEOPS complex subunit LAGE3 (LAGE3).	[8]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of EKC/KEOPS complex subunit LAGE3 (LAGE3).	[9]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of EKC/KEOPS complex subunit LAGE3 (LAGE3).	[10]
Marinol	DM70IK5	Approved	Marinol decreases the expression of EKC/KEOPS complex subunit LAGE3 (LAGE3).	[11]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of EKC/KEOPS complex subunit LAGE3 (LAGE3).	[12]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of EKC/KEOPS complex subunit LAGE3 (LAGE3).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of EKC/KEOPS complex subunit LAGE3 (LAGE3).	[15]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of EKC/KEOPS complex subunit LAGE3 (LAGE3).	[16]

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 affects the methylation of EKC/KEOPS complex subunit LAGE3 (LAGE3).	[13]

References

• [1] Purification and characterization of a cold active alkaline protease from Stenotrophomonas sp., isolated from Kashmir, India. World J Microbiol Biotechnol. 2012 Mar;28(3):1071-9. doi: 10.1007/s11274-011-0905-1. Epub 2011 Oct 1.
• [2] Nephrological and urological complications of homozygous c.974G>A (p.Arg325Gln) OSGEP mutations.Pediatr Nephrol. 2018 Nov;33(11):2201-2204. doi: 10.1007/s00467-018-4060-x. Epub 2018 Aug 23.
• [3] Genetic shifts in methicillin-resistant Staphylococcus aureus epidemic clones and toxin gene profiles in Japan: comparative analysis among pre-epidemic, epidemic and post-epidemic phases.J Med Microbiol. 2018 Mar;67(3):392-399. doi: 10.1099/jmm.0.000687. Epub 2018 Feb 2.
• [4] Mutations in KEOPS-complex genes cause nephrotic syndrome with primary microcephaly. Nat Genet. 2017 Oct;49(10):1529-1538. doi: 10.1038/ng.3933. Epub 2017 Aug 14.
• [5] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [6] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [7] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [8] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [9] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [10] The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
• [11] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [12] 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.
• [13] 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.
• [14] 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.
• [15] 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.
• [16] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.