Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT38HX9V)

• DOT Name: tRNA N6-adenosine threonylcarbamoyltransferase (OSGEP)
• Synonyms: EC 2.3.1.234; N6-L-threonylcarbamoyladenine synthase; t(6)A synthase; O-sialoglycoprotein endopeptidase; hOSGEP; t(6)A37 threonylcarbamoyladenosine biosynthesis protein OSGEP; tRNA threonylcarbamoyladenosine biosynthesis protein OSGEP
• Gene Name: OSGEP
• Related Disease:
  Nervous system disease
  Treacher Collins syndrome 3
  Allergic rhinitis
  Autosomal recessive distal renal tubular acidosis
  Galloway-Mowat syndrome 3
  Intellectual disability
  Nephrotic syndrome
  Southeast Asian ovalocytosis
  Isolated congenital microcephaly
  Steroid-resistant nephrotic syndrome
  Galloway-Mowat syndrome
• UniProt ID: OSGEP_HUMAN
• PDB ID: 6GWJ
• EC Number: 2.3.1.234
• Pfam ID: PF00814
• Sequence:
  MPAVLGFEGSANKIGVGVVRDGKVLANPRRTYVTPPGTGFLPGDTARHHRAVILDLLQEA
  LTESGLTSQDIDCIAYTKGPGMGAPLVSVAVVARTVAQLWNKPLVGVNHCIGHIEMGRLI
  TGATSPTVLYVSGGNTQVIAYSEHRYRIFGETIDIAVGNCLDRFARVLKISNDPSPGYNI
  EQMAKRGKKLVELPYTVKGMDVSFSGILSFIEDVAHRMLATGECTPEDLCFSLQETVFAM
  LVEITERAMAHCGSQEALIVGGVGCNVRLQEMMATMCQERGARLFATDERFCIDNGAMIA
  QAGWEMFRAGHRTPLSDSGVTQRYRTDEVEVTWRD
• 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. OSGEP likely plays a direct catalytic role in this reaction, but requires other protein(s) of the complex to fulfill this activity.
• Tissue Specificity: Widely expressed at low level. Expressed in heart, placenta, liver, kidney, lung, brain, skeletal muscle and pancreas.
• Reactome Pathway: tRNA modification in the nucleus and cytosol (R-HSA-6782315)

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Nervous system disease	DISJ7GGT	Definitive	Biomarker	[1]
Treacher Collins syndrome 3	DISOCTA4	Definitive	Genetic Variation	[1]
Allergic rhinitis	DIS3U9HN	Strong	Biomarker	[2]
Autosomal recessive distal renal tubular acidosis	DISCJR4O	Strong	Genetic Variation	[3]
Galloway-Mowat syndrome 3	DIS4QHHP	Strong	Autosomal recessive	[4]
Intellectual disability	DISMBNXP	Strong	Biomarker	[5]
Nephrotic syndrome	DISSPSC2	Strong	Genetic Variation	[6]
Southeast Asian ovalocytosis	DISSANVQ	Strong	Biomarker	[7]
Isolated congenital microcephaly	DISUXHZ6	moderate	Biomarker	[8]
Steroid-resistant nephrotic syndrome	DISVEBC9	moderate	Genetic Variation	[8]
Galloway-Mowat syndrome	DISVB7IM	Supportive	Autosomal recessive	[5]

6 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 tRNA N6-adenosine threonylcarbamoyltransferase (OSGEP).	[9]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of tRNA N6-adenosine threonylcarbamoyltransferase (OSGEP).	[10]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of tRNA N6-adenosine threonylcarbamoyltransferase (OSGEP).	[11]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of tRNA N6-adenosine threonylcarbamoyltransferase (OSGEP).	[13]
Selenium	DM25CGV	Approved	Selenium increases the expression of tRNA N6-adenosine threonylcarbamoyltransferase (OSGEP).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of tRNA N6-adenosine threonylcarbamoyltransferase (OSGEP).	[15]

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 tRNA N6-adenosine threonylcarbamoyltransferase (OSGEP).	[12]

References

• [1] tRNA N6-adenosine threonylcarbamoyltransferase defect due to KAE1/TCS3 (OSGEP) mutation manifest by neurodegeneration and renal tubulopathy. Eur J Hum Genet. 2017 May;25(5):545-551. doi: 10.1038/ejhg.2017.30. Epub 2017 Mar 8.
• [2] Comparison of Long-term Efficacy of Subcutaneous Immunotherapy in Pediatric and Adult Patients With Allergic Rhinitis.Allergy Asthma Immunol Res. 2019 Jan;11(1):68-78. doi: 10.4168/aair.2019.11.1.68.
• [3] Trafficking defects of a novel autosomal recessive distal renal tubular acidosis mutant (S773P) of the human kidney anion exchanger (kAE1).J Biol Chem. 2004 Sep 24;279(39):40960-71. doi: 10.1074/jbc.M405356200. Epub 2004 Jul 13.
• [4] Galloway-Mowat syndrome in Taiwan: OSGEP mutation and unique clinical phenotype. Orphanet J Rare Dis. 2018 Dec 17;13(1):226. doi: 10.1186/s13023-018-0961-9.
• [5] 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.
• [6] Novel homozygous OSGEP gene pathogenic variants in two unrelated patients with Galloway-Mowat syndrome: case report and review of the literature.BMC Nephrol. 2019 Apr 11;20(1):126. doi: 10.1186/s12882-019-1317-y.
• [7] Protein 4.2 interaction with hereditary spherocytosis mutants of the cytoplasmic domain of human anion exchanger 1.Biochem J. 2011 Jan 15;433(2):313-22. doi: 10.1042/BJ20101375.
• [8] 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.
• [9] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [10] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [11] 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.
• [12] 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.
• [13] 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.
• [14] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [15] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.