Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTV4QEVT)

• DOT Name: EKC/KEOPS complex subunit TPRKB (TPRKB)
• Synonyms: PRPK-binding protein; TP53RK-binding protein
• Gene Name: TPRKB
• Related Disease:
  Advanced cancer
  Type-1/2 diabetes
  Isolated congenital microcephaly
  Steroid-resistant nephrotic syndrome
  Galloway-Mowat syndrome
  Galloway-Mowat syndrome 5
• UniProt ID: TPRKB_HUMAN
• PDB ID: 3ENP; 6WQX; 7SZA; 7SZB; 7SZC; 7SZD
• Pfam ID: PF08617
• Sequence:
  MQLTHQLDLFPECRVTLLLFKDVKNAGDLRRKAMEGTIDGSLINPTVIVDPFQILVAANK
  AVHLYKLGKMKTRTLSTEIIFNLSPNNNISEALKKFGISANDTSILIVYIEEGEKQINQE
  YLISQVEGHQVSLKNLPEIMNITEVKKIYKLSSQEESIGTLLDAIICRMSTKDVL
• 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. TPRKB acts as an allosteric effector that regulates the t(6)A activity of the complex. TPRKB is not required for tRNA modification.
• Tissue Specificity: Widely expressed.
• Reactome Pathway: tRNA modification in the nucleus and cytosol (R-HSA-6782315)

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Type-1/2 diabetes	DISIUHAP	Strong	Genetic Variation	[2]
Isolated congenital microcephaly	DISUXHZ6	moderate	Genetic Variation	[3]
Steroid-resistant nephrotic syndrome	DISVEBC9	moderate	Genetic Variation	[3]
Galloway-Mowat syndrome	DISVB7IM	Supportive	Autosomal recessive	[4]
Galloway-Mowat syndrome 5	DISCRNK4	Limited	Autosomal recessive	[4]

4 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 EKC/KEOPS complex subunit TPRKB (TPRKB).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of EKC/KEOPS complex subunit TPRKB (TPRKB).	[6]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of EKC/KEOPS complex subunit TPRKB (TPRKB).	[7]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of EKC/KEOPS complex subunit TPRKB (TPRKB).	[8]

2 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 TPRKB (TPRKB).	[9]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of EKC/KEOPS complex subunit TPRKB (TPRKB).	[10]

References

• [1] Identification of TP53RK-Binding Protein (TPRKB) Dependency in TP53-Deficient Cancers.Mol Cancer Res. 2019 Aug;17(8):1652-1664. doi: 10.1158/1541-7786.MCR-19-0144. Epub 2019 May 20.
• [2] Mapping eGFR loci to the renal transcriptome and phenome in the VA Million Veteran Program.Nat Commun. 2019 Aug 26;10(1):3842. doi: 10.1038/s41467-019-11704-w.
• [3] 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.
• [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] 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.
• [6] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [7] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [8] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [9] 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.
• [10] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.