Details of Drug Off-Target (DOT)

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

• DOT Name: EKC/KEOPS complex subunit TP53RK (TP53RK)
• Synonyms: EC 3.6.-.-; Atypical serine/threonine protein kinase TP53RK; Nori-2; TP53-regulating kinase; EC 2.7.11.1; p53-related protein kinase
• Gene Name: TP53RK
• Related Disease:
  Colon cancer
  Colon carcinoma
  Colorectal carcinoma
  Galloway-Mowat syndrome 4
  Isolated congenital microcephaly
  Steroid-resistant nephrotic syndrome
  Galloway-Mowat syndrome
  Cutaneous squamous cell carcinoma
  Nephrotic syndrome
  Plasma cell myeloma
  Skin cancer
• UniProt ID: PRPK_HUMAN
• PDB ID: 6WQX; 7SZA; 7SZB; 7SZC; 7SZD
• EC Number: 2.7.11.1; 3.6.-.-
• Pfam ID: PF06293
• Sequence:
  MAAARATTPADGEEPAPEAEALAAARERSSRFLSGLELVKQGAEARVFRGRFQGRAAVIK
  HRFPKGYRHPALEARLGRRRTVQEARALLRCRRAGISAPVVFFVDYASNCLYMEEIEGSV
  TVRDYIQSTMETEKTPQGLSNLAKTIGQVLARMHDEDLIHGDLTTSNMLLKPPLEQLNIV
  LIDFGLSFISALPEDKGVDLYVLEKAFLSTHPNTETVFEAFLKSYSTSSKKARPVLKKLD
  EVRLRGRKRSMVG
• 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. TP53RK has ATPase activity in the context of the EKC/KEOPS complex and likely plays a supporting role to the catalytic subunit OSGEP. Atypical protein kinase that phosphorylates 'Ser-15' of p53/TP53 protein and may therefore participate in its activation.
• Tissue Specificity: Highly expressed in testis. Weakly expressed in heart kidney and spleen.
• Reactome Pathway:
  Regulation of TP53 Activity through Phosphorylation (R-HSA-6804756)
  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
Colon cancer	DISVC52G	Strong	Altered Expression	[1]
Colon carcinoma	DISJYKUO	Strong	Altered Expression	[1]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[2]
Galloway-Mowat syndrome 4	DIS1S9G0	Strong	Autosomal recessive	[3]
Isolated congenital microcephaly	DISUXHZ6	moderate	Genetic Variation	[4]
Steroid-resistant nephrotic syndrome	DISVEBC9	moderate	Genetic Variation	[4]
Galloway-Mowat syndrome	DISVB7IM	Supportive	Autosomal recessive	[3]
Cutaneous squamous cell carcinoma	DIS3LXUG	Limited	Biomarker	[5]
Nephrotic syndrome	DISSPSC2	Limited	Biomarker	[3]
Plasma cell myeloma	DIS0DFZ0	Limited	Biomarker	[6]
Skin cancer	DISTM18U	Limited	Biomarker	[5]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Afimoxifene	DMFORDT	Phase 2	EKC/KEOPS complex subunit TP53RK (TP53RK) decreases the response to substance of Afimoxifene.	[17]

8 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of EKC/KEOPS complex subunit TP53RK (TP53RK).	[7]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of EKC/KEOPS complex subunit TP53RK (TP53RK).	[8]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of EKC/KEOPS complex subunit TP53RK (TP53RK).	[9]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of EKC/KEOPS complex subunit TP53RK (TP53RK).	[10]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of EKC/KEOPS complex subunit TP53RK (TP53RK).	[11]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of EKC/KEOPS complex subunit TP53RK (TP53RK).	[12]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of EKC/KEOPS complex subunit TP53RK (TP53RK).	[15]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of EKC/KEOPS complex subunit TP53RK (TP53RK).	[16]

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 TP53RK (TP53RK).	[13]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of EKC/KEOPS complex subunit TP53RK (TP53RK).	[14]

References

• [1] Targeting PRPK Function Blocks Colon Cancer Metastasis.Mol Cancer Ther. 2018 May;17(5):1101-1113. doi: 10.1158/1535-7163.MCT-17-0628. Epub 2018 Feb 26.
• [2] Novel Epigenetic CREB-miR-630 Signaling Axis Regulates Radiosensitivity in Colorectal Cancer.PLoS One. 2015 Aug 11;10(8):e0133870. doi: 10.1371/journal.pone.0133870. eCollection 2015.
• [3] 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.
• [4] 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.
• [5] Targeting PRPK and TOPK for skin cancer prevention and therapy.Oncogene. 2018 Oct;37(42):5633-5647. doi: 10.1038/s41388-018-0350-9. Epub 2018 Jun 14.
• [6] p53-related protein kinase confers poor prognosis and represents a novel therapeutic target in multiple myeloma.Blood. 2017 Mar 9;129(10):1308-1319. doi: 10.1182/blood-2016-09-738500. Epub 2017 Jan 12.
• [7] 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.
• [8] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [9] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [10] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [11] 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.
• [12] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [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] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [15] In vitro effects of aldehydes present in tobacco smoke on gene expression in human lung alveolar epithelial cells. Toxicol In Vitro. 2013 Apr;27(3):1072-81.
• [16] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [17] High-throughput ectopic expression screen for tamoxifen resistance identifies an atypical kinase that blocks autophagy. Proc Natl Acad Sci U S A. 2011 Feb 1;108(5):2058-63.