Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTFDA384)

• DOT Name: tRNA endonuclease ANKZF1 (ANKZF1)
• Synonyms: EC 3.1.-.-; Ankyrin repeat and zinc finger domain-containing protein 1; Zinc finger protein 744
• Gene Name: ANKZF1
• Related Disease: Inflammatory bowel disease
• UniProt ID: ANKZ1_HUMAN
• EC Number: 3.1.-.-
• Pfam ID: PF00023 ; PF18826 ; PF18716
• Sequence:
  MSPAPDAAPAPASISLFDLSADAPVFQGLSLVSHAPGEALARAPRTSCSGSGERESPERK
  LLQGPMDISEKLFCSTCDQTFQNHQEQREHYKLDWHRFNLKQRLKDKPLLSALDFEKQSS
  TGDLSSISGSEDSDSASEEDLQTLDRERATFEKLSRPPGFYPHRVLFQNAQGQFLYAYRC
  VLGPHQDPPEEAELLLQNLQSRGPRDCVVLMAAAGHFAGAIFQGREVVTHKTFHRYTVRA
  KRGTAQGLRDARGGPSHSAGANLRRYNEATLYKDVRDLLAGPSWAKALEEAGTILLRAPR
  SGRSLFFGGKGAPLQRGDPRLWDIPLATRRPTFQELQRVLHKLTTLHVYEEDPREAVRLH
  SPQTHWKTVREERKKPTEEEIRKICRDEKEALGQNEESPKQGSGSEGEDGFQVELELVEL
  TVGTLDLCESEVLPKRRRRKRNKKEKSRDQEAGAHRTLLQQTQEEEPSTQSSQAVAAPLG
  PLLDEAKAPGQPELWNALLAACRAGDVGVLKLQLAPSPADPRVLSLLSAPLGSGGFTLLH
  AAAAAGRGSVVRLLLEAGADPTVQDSRARPPYTVAADKSTRNEFRRFMEKNPDAYDYNKA
  QVPGPLTPEMEARQATRKREQKAARRQREEQQQRQQEQEEREREEQRRFAALSDREKRAL
  AAERRLAAQLGAPTSPIPDSAIVNTRRCWSCGASLQGLTPFHYLDFSFCSTRCLQDHRRQ
  AGRPSS
• Function: Endonuclease that cleaves polypeptidyl-tRNAs downstream of the ribosome-associated quality control (RQC) pathway to release incompletely synthesized polypeptides for degradation. The RQC pathway disassembles aberrantly stalled translation complexes to recycle or degrade the constituent parts. ANKZF1 acts downstream disassembly of stalled ribosomes and specifically cleaves off the terminal 3'-CCA nucleotides universal to all tRNAs from polypeptidyl-tRNAs, releasing (1) ubiquitinated polypeptides from 60S ribosomal subunit for degradation and (2) cleaved tRNAs. ANKZF1-cleaved tRNAs are then repaired and recycled by ELAC1 and TRNT1. Also plays a role in the cellular response to hydrogen peroxide and in the maintenance of mitochondrial integrity under conditions of cellular stress.

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Inflammatory bowel disease	DISGN23E	Strong	Genetic Variation	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of tRNA endonuclease ANKZF1 (ANKZF1).	[2]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of tRNA endonuclease ANKZF1 (ANKZF1).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of tRNA endonuclease ANKZF1 (ANKZF1).	[4]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of tRNA endonuclease ANKZF1 (ANKZF1).	[5]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of tRNA endonuclease ANKZF1 (ANKZF1).	[6]
Curcumin	DMQPH29	Phase 3	Curcumin decreases the expression of tRNA endonuclease ANKZF1 (ANKZF1).	[7]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of tRNA endonuclease ANKZF1 (ANKZF1).	[8]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of tRNA endonuclease ANKZF1 (ANKZF1).	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of tRNA endonuclease ANKZF1 (ANKZF1).	[9]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of tRNA endonuclease ANKZF1 (ANKZF1).	[11]

References

• [1] Ankyrin repeat and zinc-finger domain-containing 1 mutations are associated with infantile-onset inflammatory bowel disease.J Biol Chem. 2017 May 12;292(19):7904-7920. doi: 10.1074/jbc.M116.772038. Epub 2017 Mar 16.
• [2] 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.
• [3] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [4] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [5] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [6] 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.
• [7] Gene-expression profiling during curcumin-induced apoptosis reveals downregulation of CXCR4. Exp Hematol. 2007 Jan;35(1):84-95.
• [8] 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.
• [9] 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.
• [10] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [11] 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.