Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTI1KPN6)

• DOT Name: ADP-ribosylhydrolase ARH3 (ADPRS)
• Synonyms: ADP-ribose glycohydrolase ARH3; ADP-ribosylhydrolase 3; O-acetyl-ADP-ribose deacetylase ARH3; EC 3.5.1.-; Poly(ADP-ribose) glycohydrolase ARH3; EC 3.2.1.143; hydrolase-like protein 2; hydrolase; EC 3.2.2.-
• Gene Name: ADPRS
• Related Disease:
  Breast cancer
  Breast neoplasm
  Cerebral infarction
  Hypercholesterolemia, familial, 4
  Neurodegeneration, childhood-onset, stress-induced, with variable ataxia and seizures
  Intellectual disability
• UniProt ID: ADPRS_HUMAN
• PDB ID: 2FOZ; 2FP0; 2G4K; 5ZQY; 6D36; 6D3A; 7AKR; 7AKS; 7ARW; 7L9F; 7L9H; 7L9I
• EC Number: 3.2.1.143; 3.2.2.-; 3.5.1.-
• Pfam ID: PF03747
• Sequence:
  MAAAAMAAAAGGGAGAARSLSRFRGCLAGALLGDCVGSFYEAHDTVDLTSVLRHVQSLEP
  DPGTPGSERTEALYYTDDTAMARALVQSLLAKEAFDEVDMAHRFAQEYKKDPDRGYGAGV
  VTVFKKLLNPKCRDVFEPARAQFNGKGSYGNGGAMRVAGISLAYSSVQDVQKFARLSAQL
  THASSLGYNGAILQALAVHLALQGESSSEHFLKQLLGHMEDLEGDAQSVLDARELGMEER
  PYSSRLKKIGELLDQASVTREEVVSELGNGIAAFESVPTAIYCFLRCMEPDPEIPSAFNS
  LQRTLIYSISLGGDTDTIATMAGAIAGAYYGMDQVPESWQQSCEGYEETDILAQSLHRVF
  QKS
• Function: ADP-ribosylhydrolase that preferentially hydrolyzes the scissile alpha-O-linkage attached to the anomeric C1'' position of ADP-ribose and acts on different substrates, such as proteins ADP-ribosylated on serine and threonine, free poly(ADP-ribose) and O-acetyl-ADP-D-ribose. Specifically acts as a serine mono-ADP-ribosylhydrolase by mediating the removal of mono-ADP-ribose attached to serine residues on proteins, thereby playing a key role in DNA damage response. Serine ADP-ribosylation of proteins constitutes the primary form of ADP-ribosylation of proteins in response to DNA damage. Does not hydrolyze ADP-ribosyl-arginine, -cysteine, -diphthamide, or -asparagine bonds. Also able to degrade protein free poly(ADP-ribose), which is synthesized in response to DNA damage: free poly(ADP-ribose) acts as a potent cell death signal and its degradation by ADPRHL2 protects cells from poly(ADP-ribose)-dependent cell death, a process named parthanatos. Also hydrolyzes free poly(ADP-ribose) in mitochondria. Specifically digests O-acetyl-ADP-D-ribose, a product of deacetylation reactions catalyzed by sirtuins. Specifically degrades 1''-O-acetyl-ADP-D-ribose isomer, rather than 2''-O-acetyl-ADP-D-ribose or 3''-O-acetyl-ADP-D-ribose isomers.
• Tissue Specificity: Ubiquitous . Expressed in skin fibroblasts .
• KEGG Pathway: Base excision repair (hsa03410)
• Reactome Pathway: POLB-Dependent Long Patch Base Excision Repair (R-HSA-110362)

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast cancer	DIS7DPX1	Strong	Biomarker	[1]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[1]
Cerebral infarction	DISR1WNP	Strong	Biomarker	[2]
Hypercholesterolemia, familial, 4	DISFLNLI	Strong	Genetic Variation	[3]
Neurodegeneration, childhood-onset, stress-induced, with variable ataxia and seizures	DISITKR1	Strong	Autosomal recessive	[4]
Intellectual disability	DISMBNXP	moderate	Biomarker	[5]

This DOT Affected the Biotransformations of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
OAADPR	DM458IH	Investigative	ADP-ribosylhydrolase ARH3 (ADPRS) increases the hydrolysis of OAADPR.	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of ADP-ribosylhydrolase ARH3 (ADPRS).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of ADP-ribosylhydrolase ARH3 (ADPRS).	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of ADP-ribosylhydrolase ARH3 (ADPRS).	[7]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of ADP-ribosylhydrolase ARH3 (ADPRS).	[8]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of ADP-ribosylhydrolase ARH3 (ADPRS).	[9]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of ADP-ribosylhydrolase ARH3 (ADPRS).	[11]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of ADP-ribosylhydrolase ARH3 (ADPRS).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of ADP-ribosylhydrolase ARH3 (ADPRS).	[13]

References

• [1] Variations in the mRNA expression of poly(ADP-ribose) polymerases, poly(ADP-ribose) glycohydrolase and ADP-ribosylhydrolase 3 in breast tumors and impact on clinical outcome.Int J Cancer. 2013 Dec 15;133(12):2791-800. doi: 10.1002/ijc.28304. Epub 2013 Aug 9.
• [2] PARP1 inhibition alleviates injury in ARH3-deficient mice and human cells.JCI Insight. 2019 Feb 21;4(4):e124519. doi: 10.1172/jci.insight.124519. eCollection 2019 Feb 21.
• [3] Prevalence and clinical features of heterozygous carriers of autosomal recessive hypercholesterolemia in Sardinia.Atherosclerosis. 2009 Nov;207(1):162-7. doi: 10.1016/j.atherosclerosis.2009.04.027. Epub 2009 May 4.
• [4] A clinical utility study of exome sequencing versus conventional genetic testing in pediatric neurology. Genet Med. 2017 Sep;19(9):1055-1063. doi: 10.1038/gim.2017.1. Epub 2017 Mar 23.
• [5] Biallelic Mutations in ADPRHL2, Encoding ADP-Ribosylhydrolase 3, Lead to a Degenerative Pediatric Stress-Induced Epileptic Ataxia Syndrome.Am J Hum Genet. 2018 Sep 6;103(3):431-439. doi: 10.1016/j.ajhg.2018.07.010. Epub 2018 Aug 9.
• [6] 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.
• [7] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [8] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [9] Identification of novel low-dose bisphenol a targets in human foreskin fibroblast cells derived from hypospadias patients. PLoS One. 2012;7(5):e36711. doi: 10.1371/journal.pone.0036711. Epub 2012 May 4.
• [10] 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.
• [11] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [12] 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.
• [13] Isobaric tags for relative and absolute quantitation-based proteomics analysis of the effect of ginger oil on bisphenol A-induced breast cancer cell proliferation. Oncol Lett. 2021 Feb;21(2):101. doi: 10.3892/ol.2020.12362. Epub 2020 Dec 8.
• [14] Hydrolysis of O-acetyl-ADP-ribose isomers by ADP-ribosylhydrolase 3. J Biol Chem. 2011 Jun 17;286(24):21110-7. doi: 10.1074/jbc.M111.237636. Epub 2011 Apr 17.