Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTLJ5511)

• DOT Name: ADP-ribosylhydrolase ARH1 (ADPRH)
• Synonyms: EC 3.2.2.19; ADP-ribose-L-arginine cleaving enzyme; hydrolase; ADP-ribosylarginine hydrolase; hARH1
• Gene Name: ADPRH
• Related Disease:
  Neoplasm
  Epithelial ovarian cancer
  Familial hypercholesterolemia
  Hypercholesterolemia, familial, 1
  Hypercholesterolemia, familial, 4
  Vibrio cholerae infection
  Cardiomyopathy
• UniProt ID: ADPRH_HUMAN
• PDB ID: 3HFW; 6G28; 6G2A; 6IUX
• EC Number: 3.2.2.19
• Pfam ID: PF03747
• Sequence:
  MEKYVAAMVLSAAGDALGYYNGKWEFLQDGEKIHRQLAQLGGLDALDVGRWRVSDDTVMH
  LATAEALVEAGKAPKLTQLYYLLAKHYQDCMEDMDGRAPGGASVHNAMQLKPGKPNGWRI
  PFNSHEGGCGAAMRAMCIGLRFPHHSQLDTLIQVSIESGRMTHHHPTGYLGALASALFTA
  YAVNSRPPLQWGKGLMELLPEAKKYIVQSGYFVEENLQHWSYFQTKWENYLKLRGILDGE
  SAPTFPESFGVKERDQFYTSLSYSGWGGSSGHDAPMIAYDAVLAAGDSWKELAHRAFFHG
  GDSDSTAAIAGCWWGVMYGFKGVSPSNYEKLEYRNRLEETARALYSLGSKEDTVISL
• Function: Specifically acts as an arginine mono-ADP-ribosylhydrolase by mediating the removal of mono-ADP-ribose attached to arginine residues on proteins.

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neoplasm	DISZKGEW	Definitive	Biomarker	[1]
Epithelial ovarian cancer	DIS56MH2	Strong	Altered Expression	[2]
Familial hypercholesterolemia	DISC06IX	Strong	Genetic Variation	[3]
Hypercholesterolemia, familial, 1	DISU411W	Strong	Genetic Variation	[3]
Hypercholesterolemia, familial, 4	DISFLNLI	Strong	Biomarker	[3]
Vibrio cholerae infection	DISW7E3U	Strong	Biomarker	[4]
Cardiomyopathy	DISUPZRG	Limited	Biomarker	[5]

This DOT Affected the Biotransformations of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
OAADPR	DM458IH	Investigative	ADP-ribosylhydrolase ARH1 (ADPRH) increases the hydrolysis of OAADPR.	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of ADP-ribosylhydrolase ARH1 (ADPRH).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of ADP-ribosylhydrolase ARH1 (ADPRH).	[7]
Hydroquinone	DM6AVR4	Approved	Hydroquinone increases the expression of ADP-ribosylhydrolase ARH1 (ADPRH).	[8]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of ADP-ribosylhydrolase ARH1 (ADPRH).	[10]

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 decreases the methylation of ADP-ribosylhydrolase ARH1 (ADPRH).	[9]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of ADP-ribosylhydrolase ARH1 (ADPRH).	[11]

References

• [1] Emerging roles of ADP-ribosyl-acceptor hydrolases (ARHs) in tumorigenesis and cell death pathways.Biochem Pharmacol. 2019 Sep;167:44-49. doi: 10.1016/j.bcp.2018.09.028. Epub 2018 Sep 27.
• [2] EZH2-induced H3K27me3 is associated with epigenetic repression of the ARHI tumor-suppressor gene in ovarian cancer.Cell Biochem Biophys. 2015 Jan;71(1):105-12. doi: 10.1007/s12013-014-0168-1.
• [3] Genetic epidemiology of autosomal recessive hypercholesterolemia in Sicily: Identification by next-generation sequencing of a new kindred.J Clin Lipidol. 2018 Jan-Feb;12(1):145-151. doi: 10.1016/j.jacl.2017.10.014. Epub 2017 Oct 27.
• [4] Enhanced sensitivity to cholera toxin in female ADP-ribosylarginine hydrolase (ARH1)-deficient mice.PLoS One. 2018 Nov 30;13(11):e0207693. doi: 10.1371/journal.pone.0207693. eCollection 2018.
• [5] Role of a TRIM72 ADP-ribosylation cycle in myocardial injury and membrane repair.JCI Insight. 2018 Nov 15;3(22):e97898. doi: 10.1172/jci.insight.97898.
• [6] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [7] 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.
• [8] Keratinocyte-derived IL-36gama plays a role in hydroquinone-induced chemical leukoderma through inhibition of melanogenesis in human epidermal melanocytes. Arch Toxicol. 2019 Aug;93(8):2307-2320.
• [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] 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.
• [11] 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.
• [12] 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.