Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTZWAB73)

• DOT Name: N-acyl-aromatic-L-amino acid amidohydrolase (ACY3)
• Synonyms: carboxylate-forming; EC 3.5.1.114; Acylase III; Aminoacylase-3; ACY-3; Aspartoacylase-2; Hepatitis C virus core-binding protein 1; HCBP1; HCV core-binding protein 1
• Gene Name: ACY3
• Related Disease:
  Advanced cancer
  Hepatocellular carcinoma
  Neoplasm
  Neuroblastoma
  Spinocerebellar ataxia type 3
• UniProt ID: ACY3_HUMAN
• EC Number: 3.5.1.114
• Pfam ID: PF04952
• Sequence:
  MCSLPVPREPLRRVAVTGGTHGNEMSGVYLARHWLHAPAELQRASFSAVPVLANPAATSG
  CRRYVDHDLNRTFTSSFLNSRPTPDDPYEVTRARELNQLLGPKASGQAFDFVLDLHNTTA
  NMGTCLIAKSSHEVFAMHLCRHLQLQYPELSCQVFLYQRSGEESYNLDSVAKNGLGLELG
  PQPQGVLRADIFSRMRTLVATVLDFIELFNQGTAFPAFEMEAYRPVGVVDFPRTEAGHLA
  GTVHPQLQDRDFQPLQPGAPIFQMFSGEDLLYEGESTVYPVFINEAAYYEKGVAFVQTEK
  FTFTVPAMPALTPAPSPAS
• Function: Plays an important role in deacetylating mercapturic acids in kidney proximal tubules. Also acts on N-acetyl-aromatic amino acids.
• Reactome Pathway: Aflatoxin activation and detoxification (R-HSA-5423646)
• BioCyc Pathway: MetaCyc:HS13441-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[2]
Neoplasm	DISZKGEW	Strong	Altered Expression	[3]
Neuroblastoma	DISVZBI4	Strong	Biomarker	[3]
Spinocerebellar ataxia type 3	DISQBQID	Limited	Altered Expression	[4]

3 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 N-acyl-aromatic-L-amino acid amidohydrolase (ACY3).	[5]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of N-acyl-aromatic-L-amino acid amidohydrolase (ACY3).	[9]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of N-acyl-aromatic-L-amino acid amidohydrolase (ACY3).	[11]

4 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 N-acyl-aromatic-L-amino acid amidohydrolase (ACY3).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of N-acyl-aromatic-L-amino acid amidohydrolase (ACY3).	[7]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of N-acyl-aromatic-L-amino acid amidohydrolase (ACY3).	[8]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of N-acyl-aromatic-L-amino acid amidohydrolase (ACY3).	[10]

References

• [1] Hepatoma targeting peptide conjugated bio-reducible polymer complexed with oncolytic adenovirus for cancer gene therapy.J Control Release. 2015 Dec 28;220(Pt B):691-703. doi: 10.1016/j.jconrel.2015.09.068. Epub 2015 Oct 3.
• [2] Aminoacylase 3 Is a New Potential Marker and Therapeutic Target in Hepatocellular Carcinoma.J Cancer. 2018 Jan 1;9(1):1-12. doi: 10.7150/jca.21747. eCollection 2018.
• [3] Differential aminoacylase expression in neuroblastoma.Int J Cancer. 2011 Sep 15;129(6):1322-30. doi: 10.1002/ijc.25798. Epub 2011 Apr 1.
• [4] Comparison of spinocerebellar ataxia type 3 mouse models identifies early gain-of-function, cell-autonomous transcriptional changes in oligodendrocytes.Hum Mol Genet. 2017 Sep 1;26(17):3362-3374. doi: 10.1093/hmg/ddx224.
• [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] 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.
• [7] 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.
• [8] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [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] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [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.