Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT9WU7X3)

• DOT Name: Aminoacylase-1 (ACY1)
• Synonyms: ACY-1; EC 3.5.1.14; N-acyl-L-amino-acid amidohydrolase
• Gene Name: ACY1
• Related Disease:
  Aminoacylase 1 deficiency
  Metabolic disorder
  Advanced cancer
  Biotinidase deficiency
  Clear cell renal carcinoma
  Colorectal carcinoma
  Dystonia
  Herpes simplex infection
  Intellectual disability
  Neoplasm
  Neuroblastoma
  Papillary renal cell carcinoma
  Prostate adenocarcinoma
  Inborn error of metabolism
  Amyotrophic lateral sclerosis
  Colonic neoplasm
  Dementia
  Non-small-cell lung cancer
  Precancerous condition
  Renal cell carcinoma
  Retinoblastoma
• UniProt ID: ACY1_HUMAN
• PDB ID: 1Q7L
• EC Number: 3.5.1.14
• Pfam ID: PF07687 ; PF01546
• Sequence:
  MTSKGPEEEHPSVTLFRQYLRIRTVQPKPDYGAAVAFFEETARQLGLGCQKVEVAPGYVV
  TVLTWPGTNPTLSSILLNSHTDVVPVFKEHWSHDPFEAFKDSEGYIYARGAQDMKCVSIQ
  YLEAVRRLKVEGHRFPRTIHMTFVPDEEVGGHQGMELFVQRPEFHALRAGFALDEGIANP
  TDAFTVFYSERSPWWVRVTSTGRPGHASRFMEDTAAEKLHKVVNSILAFREKEWQRLQSN
  PHLKEGSVTSVNLTKLEGGVAYNVIPATMSASFDFRVAPDVDFKAFEEQLQSWCQAAGEG
  VTLEFAQKWMHPQVTPTDDSNPWWAAFSRVCKDMNLTLEPEIMPAATDNRYIRAVGVPAL
  GFSPMNRTPVLLHDHDERLHEAVFLRGVDIYTRLLPALASVPALPSDS
• Function: Catalyzes the hydrolysis of N-acetylated amino acids to acetate and free amino acids.
• Tissue Specificity: Expression is highest in kidney, strong in brain and weaker in placenta and spleen.
• KEGG Pathway:
  Arginine biosynthesis (hsa00220)
  Metabolic pathways (hsa01100)
  2-Oxocarboxylic acid metabolism (hsa01210)
  Biosynthesis of amino acids (hsa01230)
• Reactome Pathway:
  Defective ACY1 causes encephalopathy (R-HSA-5579007)
  Paracetamol ADME (R-HSA-9753281)
  Aflatoxin activation and detoxification (R-HSA-5423646)
• BioCyc Pathway: MetaCyc:HS03800-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

21 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Aminoacylase 1 deficiency	DISKZTPI	Definitive	Autosomal recessive	[1]
Metabolic disorder	DIS71G5H	Definitive	Biomarker	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Biotinidase deficiency	DISFHBBV	Strong	Biomarker	[4]
Clear cell renal carcinoma	DISBXRFJ	Strong	Biomarker	[5]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[3]
Dystonia	DISJLFGW	Strong	Biomarker	[6]
Herpes simplex infection	DISL1SAV	Strong	Genetic Variation	[7]
Intellectual disability	DISMBNXP	Strong	Biomarker	[8]
Neoplasm	DISZKGEW	Strong	Biomarker	[9]
Neuroblastoma	DISVZBI4	Strong	Biomarker	[9]
Papillary renal cell carcinoma	DIS25HBV	Strong	Biomarker	[5]
Prostate adenocarcinoma	DISBZYU8	Strong	Altered Expression	[10]
Inborn error of metabolism	DISO5FAY	moderate	Biomarker	[11]
Amyotrophic lateral sclerosis	DISF7HVM	Limited	Biomarker	[12]
Colonic neoplasm	DISSZ04P	Limited	Altered Expression	[13]
Dementia	DISXL1WY	Limited	Biomarker	[12]
Non-small-cell lung cancer	DIS5Y6R9	Limited	Altered Expression	[13]
Precancerous condition	DISV06FL	Limited	Biomarker	[14]
Renal cell carcinoma	DISQZ2X8	Limited	Biomarker	[9]
Retinoblastoma	DISVPNPB	Limited	Biomarker	[13]

15 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 Aminoacylase-1 (ACY1).	[15]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Aminoacylase-1 (ACY1).	[16]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Aminoacylase-1 (ACY1).	[17]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Aminoacylase-1 (ACY1).	[18]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Aminoacylase-1 (ACY1).	[19]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of Aminoacylase-1 (ACY1).	[20]
Selenium	DM25CGV	Approved	Selenium increases the expression of Aminoacylase-1 (ACY1).	[21]
Phenobarbital	DMXZOCG	Approved	Phenobarbital increases the expression of Aminoacylase-1 (ACY1).	[22]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Aminoacylase-1 (ACY1).	[23]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone decreases the expression of Aminoacylase-1 (ACY1).	[24]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Aminoacylase-1 (ACY1).	[25]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Aminoacylase-1 (ACY1).	[26]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Aminoacylase-1 (ACY1).	[27]
Phencyclidine	DMQBEYX	Investigative	Phencyclidine decreases the expression of Aminoacylase-1 (ACY1).	[28]
OXYQUINOLINE	DMZVS9Y	Investigative	OXYQUINOLINE decreases the expression of Aminoacylase-1 (ACY1).	[18]

References

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• [2] Aminoacylase 1 deficiency associated with autistic behavior.J Inherit Metab Dis. 2010 Dec;33 Suppl 3:S211-4. doi: 10.1007/s10545-010-9089-3. Epub 2010 May 18.
• [3] Study of the expression and function of ACY1 in patients with colorectal cancer.Oncol Lett. 2017 Apr;13(4):2459-2464. doi: 10.3892/ol.2017.5702. Epub 2017 Feb 8.
• [4] Mutations in ACY1, the gene encoding aminoacylase 1, cause a novel inborn error of metabolism. Am J Hum Genet. 2006 Mar;78(3):401-9. doi: 10.1086/500563. Epub 2006 Jan 18.
• [5] Differential protein profiling in renal-cell carcinoma.Mol Carcinog. 2004 May;40(1):47-61. doi: 10.1002/mc.20015.
• [6] Expanding the phenotype in aminoacylase 1 (ACY1) deficiency: characterization of the molecular defect in a 63-year-old woman with generalized dystonia.Metab Brain Dis. 2016 Jun;31(3):587-92. doi: 10.1007/s11011-015-9778-6. Epub 2015 Dec 19.
• [7] Integration site(s) of herpes simplex virus type 1 thymidine kinase gene and regional assignment of the gene for aminoacylase-1 in human chromosomes.Cytogenet Cell Genet. 1980;26(2-4):93-103. doi: 10.1159/000131430.
• [8] Advantages and pitfalls of an extended gene panel for investigating complex neurometabolic phenotypes.Brain. 2016 Nov 1;139(11):2844-2854. doi: 10.1093/brain/aww221.
• [9] Differential aminoacylase expression in neuroblastoma.Int J Cancer. 2011 Sep 15;129(6):1322-30. doi: 10.1002/ijc.25798. Epub 2011 Apr 1.
• [10] A human gene encoding diazepam-binding inhibitor/acy1-CoA-binding protein: transcription and hormonal regulation in the androgen-sensitive human prostatic adenocarcinoma cell line LNCaP.DNA Cell Biol. 1996 Mar;15(3):197-208. doi: 10.1089/dna.1996.15.197.
• [11] Aminoacylase I deficiency due to ACY1 mRNA exon skipping.Clin Genet. 2014 Oct;86(4):367-72. doi: 10.1111/cge.12297. Epub 2013 Nov 18.
• [12] Characterization of Parkinson's disease using blood-based biomarkers: A multicohort proteomic analysis.PLoS Med. 2019 Oct 11;16(10):e1002931. doi: 10.1371/journal.pmed.1002931. eCollection 2019 Oct.
• [13] Lack of expression of aminoacylase-1 in small cell lung cancer. Evidence for inactivation of genes encoded by chromosome 3p.J Clin Invest. 1989 Jun;83(6):2120-4. doi: 10.1172/JCI114125.
• [14] Hepatocellular carcinoma-associated protein markers investigated by MALDI-TOF MS.Mol Med Rep. 2010 Jul-Aug;3(4):589-96. doi: 10.3892/mmr_00000302.
• [15] 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.
• [16] 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.
• [17] 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.
• [18] 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.
• [19] Proteomic and functional analyses reveal a dual molecular mechanism underlying arsenic-induced apoptosis in human multiple myeloma cells. J Proteome Res. 2009 Jun;8(6):3006-19.
• [20] MS4A3-HSP27 target pathway reveals potential for haematopoietic disorder treatment in alimentary toxic aleukia. Cell Biol Toxicol. 2023 Feb;39(1):201-216. doi: 10.1007/s10565-021-09639-4. Epub 2021 Sep 28.
• [21] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [22] Proteomic analysis of hepatic effects of phenobarbital in mice with humanized liver. Arch Toxicol. 2022 Oct;96(10):2739-2754. doi: 10.1007/s00204-022-03338-7. Epub 2022 Jul 26.
• [23] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [24] Transcriptomic analysis of untreated and drug-treated differentiated HepaRG cells over a 2-week period. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):27-35.
• [25] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [26] Quantitative proteomics and transcriptomics addressing the estrogen receptor subtype-mediated effects in T47D breast cancer cells exposed to the phytoestrogen genistein. Mol Cell Proteomics. 2011 Jan;10(1):M110.002170.
• [27] Low-dose Bisphenol A exposure alters the functionality and cellular environment in a human cardiomyocyte model. Environ Pollut. 2023 Oct 15;335:122359. doi: 10.1016/j.envpol.2023.122359. Epub 2023 Aug 9.
• [28] Differential response of Mono Mac 6, BEAS-2B, and Jurkat cells to indoor dust. Environ Health Perspect. 2007 Sep;115(9):1325-32.