Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTT7TDW7)

• DOT Name: Arylsulfatase G (ARSG)
• Synonyms: ASG; EC 3.1.6.1; N-sulfoglucosamine-3-sulfatase; EC 3.1.6.15
• Gene Name: ARSG
• Related Disease:
  Focal dystonia
  Advanced cancer
  Mucopolysaccharidosis
  Prostate cancer
  Prostate neoplasm
  Segmental dystonia
  Usher syndrome, type 4
  Usher syndrome
  Usher syndrome type 3
  Cerebellar ataxia
  Lysosomal storage disease
  Mucopolysaccharidosis type IIIA
  Neuronal ceroid lipofuscinosis
• UniProt ID: ARSG_HUMAN
• EC Number: 3.1.6.1; 3.1.6.15
• Pfam ID: PF00884 ; PF14707
• Sequence:
  MGWLFLKVLLAGVSFSGFLYPLVDFCISGKTRGQKPNFVIILADDMGWGDLGANWAETKD
  TANLDKMASEGMRFVDFHAAASTCSPSRASLLTGRLGLRNGVTRNFAVTSVGGLPLNETT
  LAEVLQQAGYVTGIIGKWHLGHHGSYHPNFRGFDYYFGIPYSHDMGCTDTPGYNHPPCPA
  CPQGDGPSRNLQRDCYTDVALPLYENLNIVEQPVNLSSLAQKYAEKATQFIQRASTSGRP
  FLLYVALAHMHVPLPVTQLPAAPRGRSLYGAGLWEMDSLVGQIKDKVDHTVKENTFLWFT
  GDNGPWAQKCELAGSVGPFTGFWQTRQGGSPAKQTTWEGGHRVPALAYWPGRVPVNVTST
  ALLSVLDIFPTVVALAQASLPQGRRFDGVDVSEVLFGRSQPGHRVLFHPNSGAAGEFGAL
  QTVRLERYKAFYITGGARACDGSTGPELQHKFPLIFNLEDDTAEAVPLERGGAEYQAVLP
  EVRKVLADVLQDIANDNISSADYTQDPSVTPCCNPYQIACRCQAA
• Function: Displays arylsulfatase activity at acidic pH towards artificial substrates, such as p-nitrocatechol sulfate and also, but with a lower activity towards p-nitrophenyl sulfate and 4-methylumbelliferyl sulfate. Catalyzes the hydrolysis of the 3-sulfate groups of the N-sulfo-D-glucosamine 3-O-sulfate units of heparin.
• Tissue Specificity: Widely expressed, with very low expression in brain, lung, heart and skeletal muscle.
• KEGG Pathway: Lysosome (hsa04142)
• Reactome Pathway:
  Glycosphingolipid catabolism (R-HSA-9840310)
  The activation of arylsulfatases (R-HSA-1663150)

Molecular Interaction Atlas (MIA) of This DOT

13 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Focal dystonia	DIS26D7O	Definitive	Genetic Variation	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Mucopolysaccharidosis	DISB083T	Strong	Biomarker	[3]
Prostate cancer	DISF190Y	Strong	Biomarker	[2]
Prostate neoplasm	DISHDKGQ	Strong	Biomarker	[2]
Segmental dystonia	DISOACMU	Strong	Genetic Variation	[4]
Usher syndrome, type 4	DISH1RFK	Strong	Autosomal recessive	[3]
Usher syndrome	DIS9YIS7	moderate	Genetic Variation	[5]
Usher syndrome type 3	DISRAL84	Supportive	Autosomal recessive	[5]
Cerebellar ataxia	DIS9IRAV	Limited	Biomarker	[6]
Lysosomal storage disease	DIS6QM6U	Limited	Biomarker	[6]
Mucopolysaccharidosis type IIIA	DISP7DR6	Limited	Biomarker	[6]
Neuronal ceroid lipofuscinosis	DIS9A4K4	Limited	Biomarker	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Arylsulfatase G (ARSG).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Arylsulfatase G (ARSG).	[14]

12 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 Arylsulfatase G (ARSG).	[8]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Arylsulfatase G (ARSG).	[9]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Arylsulfatase G (ARSG).	[10]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Arylsulfatase G (ARSG).	[11]
Ethanol	DMDRQZU	Approved	Ethanol increases the expression of Arylsulfatase G (ARSG).	[12]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Arylsulfatase G (ARSG).	[13]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Arylsulfatase G (ARSG).	[15]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Arylsulfatase G (ARSG).	[16]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Arylsulfatase G (ARSG).	[17]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Arylsulfatase G (ARSG).	[18]
Deguelin	DMXT7WG	Investigative	Deguelin increases the expression of Arylsulfatase G (ARSG).	[19]
PP-242	DM2348V	Investigative	PP-242 increases the expression of Arylsulfatase G (ARSG).	[20]

References

• [1] Lack of Association of the rs11655081 ARSG Gene with Blepharospasm.J Mol Neurosci. 2019 Mar;67(3):472-476. doi: 10.1007/s12031-018-1255-3. Epub 2019 Jan 18.
• [2] The Discovery and Preclinical Development of ASG-5ME, an Antibody-Drug Conjugate Targeting SLC44A4-Positive Epithelial Tumors Including Pancreatic and Prostate Cancer.Mol Cancer Ther. 2016 Nov;15(11):2679-2687. doi: 10.1158/1535-7163.MCT-16-0225. Epub 2016 Aug 22.
• [3] Degeneration of Photoreceptor Cells in Arylsulfatase G-Deficient Mice. Invest Ophthalmol Vis Sci. 2016 Mar;57(3):1120-31. doi: 10.1167/iovs.15-17645.
• [4] Genome-wide association study in musician's dystonia: a risk variant at the arylsulfatase G locus?.Mov Disord. 2014 Jun;29(7):921-7. doi: 10.1002/mds.25791. Epub 2013 Dec 26.
• [5] A homozygous founder missense variant in arylsulfatase G abolishes its enzymatic activity causing atypical Usher syndrome in humans. Genet Med. 2018 Sep;20(9):1004-1012. doi: 10.1038/gim.2017.227. Epub 2018 Jan 4.
• [6] Ataxia is the major neuropathological finding in arylsulfatase G-deficient mice: similarities and dissimilarities to Sanfilippo disease (mucopolysaccharidosis type III).Hum Mol Genet. 2015 Apr 1;24(7):1856-68. doi: 10.1093/hmg/ddu603. Epub 2014 Dec 1.
• [7] 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.
• [8] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [9] 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.
• [10] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [11] 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.
• [12] Gene expression signatures after ethanol exposure in differentiating embryoid bodies. Toxicol In Vitro. 2018 Feb;46:66-76.
• [13] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [14] 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.
• [15] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [16] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [17] 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.
• [18] 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.
• [19] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.
• [20] Marine biogenics in sea spray aerosols interact with the mTOR signaling pathway. Sci Rep. 2019 Jan 24;9(1):675.