Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTF1VTCR)

• DOT Name: Arylsulfatase L (ARSL)
• Synonyms: EC 3.1.6.1; Arylsulfatase E; ASE
• Gene Name: ARSL
• Related Disease:
  X-linked chondrodysplasia punctata 1
  Arteriosclerosis
  Atherosclerosis
  Autoimmune disease
  Cardiac disease
  Cardiac failure
  Congestive heart failure
  High blood pressure
  Keutel syndrome
  Kidney failure
  Nephropathy
  Non-insulin dependent diabetes
  Respiratory failure
  Testicular cancer
  Turner syndrome
  Advanced cancer
  Prostate cancer
  Prostate carcinoma
• UniProt ID: ARSL_HUMAN
• EC Number: 3.1.6.1
• Pfam ID: PF00884 ; PF14707
• Sequence:
  MLHLHHSCLCFRSWLPAMLAVLLSLAPSASSDISASRPNILLLMADDLGIGDIGCYGNNT
  MRTPNIDRLAEDGVKLTQHISAASLCTPSRAAFLTGRYPVRSGMVSSIGYRVLQWTGASG
  GLPTNETTFAKILKEKGYATGLIGKWHLGLNCESASDHCHHPLHHGFDHFYGMPFSLMGD
  CARWELSEKRVNLEQKLNFLFQVLALVALTLVAGKLTHLIPVSWMPVIWSALSAVLLLAS
  SYFVGALIVHADCFLMRNHTITEQPMCFQRTTPLILQEVASFLKRNKHGPFLLFVSFLHV
  HIPLITMENFLGKSLHGLYGDNVEEMDWMVGRILDTLDVEGLSNSTLIYFTSDHGGSLEN
  QLGNTQYGGWNGIYKGGKGMGGWEGGIRVPGIFRWPGVLPAGRVIGEPTSLMDVFPTVVR
  LAGGEVPQDRVIDGQDLLPLLLGTAQHSDHEFLMHYCERFLHAARWHQRDRGTMWKVHFV
  TPVFQPEGAGACYGRKVCPCFGEKVVHHDPPLLFDLSRDPSETHILTPASEPVFYQVMER
  VQQAVWEHQRTLSPVPLQLDRLGNIWRPWLQPCCGPFPLCWCLREDDPQ
• Function: Exhibits arylsulfatase activity towards the artificial substrate 4-methylumbelliferyl sulfate. May be essential for the correct composition of cartilage and bone matrix during development. Has no activity toward steroid sulfates.
• Tissue Specificity: Expressed in the pancreas, liver and kidney.
• Reactome Pathway:
  Glycosphingolipid catabolism (R-HSA-9840310)
  The activation of arylsulfatases (R-HSA-1663150)

Molecular Interaction Atlas (MIA) of This DOT

18 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
X-linked chondrodysplasia punctata 1	DISS63GL	Definitive	X-linked	[1]
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[2]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[2]
Autoimmune disease	DISORMTM	Strong	Genetic Variation	[3]
Cardiac disease	DISVO1I5	Strong	Altered Expression	[4]
Cardiac failure	DISDC067	Strong	Biomarker	[5]
Congestive heart failure	DIS32MEA	Strong	Biomarker	[5]
High blood pressure	DISY2OHH	Strong	Biomarker	[6]
Keutel syndrome	DISV1U6H	Strong	Genetic Variation	[7]
Kidney failure	DISOVQ9P	Strong	Biomarker	[6]
Nephropathy	DISXWP4P	Strong	Biomarker	[6]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Biomarker	[5]
Respiratory failure	DISVMYJO	Strong	Biomarker	[8]
Testicular cancer	DIS6HNYO	Strong	Genetic Variation	[9]
Turner syndrome	DIS2035C	Strong	Biomarker	[10]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[11]
Prostate cancer	DISF190Y	Limited	Biomarker	[12]
Prostate carcinoma	DISMJPLE	Limited	Biomarker	[12]

9 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 Arylsulfatase L (ARSL).	[13]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Arylsulfatase L (ARSL).	[14]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Arylsulfatase L (ARSL).	[15]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Arylsulfatase L (ARSL).	[16]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Arylsulfatase L (ARSL).	[17]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Arylsulfatase L (ARSL).	[18]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Arylsulfatase L (ARSL).	[19]
Warfarin	DMJYCVW	Approved	Warfarin decreases the activity of Arylsulfatase L (ARSL).	[20]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Arylsulfatase L (ARSL).	[22]

1 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 Arylsulfatase L (ARSL).	[21]

References

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• [2] Age-specific diastolic dysfunction improves prediction of symptomatic heart failure by Stage B heart failure.ESC Heart Fail. 2019 Aug;6(4):747-757. doi: 10.1002/ehf2.12449. Epub 2019 May 15.
• [3] A prospective study of brachytelephalangic chondrodysplasia punctata: identification of arylsulfatase E mutations, functional analysis of novel missense alleles, and determination of potential phenocopies.Genet Med. 2013 Aug;15(8):650-7. doi: 10.1038/gim.2013.13. Epub 2013 Mar 7.
• [4] Diastolic function deterioration in type 2 diabetes mellitus: predictive factors over a 3-year follow-up.Eur Heart J Cardiovasc Imaging. 2018 Jan 1;19(1):67-73. doi: 10.1093/ehjci/jew331.
• [5] Comparing the influence of 2009 versus 2016 ASE/EACVI diastolic function guidelines on the prevalence and echocardiographic characteristics of preclinical diastolic dysfunction (stage B heart failure) in a Hispanic population with type 2 diabetes mellitus.J Diabetes Complications. 2019 Aug;33(8):579-584. doi: 10.1016/j.jdiacomp.2019.04.015. Epub 2019 May 7.
• [6] Preserved regulation of renal perfusion pressure by small and intermediate conductance KCa channels in hypertensive mice with or without renal failure.Pflugers Arch. 2015 Apr;467(4):817-31. doi: 10.1007/s00424-014-1542-y. Epub 2014 Jun 7.
• [7] Keutel syndrome: report of two novel MGP mutations and discussion of clinical overlap with arylsulfatase E deficiency and relapsing polychondritis.Am J Med Genet A. 2014 Apr;164A(4):1062-8. doi: 10.1002/ajmg.a.36390. Epub 2014 Jan 23.
• [8] Surgical management of cervical spine deformity in chondrodysplasia punctata.J Neurosurg Pediatr. 2017 Oct;20(4):378-387. doi: 10.3171/2017.5.PEDS16554. Epub 2017 Aug 11.
• [9] Polymorphisms in RAI and in genes of nucleotide and base excision repair are not associated with risk of testicular cancer.Cancer Lett. 2005 Jul 28;225(2):245-51. doi: 10.1016/j.canlet.2005.03.021.
• [10] Neonatal detection of Turner syndrome by real-time PCR gene quantification of the ARSE and MAGEH1 genes.Genet Mol Res. 2014 Oct 31;13(4):9068-76. doi: 10.4238/2014.October.31.22.
• [11] MBASED: allele-specific expression detection in cancer tissues and cell lines.Genome Biol. 2014 Aug 7;15(8):405. doi: 10.1186/s13059-014-0405-3.
• [12] ASEQ: fast allele-specific studies from next-generation sequencing data.BMC Med Genomics. 2015 Mar 1;8:9. doi: 10.1186/s12920-015-0084-2.
• [13] 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.
• [14] 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.
• [15] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [16] 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.
• [17] 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.
• [18] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [19] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [20] A cluster of sulfatase genes on Xp22.3: mutations in chondrodysplasia punctata (CDPX) and implications for warfarin embryopathy. Cell. 1995 Apr 7;81(1):15-25. doi: 10.1016/0092-8674(95)90367-4.
• [21] 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.
• [22] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.