Details of Drug Off-Target (DOT)

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

• DOT Name: Arylsulfatase B (ARSB)
• Synonyms: ASB; EC 3.1.6.12; N-acetylgalactosamine-4-sulfatase; G4S
• Gene Name: ARSB
• Related Disease: Maroteaux-lamy syndrome
• UniProt ID: ARSB_HUMAN
• PDB ID: 1FSU
• EC Number: 3.1.6.12
• Pfam ID: PF00884
• Sequence:
  MGPRGAASLPRGPGPRRLLLPVVLPLLLLLLLAPPGSGAGASRPPHLVFLLADDLGWNDV
  GFHGSRIRTPHLDALAAGGVLLDNYYTQPLCTPSRSQLLTGRYQIRTGLQHQIIWPCQPS
  CVPLDEKLLPQLLKEAGYTTHMVGKWHLGMYRKECLPTRRGFDTYFGYLLGSEDYYSHER
  CTLIDALNVTRCALDFRDGEEVATGYKNMYSTNIFTKRAIALITNHPPEKPLFLYLALQS
  VHEPLQVPEEYLKPYDFIQDKNRHHYAGMVSLMDEAVGNVTAALKSSGLWNNTVFIFSTD
  NGGQTLAGGNNWPLRGRKWSLWEGGVRGVGFVASPLLKQKGVKNRELIHISDWLPTLVKL
  ARGHTNGTKPLDGFDVWKTISEGSPSPRIELLHNIDPNFVDSSPCPRNSMAPAKDDSSLP
  EYSAFNTSVHAAIRHGNWKLLTGYPGCGYWFPPPSQYNVSEIPSSDPPTKTLWLFDIDRD
  PEERHDLSREYPHIVTKLLSRLQFYHKHSVPVYFPAQDPRCDPKATGVWGPWM
• Function: Removes sulfate groups from chondroitin-4-sulfate (C4S) and regulates its degradation. Involved in the regulation of cell adhesion, cell migration and invasion in colonic epithelium. In the central nervous system, is a regulator of neurite outgrowth and neuronal plasticity, acting through the control of sulfate glycosaminoglycans and neurocan levels.
• KEGG Pathway:
  Glycosaminoglycan degradation (hsa00531)
  Metabolic pathways (hsa01100)
  Lysosome (hsa04142)
• Reactome Pathway:
  CS/DS degradation (R-HSA-2024101)
  MPS VI - Maroteaux-Lamy syndrome (R-HSA-2206285)
  Neutrophil degranulation (R-HSA-6798695)
  Glycosphingolipid catabolism (R-HSA-9840310)
  The activation of arylsulfatases (R-HSA-1663150)
• BioCyc Pathway: MetaCyc:HS03665-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Maroteaux-lamy syndrome	DISSLP8Z	Definitive	Autosomal recessive	[1]

This DOT Affected the Regulation of Drug Effects of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Chondroitin sulfate	DM0N19Y	Phase 4	Arylsulfatase B (ARSB) decreases the abundance of Chondroitin sulfate.	[12]

7 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 B (ARSB).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Arylsulfatase B (ARSB).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Arylsulfatase B (ARSB).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Arylsulfatase B (ARSB).	[5]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Arylsulfatase B (ARSB).	[7]
Irinotecan	DMP6SC2	Approved	Irinotecan decreases the expression of Arylsulfatase B (ARSB).	[8]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Arylsulfatase B (ARSB).	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Arylsulfatase B (ARSB).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Arylsulfatase B (ARSB).	[9]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Arylsulfatase B (ARSB).	[10]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] Stem cell transcriptome responses and corresponding biomarkers that indicate the transition from adaptive responses to cytotoxicity. Chem Res Toxicol. 2017 Apr 17;30(4):905-922.
• [3] Increased mitochondrial ROS formation by acetaminophen in human hepatic cells is associated with gene expression changes suggesting disruption of the mitochondrial electron transport chain. Toxicol Lett. 2015 Apr 16;234(2):139-50.
• [4] 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.
• [5] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [6] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [7] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [8] Clinical determinants of response to irinotecan-based therapy derived from cell line models. Clin Cancer Res. 2008 Oct 15;14(20):6647-55.
• [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] 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.
• [11] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [12] Decline in arylsulfatase B expression increases EGFR expression by inhibiting the protein-tyrosine phosphatase SHP2 and activating JNK in prostate cells. J Biol Chem. 2018 Jul 13;293(28):11076-11087. doi: 10.1074/jbc.RA117.001244. Epub 2018 May 24.