Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT1CU8VR)

• DOT Name: Arylsulfatase A (ARSA)
• Synonyms: ASA; EC 3.1.6.8; Cerebroside-sulfatase
• Gene Name: ARSA
• Related Disease:
  Metachromatic leukodystrophy
  Metachromatic leukodystrophy, juvenile form
• UniProt ID: ARSA_HUMAN
• PDB ID: 1AUK; 1E1Z; 1E2S; 1E33; 1E3C; 1N2K; 1N2L; 2AIJ; 2AIK; 2HI8
• EC Number: 3.1.6.8
• Pfam ID: PF00884 ; PF14707
• Sequence:
  MGAPRSLLLALAAGLAVARPPNIVLIFADDLGYGDLGCYGHPSSTTPNLDQLAAGGLRFT
  DFYVPVSLCTPSRAALLTGRLPVRMGMYPGVLVPSSRGGLPLEEVTVAEVLAARGYLTGM
  AGKWHLGVGPEGAFLPPHQGFHRFLGIPYSHDQGPCQNLTCFPPATPCDGGCDQGLVPIP
  LLANLSVEAQPPWLPGLEARYMAFAHDLMADAQRQDRPFFLYYASHHTHYPQFSGQSFAE
  RSGRGPFGDSLMELDAAVGTLMTAIGDLGLLEETLVIFTADNGPETMRMSRGGCSGLLRC
  GKGTTYEGGVREPALAFWPGHIAPGVTHELASSLDLLPTLAALAGAPLPNVTLDGFDLSP
  LLLGTGKSPRQSLFFYPSYPDEVRGVFAVRTGKYKAHFFTQGSAHSDTTADPACHASSSL
  TAHEPPLLYDLSKDPGENYNLLGGVAGATPEVLQALKQLQLLKAQLDAAVTFGPSQVARG
  EDPALQICCHPGCTPRPACCHCPDPHA
• Function: Hydrolyzes cerebroside sulfate.
• KEGG Pathway:
  Sphingolipid metabolism (hsa00600)
  Metabolic pathways (hsa01100)
  Lysosome (hsa04142)
• Reactome Pathway:
  Neutrophil degranulation (R-HSA-6798695)
  Glycosphingolipid catabolism (R-HSA-9840310)
  The activation of arylsulfatases (R-HSA-1663150)
• BioCyc Pathway: MetaCyc:HS02032-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Metachromatic leukodystrophy	DIS3OMWS	Definitive	Autosomal recessive	[1]
Metachromatic leukodystrophy, juvenile form	DISAI38Z	Definitive	Autosomal recessive	[2]

2 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 Arylsulfatase A (ARSA).	[3]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Arylsulfatase A (ARSA).	[8]

8 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Arylsulfatase A (ARSA).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Arylsulfatase A (ARSA).	[5]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Arylsulfatase A (ARSA).	[6]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Arylsulfatase A (ARSA).	[7]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Arylsulfatase A (ARSA).	[7]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Arylsulfatase A (ARSA).	[9]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Arylsulfatase A (ARSA).	[10]
AHPN	DM8G6O4	Investigative	AHPN decreases the expression of Arylsulfatase A (ARSA).	[11]

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] An 11-bp deletion in the arylsulfatase A gene of a patient with late infantile metachromatic leukodystrophy. Hum Genet. 1991 Jun;87(2):155-8. doi: 10.1007/BF00204172.
• [3] 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.
• [4] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [5] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [6] 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.
• [7] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [8] 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.
• [9] Targeting MYCN in neuroblastoma by BET bromodomain inhibition. Cancer Discov. 2013 Mar;3(3):308-23.
• [10] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [11] ST1926, a novel and orally active retinoid-related molecule inducing apoptosis in myeloid leukemia cells: modulation of intracellular calcium homeostasis. Blood. 2004 Jan 1;103(1):194-207.