Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT2GRC5R)

• DOT Name: Carbohydrate sulfotransferase 1 (CHST1)
• Synonyms: Galactose/N-acetylglucosamine/N-acetylglucosamine 6-O-sulfotransferase 1; GST-1; Keratan sulfate Gal-6 sulfotransferase; KS6ST; KSGal6ST; KSST; EC 2.8.2.21
• Gene Name: CHST1
• Related Disease:
  Cataract
  Osteochondrodysplasia
  Parkinson disease
• UniProt ID: CHST1_HUMAN
• EC Number: 2.8.2.21
• Pfam ID: PF00685
• Sequence:
  MQCSWKAVLLLALASIAIQYTAIRTFTAKSFHTCPGLAEAGLAERLCEESPTFAYNLSRK
  THILILATTRSGSSFVGQLFNQHLDVFYLFEPLYHVQNTLIPRFTQGKSPADRRVMLGAS
  RDLLRSLYDCDLYFLENYIKPPPVNHTTDRIFRRGASRVLCSRPVCDPPGPADLVLEEGD
  CVRKCGLLNLTVAAEACRERSHVAIKTVRVPEVNDLRALVEDPRLNLKVIQLVRDPRGIL
  ASRSETFRDTYRLWRLWYGTGRKPYNLDVTQLTTVCEDFSNSVSTGLMRPPWLKGKYMLV
  RYEDLARNPMKKTEEIYGFLGIPLDSHVARWIQNNTRGDPTLGKHKYGTVRNSAATAEKW
  RFRLSYDIVAFAQNACQQVLAQLGYKIAASEEELKNPSVSLVEERDFRPFS
• Function: Sulfotransferase that utilizes 3'-phospho-5'-adenylyl sulfate (PAPS) as sulfonate donor to catalyze the transfer of sulfate to position 6 of internal galactose (Gal) residues of keratan. Cooperates with B4GALT4 and B3GNT7 glycosyltransferases and CHST6 sulfotransferase to construct and elongate disulfated disaccharide unit [->3(6-sulfoGalbeta)1->4(6-sulfoGlcNAcbeta)1->] within keratan sulfate polymer. Has a preference for sulfating keratan sulfate, but it also transfers sulfate to the unsulfated polymer. Involved in biosynthesis of phosphacan, a major keratan sulfate proteoglycan in the developing brain. Involved in biosynthesis of 6-sulfoGalbeta-containing O-linked glycans in high endothelial venules of lymph nodes. May act in a synergistic manner with CHST4 to generate sialyl 6',6-disulfo Lewis X motif, a recognition determinant for immune cell receptors implicated in leukocyte trafficking. Catalyzes sulfation of N-acetyllactosamine (LacNAc) oligosaccharides with highest efficiency for sialylated LacNAc structures.
• Tissue Specificity: Widely expressed at low level. Expressed in brain and skeletal muscle. Expressed by high endothelial cells (HEVs) and leukocytes.
• KEGG Pathway: Glycosaminoglycan biosynthesis - keratan sulfate (hsa00533)
• Reactome Pathway: Keratan sulfate biosynthesis (R-HSA-2022854)
• BioCyc Pathway: MetaCyc:HS10902-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cataract	DISUD7SL	Strong	Genetic Variation	[1]
Osteochondrodysplasia	DIS9SPWW	Limited	Genetic Variation	[2]
Parkinson disease	DISQVHKL	Limited	Genetic Variation	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Carbohydrate sulfotransferase 1 (CHST1).	[4]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Carbohydrate sulfotransferase 1 (CHST1).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Carbohydrate sulfotransferase 1 (CHST1).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Carbohydrate sulfotransferase 1 (CHST1).	[7]
Arsenic	DMTL2Y1	Approved	Arsenic decreases the expression of Carbohydrate sulfotransferase 1 (CHST1).	[8]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Carbohydrate sulfotransferase 1 (CHST1).	[9]
Permethrin	DMZ0Q1G	Approved	Permethrin increases the expression of Carbohydrate sulfotransferase 1 (CHST1).	[10]
Ibrolipim	DMOPWSX	Phase 2	Ibrolipim increases the expression of Carbohydrate sulfotransferase 1 (CHST1).	[11]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Carbohydrate sulfotransferase 1 (CHST1).	[13]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Carbohydrate sulfotransferase 1 (CHST1).	[15]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate increases the expression of Carbohydrate sulfotransferase 1 (CHST1).	[16]
Phencyclidine	DMQBEYX	Investigative	Phencyclidine increases the expression of Carbohydrate sulfotransferase 1 (CHST1).	[17]

2 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 affects the methylation of Carbohydrate sulfotransferase 1 (CHST1).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Carbohydrate sulfotransferase 1 (CHST1).	[14]

References

• [1] Frequency of glutathione-S-transferase 1 gene deletion and its possible correlation with cataract formation.Exp Eye Res. 1995 Feb;60(2):159-63. doi: 10.1016/s0014-4835(95)80006-9.
• [2] Spondyloepiphyseal dysplasia, Omani type: further definition of the phenotype.Am J Med Genet A. 2008 Sep 15;146A(18):2376-84. doi: 10.1002/ajmg.a.32482.
• [3] Glutathione-S-transferase-1 and interleukin-1beta gene polymorphisms in Japanese patients with Parkinson's disease.Mov Disord. 2005 Jul;20(7):901-2. doi: 10.1002/mds.20477.
• [4] The neuroprotective action of the mood stabilizing drugs lithium chloride and sodium valproate is mediated through the up-regulation of the homeodomain protein Six1. Toxicol Appl Pharmacol. 2009 Feb 15;235(1):124-34.
• [5] 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.
• [6] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [7] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [8] Arsenic alters transcriptional responses to Pseudomonas aeruginosa infection and decreases antimicrobial defense of human airway epithelial cells. Toxicol Appl Pharmacol. 2017 Sep 15;331:154-163.
• [9] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
• [10] Exposure to Insecticides Modifies Gene Expression and DNA Methylation in Hematopoietic Tissues In Vitro. Int J Mol Sci. 2023 Mar 26;24(7):6259. doi: 10.3390/ijms24076259.
• [11] Effects of NO-1886 (Ibrolipim), a lipoprotein lipase-promoting agent, on gene induction of cytochrome P450s, carboxylesterases, and sulfotransferases in primary cultures of human hepatocytes. Drug Metab Pharmacokinet. 2004 Dec;19(6):422-9.
• [12] 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.
• [13] 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.
• [14] 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.
• [15] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.
• [16] Comparison of the global gene expression profiles produced by methylparaben, n-butylparaben and 17beta-oestradiol in MCF7 human breast cancer cells. J Appl Toxicol. 2007 Jan-Feb;27(1):67-77. doi: 10.1002/jat.1200.
• [17] Differential response of Mono Mac 6, BEAS-2B, and Jurkat cells to indoor dust. Environ Health Perspect. 2007 Sep;115(9):1325-32.