Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTCB1Z47)

• DOT Name: Carbohydrate sulfotransferase 3 (CHST3)
• Synonyms: EC 2.8.2.17; EC 2.8.2.21; Chondroitin 6-O-sulfotransferase 1; C6ST-1; Chondroitin 6-sulfotransferase; C6ST; Galactose/N-acetylglucosamine/N-acetylglucosamine 6-O-sulfotransferase 0; GST-0
• Gene Name: CHST3
• Related Disease: Spondyloepiphyseal dysplasia with congenital joint dislocations
• UniProt ID: CHST3_HUMAN
• EC Number: 2.8.2.17; 2.8.2.21
• Pfam ID: PF00685
• Sequence:
  MEKGLTLPQDCRDFVHSLKMRSKYALFLVFVVIVFVFIEKENKIISRVSDKLKQIPQALA
  DANSTDPALILAENASLLSLSELDSAFSQLQSRLRNLSLQLGVEPAMEAAGEEEEEQRKE
  EEPPRPAVAGPRRHVLLMATTRTGSSFVGEFFNQQGNIFYLFEPLWHIERTVSFEPGGAN
  AAGSALVYRDVLKQLFLCDLYVLEHFITPLPEDHLTQFMFRRGSSRSLCEDPVCTPFVKK
  VFEKYHCKNRRCGPLNVTLAAEACRRKEHMALKAVRIRQLEFLQPLAEDPRLDLRVIQLV
  RDPRAVLASRMVAFAGKYKTWKKWLDDEGQDGLREEEVQRLRGNCESIRLSAELGLRQPA
  WLRGRYMLVRYEDVARGPLQKAREMYRFAGIPLTPQVEDWIQKNTQAAHDGSGIYSTQKN
  SSEQFEKWRFSMPFKLAQVVQAACGPAMRLFGYKLARDAAALTNRSVSLLEERGTFWVT
• Function: Sulfotransferase that utilizes 3'-phospho-5'-adenylyl sulfate (PAPS) as sulfonate donor to catalyze the transfer of sulfate to position 6 of the N-acetylgalactosamine (GalNAc) residue of chondroitin. Chondroitin sulfate constitutes the predominant proteoglycan present in cartilage and is distributed on the surfaces of many cells and extracellular matrices. Catalyzes with a lower efficiency the sulfation of Gal residues of keratan sulfate, another glycosaminoglycan. Can also catalyze the sulfation of the Gal residues in sialyl N-acetyllactosamine (sialyl LacNAc) oligosaccharides. May play a role in the maintenance of naive T-lymphocytes in the spleen.
• Tissue Specificity: Widely expressed in adult tissues. Expressed in heart, placenta, skeletal muscle and pancreas. Also expressed in various immune tissues such as spleen, lymph node, thymus and appendix.
• KEGG Pathway: Glycosaminoglycan biosynthesis - chondroitin sulfate / dermatan sulfate (hsa00532)
• Reactome Pathway:
  Defective CHST3 causes SEDCJD (R-HSA-3595172)
  Chondroitin sulfate biosynthesis (R-HSA-2022870)
• BioCyc Pathway: MetaCyc:HS04610-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
Spondyloepiphyseal dysplasia with congenital joint dislocations	DISR9PTZ	Definitive	Autosomal recessive	[1]

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 Carbohydrate sulfotransferase 3 (CHST3).	[2]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Carbohydrate sulfotransferase 3 (CHST3).	[14]

18 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 Carbohydrate sulfotransferase 3 (CHST3).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Carbohydrate sulfotransferase 3 (CHST3).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Carbohydrate sulfotransferase 3 (CHST3).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Carbohydrate sulfotransferase 3 (CHST3).	[6]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Carbohydrate sulfotransferase 3 (CHST3).	[7]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Carbohydrate sulfotransferase 3 (CHST3).	[8]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Carbohydrate sulfotransferase 3 (CHST3).	[9]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Carbohydrate sulfotransferase 3 (CHST3).	[10]
Selenium	DM25CGV	Approved	Selenium increases the expression of Carbohydrate sulfotransferase 3 (CHST3).	[11]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Carbohydrate sulfotransferase 3 (CHST3).	[12]
Phenol	DM1QSM3	Phase 2/3	Phenol increases the expression of Carbohydrate sulfotransferase 3 (CHST3).	[13]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Carbohydrate sulfotransferase 3 (CHST3).	[11]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Carbohydrate sulfotransferase 3 (CHST3).	[15]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Carbohydrate sulfotransferase 3 (CHST3).	[16]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Carbohydrate sulfotransferase 3 (CHST3).	[17]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Carbohydrate sulfotransferase 3 (CHST3).	[18]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Carbohydrate sulfotransferase 3 (CHST3).	[19]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate increases the expression of Carbohydrate sulfotransferase 3 (CHST3).	[20]

References

• [1] Humero-spinal dysostosis. Pediatr Radiol. 1979 Jul 24;8(3):188-90. doi: 10.1007/BF00973833.
• [2] 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.
• [3] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [4] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [5] 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.
• [6] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [7] 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.
• [8] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [9] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [10] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [11] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [12] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [13] Classification of heavy-metal toxicity by human DNA microarray analysis. Environ Sci Technol. 2007 May 15;41(10):3769-74.
• [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] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [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] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [20] Transcriptome dynamics of alternative splicing events revealed early phase of apoptosis induced by methylparaben in H1299 human lung carcinoma cells. Arch Toxicol. 2020 Jan;94(1):127-140. doi: 10.1007/s00204-019-02629-w. Epub 2019 Nov 20.