Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTXD2IWK)

• DOT Name: Carbohydrate sulfotransferase 6 (CHST6)
• Synonyms: Corneal N-acetylglucosamine-6-O-sulfotransferase; C-GlcNAc6ST; hCGn6ST; EC 2.8.2.21; Galactose/N-acetylglucosamine/N-acetylglucosamine 6-O-sulfotransferase 4-beta; GST4-beta; N-acetylglucosamine 6-O-sulfotransferase 5; GlcNAc6ST-5; Gn6st-5
• Gene Name: CHST6
• Related Disease:
  Amyloidosis
  Corneal dystrophy
  Macular corneal dystrophy
• UniProt ID: CHST6_HUMAN
• EC Number: 2.8.2.21
• Pfam ID: PF00685
• Sequence:
  MWLPRVSSTAVTALLLAQTFLLLFLVSRPGPSSPAGGEARVHVLVLSSWRSGSSFVGQLF
  NQHPDVFYLMEPAWHVWTTLSQGSAATLHMAVRDLVRSVFLCDMDVFDAYLPWRRNLSDL
  FQWAVSRALCSPPACSAFPRGAISSEAVCKPLCARQSFTLAREACRSYSHVVLKEVRFFN
  LQVLYPLLSDPALNLRIVHLVRDPRAVLRSREQTAKALARDNGIVLGTNGTWVEADPGLR
  VVREVCRSHVRIAEAATLKPPPFLRGRYRLVRFEDLAREPLAEIRALYAFTGLSLTPQLE
  AWIHNITHGSGPGARREAFKTSSRNALNVSQAWRHALPFAKIRRVQELCAGALQLLGYRP
  VYSEDEQRNLALDLVLPRGLNGFTWASSTASHPRN
• Function: Sulfotransferase that utilizes 3'-phospho-5'-adenylyl sulfate (PAPS) as sulfonate donor to catalyze the transfer of sulfate to position 6 of non-reducing N-acetylglucosamine (GlcNAc) residues of keratan. Cooperates with B4GALT4 galactosyltransferase and B3GNT7 N-acetylglucosaminyltransferase to construct and elongate the sulfated disaccharide unit [->3Galbeta1->4(6-sulfoGlcNAcbeta)1->] within keratan sulfate polymer. Involved in biosynthesis of keratan sulfate in cornea, with an impact on proteoglycan fibril organization and corneal transparency. Involved in sulfation of endothelial mucins such as GLYCAM1.
• Tissue Specificity: Expressed in cornea. Mainly expressed in brain. Also expressed in spinal cord and trachea.
• KEGG Pathway: Glycosaminoglycan biosynthesis - keratan sulfate (hsa00533)
• Reactome Pathway:
  Defective CHST6 causes MCDC1 (R-HSA-3656225)
  Keratan sulfate biosynthesis (R-HSA-2022854)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Amyloidosis	DISHTAI2	Strong	Genetic Variation	[1]
Corneal dystrophy	DISRDPA6	Strong	Genetic Variation	[2]
Macular corneal dystrophy	DISOLD0H	Strong	Autosomal recessive	[3]

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 6 (CHST6).	[4]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the methylation of Carbohydrate sulfotransferase 6 (CHST6).	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Carbohydrate sulfotransferase 6 (CHST6).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate affects the expression of Carbohydrate sulfotransferase 6 (CHST6).	[7]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Carbohydrate sulfotransferase 6 (CHST6).	[8]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Carbohydrate sulfotransferase 6 (CHST6).	[9]
Selenium	DM25CGV	Approved	Selenium increases the expression of Carbohydrate sulfotransferase 6 (CHST6).	[10]
Dexamethasone	DMMWZET	Approved	Dexamethasone decreases the expression of Carbohydrate sulfotransferase 6 (CHST6).	[11]
Isotretinoin	DM4QTBN	Approved	Isotretinoin increases the expression of Carbohydrate sulfotransferase 6 (CHST6).	[12]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Carbohydrate sulfotransferase 6 (CHST6).	[13]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Carbohydrate sulfotransferase 6 (CHST6).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Carbohydrate sulfotransferase 6 (CHST6).	[14]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Carbohydrate sulfotransferase 6 (CHST6).	[15]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Carbohydrate sulfotransferase 6 (CHST6).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Carbohydrate sulfotransferase 6 (CHST6).	[17]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Carbohydrate sulfotransferase 6 (CHST6).	[18]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Carbohydrate sulfotransferase 6 (CHST6).	[19]

References

• [1] Novel CHST6 gene mutations in 2 unrelated cases of macular corneal dystrophy.Cornea. 2011 Jun;30(6):664-9. doi: 10.1097/ICO.0b013e3182012888.
• [2] TGFBI, CHST6, and GSN gene analysis in Mexican patients with stromal corneal dystrophies.Graefes Arch Clin Exp Ophthalmol. 2014 Aug;252(8):1267-72. doi: 10.1007/s00417-014-2648-9. Epub 2014 May 7.
• [3] Novel mutations in the CHST6 gene associated with macular corneal dystrophy in southern India. Arch Ophthalmol. 2003 Nov;121(11):1608-12. doi: 10.1001/archopht.121.11.1608.
• [4] 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.
• [5] 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.
• [6] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] Human drug metabolism genes in parathion-and estrogen-treated breast cells. Int J Mol Med. 2007 Dec;20(6):875-81.
• [9] Role of NADPH oxidase in arsenic-induced reactive oxygen species formation and cytotoxicity in myeloid leukemia cells. Proc Natl Acad Sci U S A. 2004 Mar 30;101(13):4578-83.
• [10] 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.
• [11] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [12] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [13] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [14] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
• [15] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [16] 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.
• [17] Bisphenol A and bisphenol S induce distinct transcriptional profiles in differentiating human primary preadipocytes. PLoS One. 2016 Sep 29;11(9):e0163318.
• [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] 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.