Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTV11IZF)

• DOT Name: Carbohydrate sulfotransferase 2 (CHST2)
• Synonyms: EC 2.8.2.-; Galactose/N-acetylglucosamine/N-acetylglucosamine 6-O-sulfotransferase 2; GST-2; N-acetylglucosamine 6-O-sulfotransferase 1; GlcNAc6ST-1; Gn6ST-1
• Gene Name: CHST2
• Related Disease:
  Peptic ulcer
  Neoplasm
  Ulcerative colitis
  Adenocarcinoma
  Gastritis
  MALT lymphoma
  Amyotrophic lateral sclerosis
• UniProt ID: CHST2_HUMAN
• EC Number: 2.8.2.-
• Pfam ID: PF00685
• Sequence:
  MSRSPQRALPPGALPRLLQAAPAAAPRALLPQWPRRPGRRWPASPLGMKVFRRKALVLCA
  GYALLLVLTMLNLLDYKWHKEPLQQCNPDGPLGAAAGAAGGSWGRPGPPPAGPPRAHARL
  DLRTPYRPPAAAVGAAPAAAAGMAGVAAPPGNGTRGTGGVGDKRQLVYVFTTWRSGSSFF
  GELFNQNPEVFFLYEPVWHVWQKLYPGDAVSLQGAARDMLSALYRCDLSVFQLYSPAGSG
  GRNLTTLGIFGAATNKVVCSSPLCPAYRKEVVGLVDDRVCKKCPPQRLARFEEECRKYRT
  LVIKGVRVFDVAVLAPLLRDPALDLKVIHLVRDPRAVASSRIRSRHGLIRESLQVVRSRD
  PRAHRMPFLEAAGHKLGAKKEGVGGPADYHALGAMEVICNSMAKTLQTALQPPDWLQGHY
  LVVRYEDLVGDPVKTLRRVYDFVGLLVSPEMEQFALNMTSGSGSSSKPFVVSARNATQAA
  NAWRTALTFQQIKQVEEFCYQPMAVLGYERVNSPEEVKDLSKTLLRKPRL
• 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 within keratan-like structures on N-linked glycans and within mucin-associated glycans that can ultimately serve as SELL ligands. SELL ligands are present in high endothelial cells (HEVs) and play a central role in lymphocyte homing at sites of inflammation. Participates in biosynthesis of the SELL ligand sialyl 6-sulfo Lewis X and in lymphocyte homing to Peyer patches. Has no activity toward O-linked sugars. Its substrate specificity may be influenced by its subcellular location. Sulfates GlcNAc residues at terminal, non-reducing ends of oligosaccharide chains.
• Tissue Specificity: Widely expressed. Highly expressed in bone marrow, peripheral blood leukocytes, spleen, brain, spinal cord, ovary and placenta. 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:ENSG00000175040-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Peptic ulcer	DISL8XZI	Definitive	Genetic Variation	[1]
Neoplasm	DISZKGEW	Strong	Biomarker	[2]
Ulcerative colitis	DIS8K27O	Strong	Biomarker	[3]
Adenocarcinoma	DIS3IHTY	moderate	Altered Expression	[4]
Gastritis	DIS8G07K	moderate	Altered Expression	[5]
MALT lymphoma	DIS1AVVE	moderate	Biomarker	[5]
Amyotrophic lateral sclerosis	DISF7HVM	Limited	Genetic Variation	[6]

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 2 (CHST2).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Carbohydrate sulfotransferase 2 (CHST2).	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Carbohydrate sulfotransferase 2 (CHST2).	[8]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Carbohydrate sulfotransferase 2 (CHST2).	[9]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Carbohydrate sulfotransferase 2 (CHST2).	[10]
Marinol	DM70IK5	Approved	Marinol increases the expression of Carbohydrate sulfotransferase 2 (CHST2).	[11]
Bortezomib	DMNO38U	Approved	Bortezomib decreases the expression of Carbohydrate sulfotransferase 2 (CHST2).	[12]
Hydroquinone	DM6AVR4	Approved	Hydroquinone increases the expression of Carbohydrate sulfotransferase 2 (CHST2).	[13]
Ethanol	DMDRQZU	Approved	Ethanol increases the expression of Carbohydrate sulfotransferase 2 (CHST2).	[14]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Carbohydrate sulfotransferase 2 (CHST2).	[15]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Carbohydrate sulfotransferase 2 (CHST2).	[16]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Carbohydrate sulfotransferase 2 (CHST2).	[18]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Carbohydrate sulfotransferase 2 (CHST2).	[19]

References

• [1] Single nucleotide polymorphism markers for low-dose aspirin-associated peptic ulcer and ulcer bleeding.J Gastroenterol Hepatol. 2014 Dec;29 Suppl 4:47-52. doi: 10.1111/jgh.12770.
• [2] Diagnostic marker signature for esophageal cancer from transcriptome analysis.Tumour Biol. 2016 May;37(5):6349-58. doi: 10.1007/s13277-015-4400-4. Epub 2015 Dec 2.
• [3] GlcNAc6ST-1-mediated decoration of MAdCAM-1 protein with L-selectin ligand carbohydrates directs disease activity of ulcerative colitis.Inflamm Bowel Dis. 2009 May;15(5):697-706. doi: 10.1002/ibd.20827.
• [4] Ectopic expression of N-acetylglucosamine 6-O-sulfotransferase 2 in chemotherapy-resistant ovarian adenocarcinomas.Glycoconj J. 2006 Jul;23(5-6):453-60. doi: 10.1007/s10719-006-6979-6.
• [5] Induction of high endothelial venule-like vessels expressing GlcNAc6ST-1-mediated L-selectin ligand carbohydrate and mucosal addressin cell adhesion molecule 1 (MAdCAM-1) in a mouse model of "Candidatus Helicobacter heilmannii"-induced gastritis and gastric mucosa-associated lymphoid tissue (MALT) lymphoma.Helicobacter. 2010 Dec;15(6):538-48. doi: 10.1111/j.1523-5378.2010.00801.x.
• [6] Ablation of keratan sulfate accelerates early phase pathogenesis of ALS.PLoS One. 2013 Jun 25;8(6):e66969. doi: 10.1371/journal.pone.0066969. Print 2013.
• [7] 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.
• [8] 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.
• [9] 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.
• [10] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [11] Single-cell Transcriptome Mapping Identifies Common and Cell-type Specific Genes Affected by Acute Delta9-tetrahydrocannabinol in Humans. Sci Rep. 2020 Feb 26;10(1):3450. doi: 10.1038/s41598-020-59827-1.
• [12] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [13] Keratinocyte-derived IL-36gama plays a role in hydroquinone-induced chemical leukoderma through inhibition of melanogenesis in human epidermal melanocytes. Arch Toxicol. 2019 Aug;93(8):2307-2320.
• [14] Gene expression signatures after ethanol exposure in differentiating embryoid bodies. Toxicol In Vitro. 2018 Feb;46:66-76.
• [15] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [16] 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.
• [17] 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.
• [18] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.
• [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.