Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTGSRHS4)

• DOT Name: Heparan sulfate glucosamine 3-O-sulfotransferase 6 (HS3ST6)
• Synonyms: EC 2.8.2.23; Heparan sulfate D-glucosaminyl 3-O-sulfotransferase 6; 3-OST-6; Heparan sulfate 3-O-sulfotransferase 6; h3-OST-6
• Gene Name: HS3ST6
• Related Disease:
  Herpes simplex infection
  Pneumoconiosis
• UniProt ID: HS3S6_HUMAN
• EC Number: 2.8.2.23
• Pfam ID: PF00685
• Sequence:
  MAGSGGLGGGAGGGQGAGAGQGAALRASRAPMLLVALVLGAYCLCALPGRCPPAARAPAP
  APAPSEPSSSVHRPGAPGLPLASGPGRRRFPQALIVGVKKGGTRALLEFLRLHPDVRALG
  SEPHFFDRCYERGLAWYRSLMPRTLDGQITMEKTPSYFVTREAPRRIHAMSPDTKLIVVV
  RNPVTRAISDYAQTLSKTPGLPSFRALAFRHGLGPVDTAWSAVRIGLYAQHLDHWLRYFP
  LSHFLFVSGERLVSDPAGEVGRVQDFLGLKRVVTDKHFYFNATKGFPCLKKAQGGSRPRC
  LGKSKGRPHPRVPQALVRRLQEFYRPFNRRFYQMTGQDFGWG
• Function: Sulfotransferase that utilizes 3'-phospho-5'-adenylyl sulfate (PAPS) to catalyze the transfer of a sulfo group to heparan sulfate. The substrate-specific O-sulfation generates an enzyme-modified heparan sulfate which acts as a binding receptor to Herpes Simplex Virus-1 (HSV-1) and permits its entry. Unlike 3-OST-1, does not convert non-anticoagulant heparan sulfate to anticoagulant heparan sulfate.
• Reactome Pathway: HS-GAG biosynthesis (R-HSA-2022928)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Herpes simplex infection	DISL1SAV	Strong	Biomarker	[1]
Pneumoconiosis	DISSJLBN	Strong	Biomarker	[2]

3 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 Heparan sulfate glucosamine 3-O-sulfotransferase 6 (HS3ST6).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the methylation of Heparan sulfate glucosamine 3-O-sulfotransferase 6 (HS3ST6).	[4]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Heparan sulfate glucosamine 3-O-sulfotransferase 6 (HS3ST6).	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Heparan sulfate glucosamine 3-O-sulfotransferase 6 (HS3ST6).	[5]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Heparan sulfate glucosamine 3-O-sulfotransferase 6 (HS3ST6).	[6]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Heparan sulfate glucosamine 3-O-sulfotransferase 6 (HS3ST6).	[7]

References

• [1] Heparan sulfate 3-O-sulfotransferase isoform 5 generates both an antithrombin-binding site and an entry receptor for herpes simplex virus, type 1.J Biol Chem. 2002 Oct 4;277(40):37912-9. doi: 10.1074/jbc.M204209200. Epub 2002 Jul 23.
• [2] Pathway analysis for a genome-wide association study of pneumoconiosis.Toxicol Lett. 2015 Jan 5;232(1):284-92. doi: 10.1016/j.toxlet.2014.10.028. Epub 2014 Nov 4.
• [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] 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.
• [5] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [6] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [7] Endoplasmic reticulum stress contributes to arsenic trioxide-induced intrinsic apoptosis in human umbilical and bone marrow mesenchymal stem cells. Environ Toxicol. 2016 Mar;31(3):314-28.
• [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.