Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT5DVN9P)

• DOT Name: Heparan sulfate glucosamine 3-O-sulfotransferase 1 (HS3ST1)
• Synonyms: EC 2.8.2.23; Heparan sulfate D-glucosaminyl 3-O-sulfotransferase 1; 3-OST-1; Heparan sulfate 3-O-sulfotransferase 1; h3-OST-1
• Gene Name: HS3ST1
• Related Disease:
  Arteriosclerosis
  Neoplasm
  Advanced cancer
  Alzheimer disease
  Atherosclerosis
  Chondrosarcoma
  Herpes simplex infection
  Coronary heart disease
• UniProt ID: HS3S1_HUMAN
• PDB ID: 1ZRH
• EC Number: 2.8.2.23
• Pfam ID: PF00685
• Sequence:
  MAALLLGAVLLVAQPQLVPSRPAELGQQELLRKAGTLQDDVRDGVAPNGSAQQLPQTIII
  GVRKGGTRALLEMLSLHPDVAAAENEVHFFDWEEHYSHGLGWYLSQMPFSWPHQLTVEKT
  PAYFTSPKVPERVYSMNPSIRLLLILRDPSERVLSDYTQVFYNHMQKHKPYPSIEEFLVR
  DGRLNVDYKALNRSLYHVHMQNWLRFFPLRHIHIVDGDRLIRDPFPEIQKVERFLKLSPQ
  INASNFYFNKTKGFYCLRDSGRDRCLHESKGRAHPQVDPKLLNKLHEYFHEPNKKFFELV
  GRTFDWH
• Function: Sulfotransferase that utilizes 3'-phospho-5'-adenylyl sulfate (PAPS) to catalyze the transfer of a sulfo group to position 3 of glucosamine residues in heparan. Catalyzes the rate limiting step in the biosynthesis of heparan sulfate (HSact). This modification is a crucial step in the biosynthesis of anticoagulant heparan sulfate as it completes the structure of the antithrombin pentasaccharide binding site.
• Tissue Specificity: Highly expressed in the brain and kidney and weakly expressed in the heart, lung and placenta.
• KEGG Pathway: Glycosaminoglycan biosynthesis - heparan sulfate / heparin (hsa00534)
• Reactome Pathway: HS-GAG biosynthesis (R-HSA-2022928)
• BioCyc Pathway: MetaCyc:HS00082-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Arteriosclerosis	DISK5QGC	Definitive	Genetic Variation	[1]
Neoplasm	DISZKGEW	Definitive	Biomarker	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Alzheimer disease	DISF8S70	Strong	Altered Expression	[4]
Atherosclerosis	DISMN9J3	Strong	Genetic Variation	[1]
Chondrosarcoma	DIS4I7JB	Strong	Posttranslational Modification	[5]
Herpes simplex infection	DISL1SAV	Strong	Biomarker	[6]
Coronary heart disease	DIS5OIP1	moderate	SusceptibilityMutation	[7]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Heparan sulfate glucosamine 3-O-sulfotransferase 1 (HS3ST1) affects the response to substance of Doxorubicin.	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Heparan sulfate glucosamine 3-O-sulfotransferase 1 (HS3ST1).	[8]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Heparan sulfate glucosamine 3-O-sulfotransferase 1 (HS3ST1).	[9]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Heparan sulfate glucosamine 3-O-sulfotransferase 1 (HS3ST1).	[10]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Heparan sulfate glucosamine 3-O-sulfotransferase 1 (HS3ST1).	[11]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Heparan sulfate glucosamine 3-O-sulfotransferase 1 (HS3ST1).	[12]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Heparan sulfate glucosamine 3-O-sulfotransferase 1 (HS3ST1).	[13]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of Heparan sulfate glucosamine 3-O-sulfotransferase 1 (HS3ST1).	[14]
Epanova	DMHEAGL	Approved	Epanova increases the expression of Heparan sulfate glucosamine 3-O-sulfotransferase 1 (HS3ST1).	[15]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Heparan sulfate glucosamine 3-O-sulfotransferase 1 (HS3ST1).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Heparan sulfate glucosamine 3-O-sulfotransferase 1 (HS3ST1).	[17]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Heparan sulfate glucosamine 3-O-sulfotransferase 1 (HS3ST1).	[18]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Heparan sulfate glucosamine 3-O-sulfotransferase 1 (HS3ST1).	[19]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Heparan sulfate glucosamine 3-O-sulfotransferase 1 (HS3ST1).	[20]

References

• [1] HS3ST1 genotype regulates antithrombin's inflammomodulatory tone and associates with atherosclerosis.Matrix Biol. 2017 Nov;63:69-90. doi: 10.1016/j.matbio.2017.01.003. Epub 2017 Jan 23.
• [2] Selectin ligand sialyl-Lewis x antigen drives metastasis of hormone-dependent breast cancers.Cancer Res. 2011 Dec 15;71(24):7683-93. doi: 10.1158/0008-5472.CAN-11-1139. Epub 2011 Oct 24.
• [3] Tissue-specificity of heparan sulfate biosynthetic machinery in cancer.Cell Adh Migr. 2015;9(6):452-9. doi: 10.1080/19336918.2015.1049801.
• [4] Polygenic Overlap Between C-Reactive Protein, Plasma Lipids, and Alzheimer Disease.Circulation. 2015 Jun 9;131(23):2061-2069. doi: 10.1161/CIRCULATIONAHA.115.015489. Epub 2015 Apr 10.
• [5] Epigenetics: methylation-associated repression of heparan sulfate 3-O-sulfotransferase gene expression contributes to the invasive phenotype of H-EMC-SS chondrosarcoma cells.FASEB J. 2010 Feb;24(2):436-50. doi: 10.1096/fj.09-136291. Epub 2009 Oct 7.
• [6] Portable sulphotransferase domain determines sequence specificity of heparan sulphate 3-O-sulphotransferases.Biochem J. 2001 Oct 1;359(Pt 1):235-41. doi: 10.1042/0264-6021:3590235.
• [7] Assessing the function of genetic variants in candidate gene association studies.Nat Rev Genet. 2004 Aug;5(8):589-97. doi: 10.1038/nrg1403.
• [8] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [9] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [10] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [11] 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.
• [12] 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.
• [13] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [14] Cytosine arabinoside induces ectoderm and inhibits mesoderm expression in human embryonic stem cells during multilineage differentiation. Br J Pharmacol. 2011 Apr;162(8):1743-56.
• [15] Differential effects of omega-3 and omega-6 Fatty acids on gene expression in breast cancer cells. Breast Cancer Res Treat. 2007 Jan;101(1):7-16. doi: 10.1007/s10549-006-9269-x. Epub 2006 Jul 6.
• [16] 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.
• [17] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [18] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [19] 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.
• [20] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [21] Prediction of doxorubicin sensitivity in breast tumors based on gene expression profiles of drug-resistant cell lines correlates with patient survival. Oncogene. 2005 Nov 17;24(51):7542-51. doi: 10.1038/sj.onc.1208908.