Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTUOM1GV)

• DOT Name: Heparan sulfate glucosamine 3-O-sulfotransferase 3A1 (HS3ST3A1)
• Synonyms: EC 2.8.2.30; Heparan sulfate D-glucosaminyl 3-O-sulfotransferase 3A1; 3-OST-3A; Heparan sulfate 3-O-sulfotransferase 3A1; h3-OST-3A
• Gene Name: HS3ST3A1
• Related Disease:
  Breast cancer
  Breast carcinoma
• UniProt ID: HS3SA_HUMAN
• PDB ID: 1T8T; 1T8U; 6XKG; 6XL8
• EC Number: 2.8.2.30
• Pfam ID: PF00685
• Sequence:
  MAPPGPASALSTSAEPLSRSIFRKFLLMLCSLLTSLYVFYCLAERCQTLSGPVVGLSGGG
  EEAGAPGGGVLAGGPRELAVWPAAAQRKRLLQLPQWRRRRPPAPRDDGEEAAWEEESPGL
  SGGPGGSGAGSTVAEAPPGTLALLLDEGSKQLPQAIIIGVKKGGTRALLEFLRVHPDVRA
  VGAEPHFFDRSYDKGLAWYRDLMPRTLDGQITMEKTPSYFVTREAPARISAMSKDTKLIV
  VVRDPVTRAISDYTQTLSKRPDIPTFESLTFKNRTAGLIDTSWSAIQIGIYAKHLEHWLR
  HFPIRQMLFVSGERLISDPAGELGRVQDFLGLKRIITDKHFYFNKTKGFPCLKKAEGSSR
  PHCLGKTKGRTHPEIDREVVRRLREFYRPFNLKFYQMTGHDFGWDG
• Function: Sulfotransferase that utilizes 3'-phospho-5'-adenylyl sulfate (PAPS) to catalyze the transfer of a sulfo group to an N-unsubstituted glucosamine linked to a 2-O-sulfo iduronic acid unit on heparan sulfate. Catalyzes the O-sulfation of glucosamine in IdoUA2S-GlcNS and also in IdoUA2S-GlcNH2. 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 HS3ST1/3-OST-1, does not convert non-anticoagulant heparan sulfate to anticoagulant heparan sulfate.
• Tissue Specificity: Ubiquitous. Most abundant in heart and placenta, followed by liver and kidney.
• KEGG Pathway: Glycosaminoglycan biosynthesis - heparan sulfate / heparin (hsa00534)
• Reactome Pathway: HS-GAG biosynthesis (R-HSA-2022928)
• BioCyc Pathway: MetaCyc:HS07937-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast cancer	DIS7DPX1	Strong	Biomarker	[1]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[1]

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 3A1 (HS3ST3A1).	[2]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Heparan sulfate glucosamine 3-O-sulfotransferase 3A1 (HS3ST3A1).	[10]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Heparan sulfate glucosamine 3-O-sulfotransferase 3A1 (HS3ST3A1).	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Heparan sulfate glucosamine 3-O-sulfotransferase 3A1 (HS3ST3A1).	[3]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Heparan sulfate glucosamine 3-O-sulfotransferase 3A1 (HS3ST3A1).	[4]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Heparan sulfate glucosamine 3-O-sulfotransferase 3A1 (HS3ST3A1).	[5]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Heparan sulfate glucosamine 3-O-sulfotransferase 3A1 (HS3ST3A1).	[6]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Heparan sulfate glucosamine 3-O-sulfotransferase 3A1 (HS3ST3A1).	[7]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Heparan sulfate glucosamine 3-O-sulfotransferase 3A1 (HS3ST3A1).	[8]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Heparan sulfate glucosamine 3-O-sulfotransferase 3A1 (HS3ST3A1).	[9]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Heparan sulfate glucosamine 3-O-sulfotransferase 3A1 (HS3ST3A1).	[11]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Heparan sulfate glucosamine 3-O-sulfotransferase 3A1 (HS3ST3A1).	[13]

References

• [1] The heparan sulfate 3-O-sulfotransferases (HS3ST) 2, 3B and 4 enhance proliferation and survival in breast cancer MDA-MB-231 cells.PLoS One. 2018 Mar 16;13(3):e0194676. doi: 10.1371/journal.pone.0194676. eCollection 2018.
• [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] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [4] The thioxotriazole copper(II) complex A0 induces endoplasmic reticulum stress and paraptotic death in human cancer cells. J Biol Chem. 2009 Sep 4;284(36):24306-19.
• [5] 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.
• [6] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [7] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [8] 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.
• [9] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [10] 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.
• [11] 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.
• [12] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [13] 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.