Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTTW9PDL)

• DOT Name: Heparan-sulfate 6-O-sulfotransferase 3 (HS6ST3)
• Synonyms: HS6ST-3; EC 2.8.2.-
• Gene Name: HS6ST3
• Related Disease:
  Narcolepsy
  Breast cancer
  Breast carcinoma
  Hepatitis B virus infection
  Neoplasm
  Obesity
  Non-insulin dependent diabetes
• UniProt ID: H6ST3_HUMAN
• EC Number: 2.8.2.-
• Pfam ID: PF03567
• Sequence:
  MDERFNKWLLTPVLTLLFVVIMYQYVSPSCTSSCTNFGEQPRAGEAGPPAVPGPARRAQA
  PPEEWERRPQLPPPPRGPPEGPRGAAAPEEEDEEPGDPREGEEEEEEDEPDPEAPENGSL
  PRFVPRFNFSLKDLTRFVDFNIKGRDVIVFLHIQKTGGTTFGRHLVKNIRLEQPCSCKAG
  QKKCTCHRPGKKETWLFSRFSTGWSCGLHADWTELTNCVPAIMEKKDCPRNHSHTRNFYY
  ITMLRDPVSRYLSEWKHVQRGATWKTSLHMCDGRSPTPDELPTCYPGDDWSGVSLREFMD
  CTYNLANNRQVRMLADLSLVGCYNLTFMNESERNTILLQSAKNNLKNMAFFGLTEFQRKT
  QFLFERTFNLKFISPFTQFNITRASNVEINEGARQRIEDLNFLDMQLYEYAKDLFQQRYH
  HTKQLEHQRDRQKRREERRLQREHRDHQWPKEDGAAEGTVTEDYNSQVVRW
• Function: 6-O-sulfation enzyme which catalyzes the transfer of sulfate from 3'-phosphoadenosine 5'-phosphosulfate (PAPS) to position 6 of the N-sulfoglucosamine residue (GlcNS) of heparan sulfate.
• KEGG Pathway: Glycosaminoglycan biosynthesis - heparan sulfate / heparin (hsa00534)
• Reactome Pathway: HS-GAG biosynthesis (R-HSA-2022928)
• BioCyc Pathway: MetaCyc:MONOMER-15787

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Narcolepsy	DISLCNLI	Definitive	Genetic Variation	[1]
Breast cancer	DIS7DPX1	Strong	Biomarker	[2]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[2]
Hepatitis B virus infection	DISLQ2XY	Strong	Biomarker	[3]
Neoplasm	DISZKGEW	Strong	Biomarker	[2]
Obesity	DIS47Y1K	Strong	Genetic Variation	[4]
Non-insulin dependent diabetes	DISK1O5Z	Limited	Biomarker	[5]

2 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Heparan-sulfate 6-O-sulfotransferase 3 (HS6ST3).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Heparan-sulfate 6-O-sulfotransferase 3 (HS6ST3).	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Heparan-sulfate 6-O-sulfotransferase 3 (HS6ST3).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Heparan-sulfate 6-O-sulfotransferase 3 (HS6ST3).	[8]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Heparan-sulfate 6-O-sulfotransferase 3 (HS6ST3).	[9]
Permethrin	DMZ0Q1G	Approved	Permethrin decreases the expression of Heparan-sulfate 6-O-sulfotransferase 3 (HS6ST3).	[10]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Heparan-sulfate 6-O-sulfotransferase 3 (HS6ST3).	[11]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Heparan-sulfate 6-O-sulfotransferase 3 (HS6ST3).	[13]

References

• [1] Genome-wide association database developed in the Japanese Integrated Database Project.J Hum Genet. 2009 Sep;54(9):543-6. doi: 10.1038/jhg.2009.68. Epub 2009 Jul 24.
• [2] Silencing HS6ST3 inhibits growth and progression of breast cancer cells through suppressing IGF1R and inducing XAF1.Exp Cell Res. 2017 Jan 15;350(2):380-389. doi: 10.1016/j.yexcr.2016.12.019. Epub 2016 Dec 23.
• [3] Impact of AAV2 and Hepatitis B Virus Integration Into Genome on Development of Hepatocellular Carcinoma in Patients with Prior Hepatitis B Virus Infection.Clin Cancer Res. 2019 Oct 15;25(20):6217-6227. doi: 10.1158/1078-0432.CCR-18-4041. Epub 2019 Jul 18.
• [4] Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture.Nat Genet. 2013 May;45(5):501-12. doi: 10.1038/ng.2606. Epub 2013 Apr 7.
• [5] Impact of diabetes-related gene polymorphisms on the clinical characteristics of type 2 diabetes Chinese Han population.Oncotarget. 2016 Dec 20;7(51):85464-85471. doi: 10.18632/oncotarget.13399.
• [6] 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.
• [7] 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.
• [8] Real-time monitoring of cisplatin-induced cell death. PLoS One. 2011;6(5):e19714. doi: 10.1371/journal.pone.0019714. Epub 2011 May 16.
• [9] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [10] Exposure to Insecticides Modifies Gene Expression and DNA Methylation in Hematopoietic Tissues In Vitro. Int J Mol Sci. 2023 Mar 26;24(7):6259. doi: 10.3390/ijms24076259.
• [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] 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.
• [13] 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.