Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTABV7D2)

• DOT Name: Heparan-sulfate 6-O-sulfotransferase 1 (HS6ST1)
• Synonyms: HS6ST-1; EC 2.8.2.-
• Gene Name: HS6ST1
• Related Disease:
  Schizophrenia
  Type-1/2 diabetes
  Hypogonadotropic hypogonadism 7 with or without anosmia
  Hypogonadotropic hypogonadism
  Kallmann syndrome
  Hypogonadotropic hypogonadism 15 with or without anosmia
• UniProt ID: H6ST1_HUMAN
• EC Number: 2.8.2.-
• Pfam ID: PF03567
• Sequence:
  MRRRRAGGRTMVERASKFVLVVAGSVCFMLILYQYAGPGLSLGAPGGRAPPDDLDLFPTP
  DPHYEKKYYFPVRELERSLRFDMKGDDVIVFLHIQKTGGTTFGRHLVQNVRLEVPCDCRP
  GQKKCTCYRPNRRETWLFSRFSTGWSCGLHADWTELTNCVPGVLDRRDSAALRTPRKFYY
  ITLLRDPVSRYLSEWRHVQRGATWKTSLHMCDGRTPTPEELPPCYEGTDWSGCTLQEFMD
  CPYNLANNRQVRMLADLSLVGCYNLSFIPEGKRAQLLLESAKKNLRGMAFFGLTEFQRKT
  QYLFERTFNLKFIRPFMQYNSTRAGGVEVDEDTIRRIEELNDLDMQLYDYAKDLFQQRYQ
  YKRQLERREQRLRSREERLLHRAKEALPREDADEPGRVPTEDYMSHIIEKW
• 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. Critical for normal neuronal development where it may play a role in neuron branching. May also play a role in limb development. May prefer iduronic acid.
• Tissue Specificity: Expressed in fetal brain.
• KEGG Pathway: Glycosaminoglycan biosynthesis - heparan sulfate / heparin (hsa00534)
• Reactome Pathway: HS-GAG biosynthesis (R-HSA-2022928)
• BioCyc Pathway: MetaCyc:ENSG00000136720-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[1]
Type-1/2 diabetes	DISIUHAP	Strong	Genetic Variation	[2]
Hypogonadotropic hypogonadism 7 with or without anosmia	DISPBWEU	moderate	Genetic Variation	[3]
Hypogonadotropic hypogonadism	DIS8JSKR	Supportive	Autosomal dominant	[3]
Kallmann syndrome	DISO3HDG	Supportive	Autosomal dominant	[3]
Hypogonadotropic hypogonadism 15 with or without anosmia	DIS2W8AS	Limited	Unknown	[4]

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 Heparan-sulfate 6-O-sulfotransferase 1 (HS6ST1).	[5]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Heparan-sulfate 6-O-sulfotransferase 1 (HS6ST1).	[12]

7 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 6-O-sulfotransferase 1 (HS6ST1).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Heparan-sulfate 6-O-sulfotransferase 1 (HS6ST1).	[7]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Heparan-sulfate 6-O-sulfotransferase 1 (HS6ST1).	[8]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of Heparan-sulfate 6-O-sulfotransferase 1 (HS6ST1).	[9]
Niclosamide	DMJAGXQ	Approved	Niclosamide decreases the expression of Heparan-sulfate 6-O-sulfotransferase 1 (HS6ST1).	[10]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Heparan-sulfate 6-O-sulfotransferase 1 (HS6ST1).	[11]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Heparan-sulfate 6-O-sulfotransferase 1 (HS6ST1).	[13]

References

• [1] A molecular pathway analysis informs the genetic risk for arrhythmias during antipsychotic treatment.Int Clin Psychopharmacol. 2018 Jan;33(1):1-14. doi: 10.1097/YIC.0000000000000198.
• [2] Genome-wide Association Studies Identify Genetic Loci Associated With Albuminuria in Diabetes.Diabetes. 2016 Mar;65(3):803-17. doi: 10.2337/db15-1313. Epub 2015 Dec 2.
• [3] Heparan sulfate 6-O-sulfotransferase 1, a gene involved in extracellular sugar modifications, is mutated in patients with idiopathic hypogonadotrophic hypogonadism. Proc Natl Acad Sci U S A. 2011 Jul 12;108(28):11524-9. doi: 10.1073/pnas.1102284108. Epub 2011 Jun 23.
• [4] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [5] 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.
• [6] 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.
• [7] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [8] 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.
• [9] Gene expression in endometrial cancer cells (Ishikawa) after short time high dose exposure to progesterone. Steroids. 2008 Jan;73(1):116-28.
• [10] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [11] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [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.