Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT8TWYOG)

• DOT Name: Bifunctional heparan sulfate N-deacetylase/N-sulfotransferase 3 (NDST3)
• Synonyms: Glucosaminyl N-deacetylase/N-sulfotransferase 3; NDST-3; hNDST-3; N-heparan sulfate sulfotransferase 3; N-HSST 3) -glucosamine N-sulfotransferase NDST3 (EC 2.8.2.8)]
• Gene Name: NDST3
• Related Disease:
  Bipolar disorder
  Anxiety
  Mental disorder
  Narcolepsy
• UniProt ID: NDST3_HUMAN
• EC Number: 2.8.2.8; 3.-.-.-
• Pfam ID: PF12062 ; PF00685
• Sequence:
  MSFIMKLHRHFQRTVILLATFCMVSIIISAYYLYSGYKQENELSETASEVDCGDLQHLPY
  QLMEVKAMKLFDASRTDPTVLVFVESQYSSLGQDIIMILESSRFQYHIEIAPGKGDLPVL
  IDKMKGKYILIIYENILKYINMDSWNRSLLDKYCVEYGVGVIGFHKTSEKSVQSFQLKGF
  PFSIYGNLAVKDCCINPHSPLIRVTKSSKLEKGSLPGTDWTVFQINHSAYQPVIFAKVKT
  PENLSPSISKGAFYATIIHDLGLHDGIQRVLFGNNLNFWLHKLIFIDAISFLSGKRLTLS
  LDRYILVDIDDIFVGKEGTRMNTNDVKALLDTQNLLRAQITNFTFNLGFSGKFYHTGTEE
  EDEGDDCLLGSVDEFWWFPHMWSHMQPHLFHNESSLVEQMILNKKFALEHGIPTDMGYAV
  APHHSGVYPVHVQLYEAWKKVWNIKITSTEEYPHLKPARYRRGFIHKNIMVLPRQTCGLF
  THTIFYKEYPGGPKELDKSIQGGELFFTVVLNPISIFMTHLSNYGNDRLGLYTFVNLANF
  VKSWTNLRLQTLPPVQLAHKYFELFPDQKDPLWQNPCDDKRHRDIWSKEKTCDRLPKFLV
  IGPQKTGTTALYLFLVMHPSILSNSPSPKTFEEVQFFNRNNYHRGIDWYMDFFPVPSNVT
  TDFLFEKSANYFHSEEAPKRAASLVPKAKIITILIDPSDRAYSWYQHQRSHEDPAALKFS
  FYEVISAGPRAPSELRALQKRCLVPGWYASHIERWLVYFPPFQLLIIDGQQLRTDPATVM
  DEVQKFLGVLPHYNYSEALTFDSHKGFWCQLLEEGKTKCLGKSKGRKYPPMDSDSRTFLS
  SYYRDHNVELSKLLHKLGQPLPSWLRQELQKVR
• Function: Essential bifunctional enzyme that catalyzes both the N-deacetylation and the N-sulfation of glucosamine (GlcNAc) of the glycosaminoglycan in heparan sulfate. Modifies the GlcNAc-GlcA disaccharide repeating sugar backbone to make N-sulfated heparosan, a prerequisite substrate for later modifications in heparin biosynthesis. Has high deacetylase activity but low sulfotransferase activity.
• Tissue Specificity: Expressed in brain, kidney, liver, fetal and adult lung, adult pancreas, placenta, fetal spleen and fetal thymus. Not detected in adult/ fetal heart and skeletal muscle.
• KEGG Pathway:
  Glycosaminoglycan biosynthesis - heparan sulfate / heparin (hsa00534)
  Metabolic pathways (hsa01100)
• Reactome Pathway: HS-GAG biosynthesis (R-HSA-2022928)
• BioCyc Pathway: MetaCyc:HS09011-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Bipolar disorder	DISAM7J2	Definitive	Biomarker	[1]
Anxiety	DISIJDBA	Strong	Genetic Variation	[2]
Mental disorder	DIS3J5R8	Strong	Genetic Variation	[3]
Narcolepsy	DISLCNLI	Strong	Genetic Variation	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Bifunctional heparan sulfate N-deacetylase/N-sulfotransferase 3 (NDST3).	[5]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Bifunctional heparan sulfate N-deacetylase/N-sulfotransferase 3 (NDST3).	[6]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Bifunctional heparan sulfate N-deacetylase/N-sulfotransferase 3 (NDST3).	[7]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Bifunctional heparan sulfate N-deacetylase/N-sulfotransferase 3 (NDST3).	[5]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Bifunctional heparan sulfate N-deacetylase/N-sulfotransferase 3 (NDST3).	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Bifunctional heparan sulfate N-deacetylase/N-sulfotransferase 3 (NDST3).	[8]

References

• [1] A comprehensive analysis of NDST3 for schizophrenia and bipolar disorder in Han Chinese.Transl Psychiatry. 2016 Jan 5;6(1):e701. doi: 10.1038/tp.2015.199.
• [2] Meta-analysis of genome-wide association studies for neuroticism in 449,484 individuals identifies novel genetic loci and pathways.Nat Genet. 2018 Jul;50(7):920-927. doi: 10.1038/s41588-018-0151-7. Epub 2018 Jun 25.
• [3] Association study of NDST3 gene for schizophrenia, bipolar disorder, major depressive disorder in the Han Chinese population.Am J Med Genet B Neuropsychiatr Genet. 2018 Jan;177(1):3-9. doi: 10.1002/ajmg.b.32573. Epub 2017 Nov 15.
• [4] 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.
• [5] 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.
• [6] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
• [7] 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.
• [8] 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.