Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTEKG7JJ)

• DOT Name: Bifunctional heparan sulfate N-deacetylase/N-sulfotransferase 4 (NDST4)
• Synonyms: EC 2.8.2.8; Glucosaminyl N-deacetylase/N-sulfotransferase 4; NDST-4; N-heparan sulfate sulfotransferase 4; N-HSST 4
• Gene Name: NDST4
• Related Disease:
  Advanced cancer
  Colorectal carcinoma
  Language disorder
  Neoplasm
  Prostate cancer
  Prostate neoplasm
  Coronary atherosclerosis
  Coronary heart disease
• UniProt ID: NDST4_HUMAN
• EC Number: 2.8.2.-; 2.8.2.8; 3.-.-.-
• Pfam ID: PF12062 ; PF00685
• Sequence:
  MNLIVKLRRSFRTLIVLLATFCLVSIVISAYFLYSGYKQEMTLIETTAEAECTDIKILPY
  RSMELKTVKPIDTSKTDPTVLLFVESQYSQLGQDIIAILESSRFQYHMVIAPGKGDIPPL
  TDNGKGKYTLVIYENILKYVSMDSWNRELLEKYCVEYSVSIIGFHKANENSLPSTQLKGF
  PLNLFNNLALKDCFVNPQSPLLHITKAPKVEKGPLPGEDWTIFQYNHSTYQPVLLTELQT
  EKSLSSLSSKTLFATVIQDLGLHDGIQRVLFGNNLNFWLHKLIFIDAISFLSGKRLTLSL
  DRYILVDIDDIFVGKEGTRMNVKDVKALLETQNLLRTQVANFTFNLGFSGKFYHTGTEEE
  DEGDDLLLRSVDEFWWFPHMWSHMQPHLFHNESSLVEQMILNKEFALEHGIPINMGYAVA
  PHHSGVYPVHIQLYAAWKKVWGIQVTSTEEYPHLKPARYRKGFIHNSIMVLPRQTCGLFT
  HTIFYKEYPGGPQELDKSIRGGELFLTILLNPISIFMTHLSNYGNDRLGLYTFVNLVNFV
  QSWTNLKLQTLPPVQLAHQYFELFPEQKDPLWQNPCDDKRHKDIWSREKTCDHLPKFLVI
  GPQKTGTTALYLFLLMHPSIISNLPSPKTFEEVQFFNGNNYHKGIDWYMDFFPTPSNTTS
  DFLFEKSANYFHSEEAPRRAASLVPKAKIITILIDPSDRAYSWYQHQRSHEDPAALRFNF
  YEVISTGHWAPSDLKTLQRRCLVPGWYAVHIERWLTYFATSQLLIIDGQQLRSDPATVMD
  EVQKFLGVTPRYNYSEALTFDPQKGFWCQLLEGGKTKCLGKSKGRKYPPMDPESRTFLSN
  YYRDHNVELSKLLHRLGQPLPSWLRQELQKVR
• 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 low deacetylase activity but high sulfotransferase activity.
• KEGG Pathway:
  Glycosaminoglycan biosynthesis - heparan sulfate / heparin (hsa00534)
  Metabolic pathways (hsa01100)
• Reactome Pathway: HS-GAG biosynthesis (R-HSA-2022928)
• BioCyc Pathway: MetaCyc:HS06527-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
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[2]
Language disorder	DISTLKP7	Strong	Genetic Variation	[3]
Neoplasm	DISZKGEW	Strong	Biomarker	[2]
Prostate cancer	DISF190Y	Strong	Biomarker	[4]
Prostate neoplasm	DISHDKGQ	Strong	Biomarker	[4]
Coronary atherosclerosis	DISKNDYU	Limited	Genetic Variation	[5]
Coronary heart disease	DIS5OIP1	Limited	Genetic Variation	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Bifunctional heparan sulfate N-deacetylase/N-sulfotransferase 4 (NDST4).	[6]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Bifunctional heparan sulfate N-deacetylase/N-sulfotransferase 4 (NDST4).	[7]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Bifunctional heparan sulfate N-deacetylase/N-sulfotransferase 4 (NDST4).	[8]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Bifunctional heparan sulfate N-deacetylase/N-sulfotransferase 4 (NDST4).	[9]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Bifunctional heparan sulfate N-deacetylase/N-sulfotransferase 4 (NDST4).	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Bifunctional heparan sulfate N-deacetylase/N-sulfotransferase 4 (NDST4).	[10]

References

• [1] NDST4 is a novel candidate tumor suppressor gene at chromosome 4q26 and its genetic loss predicts adverse prognosis in colorectal cancer.PLoS One. 2013 Jun 25;8(6):e67040. doi: 10.1371/journal.pone.0067040. Print 2013.
• [2] Alteration of colonic epithelial cell differentiation in mice deficient for glucosaminyl N-deacetylase/N-sulfotransferase 4.Oncotarget. 2016 Dec 20;7(51):84938-84950. doi: 10.18632/oncotarget.12915.
• [3] Genome-wide association study of shared components of reading disability and language impairment.Genes Brain Behav. 2013 Nov;12(8):792-801. doi: 10.1111/gbb.12085. Epub 2013 Oct 9.
• [4] Sequencing of prostate cancers identifies new cancer genes, routes of progression and drug targets.Nat Genet. 2018 May;50(5):682-692. doi: 10.1038/s41588-018-0086-z. Epub 2018 Apr 16.
• [5] Genome-wide association analysis identifies TYW3/CRYZ and NDST4 loci associated with circulating resistin levels.Hum Mol Genet. 2012 Nov 1;21(21):4774-80. doi: 10.1093/hmg/dds300. Epub 2012 Jul 26.
• [6] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [7] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [8] 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.
• [9] 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.
• [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.