Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT9E10W2)

• DOT Name: Bifunctional heparan sulfate N-deacetylase/N-sulfotransferase 1 (NDST1)
• Synonyms: Glucosaminyl N-deacetylase/N-sulfotransferase 1; NDST-1; N-heparan sulfate sulfotransferase 1; N-HSST 1; -glucosamine N-sulfotransferase 1; HSNST 1
• Gene Name: NDST1
• Related Disease:
  Chikungunya virus infection
  Congenital alveolar dysplasia
  Congenital diaphragmatic hernia
  Gastrointestinal stromal tumour
  Intellectual disability, autosomal recessive 46
  Liver cirrhosis
  Myocardial infarction
  Neoplasm
  Respiratory failure
  Rheumatoid arthritis
  Treacher-Collins syndrome
  Advanced cancer
  Autosomal recessive non-syndromic intellectual disability
  Adult glioblastoma
  Breast cancer
  Breast carcinoma
  Clear cell renal carcinoma
  Glioblastoma multiforme
  Intellectual disability
  Nervous system inflammation
  Type-1/2 diabetes
• UniProt ID: NDST1_HUMAN
• PDB ID: 1NST
• EC Number: 2.8.2.8; 3.5.1.-
• Pfam ID: PF12062 ; PF00685
• Sequence:
  MPALACLRRLCRHVSPQAVLFLLFIFCLFSVFISAYYLYGWKRGLEPSADAPEPDCGDPP
  PVAPSRLLPLKPVQAATPSRTDPLVLVFVESLYSQLGQEVVAILESSRFKYRTEIAPGKG
  DMPTLTDKGRGRFALIIYENILKYVNLDAWNRELLDKYCVAYGVGIIGFFKANENSLLSA
  QLKGFPLFLHSNLGLKDCSINPKSPLLYVTRPSEVEKGVLPGEDWTVFQSNHSTYEPVLL
  AKTRSSESIPHLGADAGLHAALHATVVQDLGLHDGIQRVLFGNNLNFWLHKLVFVDAVAF
  LTGKRLSLPLDRYILVDIDDIFVGKEGTRMKVEDVKALFDTQNELRAHIPNFTFNLGYSG
  KFFHTGTNAEDAGDDLLLSYVKEFWWFPHMWSHMQPHLFHNQSVLAEQMALNKKFAVEHG
  IPTDMGYAVAPHHSGVYPVHVQLYEAWKQVWSIRVTSTEEYPHLKPARYRRGFIHNGIMV
  LPRQTCGLFTHTIFYNEYPGGSSELDKIINGGELFLTVLLNPISIFMTHLSNYGNDRLGL
  YTFKHLVRFLHSWTNLRLQTLPPVQLAQKYFQIFSEEKDPLWQDPCEDKRHKDIWSKEKT
  CDRFPKLLIIGPQKTGTTALYLFLGMHPDLSSNYPSSETFEEIQFFNGHNYHKGIDWYME
  FFPIPSNTTSDFYFEKSANYFDSEVAPRRAAALLPKAKVLTILINPADRAYSWYQHQRAH
  DDPVALKYTFHEVITAGSDASSKLRALQNRCLVPGWYATHIERWLSAYHANQILVLDGKL
  LRTEPAKVMDMVQKFLGVTNTIDYHKTLAFDPKKGFWCQLLEGGKTKCLGKSKGRKYPEM
  DLDSRAFLKDYYRDHNIELSKLLYKMGQTLPTWLREDLQNTR
• Function: [Isoform 1]: 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. Plays a role in determining the extent and pattern of sulfation of heparan sulfate. Participates in biosynthesis of heparan sulfate that can ultimately serve as L-selectin ligands, thereby playing a role in inflammatory response. Required for the exosomal release of SDCBP, CD63 and syndecan ; [Isoform 3]: Lacks both N-deacetylase and N-sulfotransferase activities. Acts as a dominant negative on isoform 1, likely by changing the composition of enzyme complexes responsible for elongation and modification of heparan sulfates.
• Tissue Specificity: Widely expressed. Expression is most abundant in heart, liver and pancreas.
• KEGG Pathway:
  Glycosaminoglycan biosynthesis - heparan sulfate / heparin (hsa00534)
  Metabolic pathways (hsa01100)
• Reactome Pathway: HS-GAG biosynthesis (R-HSA-2022928)
• BioCyc Pathway: MetaCyc:HS01001-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

21 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Chikungunya virus infection	DISDXEHY	Strong	Biomarker	[1]
Congenital alveolar dysplasia	DIS1IYUN	Strong	Biomarker	[2]
Congenital diaphragmatic hernia	DIS0IPVU	Strong	Altered Expression	[3]
Gastrointestinal stromal tumour	DIS6TJYS	Strong	Biomarker	[4]
Intellectual disability, autosomal recessive 46	DISK0GXF	Strong	Autosomal recessive	[5]
Liver cirrhosis	DIS4G1GX	Strong	Altered Expression	[6]
Myocardial infarction	DIS655KI	Strong	Genetic Variation	[7]
Neoplasm	DISZKGEW	Strong	Biomarker	[8]
Respiratory failure	DISVMYJO	Strong	Biomarker	[9]
Rheumatoid arthritis	DISTSB4J	Strong	Biomarker	[10]
Treacher-Collins syndrome	DIS2GXZ1	Strong	Biomarker	[11]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[12]
Autosomal recessive non-syndromic intellectual disability	DISJWRZZ	Supportive	Autosomal recessive	[13]
Adult glioblastoma	DISVP4LU	Limited	Altered Expression	[14]
Breast cancer	DIS7DPX1	Limited	Altered Expression	[15]
Breast carcinoma	DIS2UE88	Limited	Biomarker	[15]
Clear cell renal carcinoma	DISBXRFJ	Limited	Altered Expression	[16]
Glioblastoma multiforme	DISK8246	Limited	Altered Expression	[14]
Intellectual disability	DISMBNXP	Limited	Genetic Variation	[13]
Nervous system inflammation	DISB3X5A	Limited	Altered Expression	[17]
Type-1/2 diabetes	DISIUHAP	Limited	Genetic Variation	[18]

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 Bifunctional heparan sulfate N-deacetylase/N-sulfotransferase 1 (NDST1).	[19]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Bifunctional heparan sulfate N-deacetylase/N-sulfotransferase 1 (NDST1).	[26]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Bifunctional heparan sulfate N-deacetylase/N-sulfotransferase 1 (NDST1).	[20]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Bifunctional heparan sulfate N-deacetylase/N-sulfotransferase 1 (NDST1).	[21]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Bifunctional heparan sulfate N-deacetylase/N-sulfotransferase 1 (NDST1).	[22]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Bifunctional heparan sulfate N-deacetylase/N-sulfotransferase 1 (NDST1).	[23]
Marinol	DM70IK5	Approved	Marinol increases the expression of Bifunctional heparan sulfate N-deacetylase/N-sulfotransferase 1 (NDST1).	[24]
Folic acid	DMEMBJC	Approved	Folic acid affects the expression of Bifunctional heparan sulfate N-deacetylase/N-sulfotransferase 1 (NDST1).	[25]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Bifunctional heparan sulfate N-deacetylase/N-sulfotransferase 1 (NDST1).	[27]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Bifunctional heparan sulfate N-deacetylase/N-sulfotransferase 1 (NDST1).	[28]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Bifunctional heparan sulfate N-deacetylase/N-sulfotransferase 1 (NDST1).	[29]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Bifunctional heparan sulfate N-deacetylase/N-sulfotransferase 1 (NDST1).	[30]

References

• [1] Genome-Wide Screening Uncovers the Significance of N-Sulfation of Heparan Sulfate as a Host Cell Factor for Chikungunya Virus Infection.J Virol. 2017 Jun 9;91(13):e00432-17. doi: 10.1128/JVI.00432-17. Print 2017 Jul 1.
• [2] Targeted disruption of NDST-1 gene leads to pulmonary hypoplasia and neonatal respiratory distress in mice.FEBS Lett. 2000 Feb 4;467(1):7-11. doi: 10.1016/s0014-5793(00)01111-x.
• [3] Down-regulation of N-deacetylase-N-sulfotransferase-1 signaling in the developing diaphragmatic vasculature of nitrofen-induced congenital diaphragmatic hernia.J Pediatr Surg. 2017 Jun;52(6):1035-1039. doi: 10.1016/j.jpedsurg.2017.03.036. Epub 2017 Mar 18.
• [4] Hedgehog pathway dysregulation contributes to the pathogenesis of human gastrointestinal stromal tumors via GLI-mediated activation of KIT expression. Oncotarget. 2016 Nov 29;7(48):78226-78241. doi: 10.18632/oncotarget.12909.
• [5] Mice deficient in heparan sulfate N-deacetylase/N-sulfotransferase 1. Prog Mol Biol Transl Sci. 2010;93:35-58. doi: 10.1016/S1877-1173(10)93003-2.
• [6] Pro-Brain Natriuretic Peptide and Troponin T-Hypersensitivity Levels Correlate With the Severity of Liver Dysfunction in Liver Cirrhosis.Am J Med Sci. 2017 Aug;354(2):131-139. doi: 10.1016/j.amjms.2017.04.005. Epub 2017 Apr 7.
• [7] Association of a polymorphism of BTN2A1 with myocardial infarction in East Asian populations.Atherosclerosis. 2011 Mar;215(1):145-52. doi: 10.1016/j.atherosclerosis.2010.12.005. Epub 2010 Dec 15.
• [8] Specifically Increased Paclitaxel Release in Tumor and Synergetic Therapy by a Hyaluronic Acid-Tocopherol Nanomicelle.ACS Appl Mater Interfaces. 2017 Jun 21;9(24):20385-20398. doi: 10.1021/acsami.7b02606. Epub 2017 Jun 6.
• [9] A girl with developmental delay, ataxia, cranial nerve palsies, severe respiratory problems in infancy-Expanding NDST1 syndrome.Am J Med Genet A. 2017 Mar;173(3):712-715. doi: 10.1002/ajmg.a.37621.
• [10] RIPK1 inhibition attenuates experimental autoimmune arthritis via suppression of osteoclastogenesis.J Transl Med. 2019 Mar 15;17(1):84. doi: 10.1186/s12967-019-1809-3.
• [11] Genomic organization of the human heparan sulfate-N-deacetylase/N-sulfotransferase gene: exclusion from a causative role in the pathogenesis of Treacher Collins syndrome.Genomics. 1996 Mar 15;32(3):471-3. doi: 10.1006/geno.1996.0145.
• [12] Tissue-specificity of heparan sulfate biosynthetic machinery in cancer.Cell Adh Migr. 2015;9(6):452-9. doi: 10.1080/19336918.2015.1049801.
• [13] NDST1 missense mutations in autosomal recessive intellectual disability. Am J Med Genet A. 2014 Nov;164A(11):2753-63. doi: 10.1002/ajmg.a.36723. Epub 2014 Aug 14.
• [14] MiRNA-191 functions as an oncogene in primary glioblastoma by directly targeting NDST1.Eur Rev Med Pharmacol Sci. 2019 Jul;23(14):6242-6249. doi: 10.26355/eurrev_201907_18443.
• [15] Methylation-regulated miR-149 modulates chemoresistance by targeting GlcNAc N-deacetylase/N-sulfotransferase-1 in human breast cancer.FEBS J. 2014 Oct;281(20):4718-30. doi: 10.1111/febs.13012. Epub 2014 Sep 30.
• [16] IDUA, NDST1, SAP30L, CRYBA4, and SI as novel prognostic signatures clear cell renal cell carcinoma.J Cell Physiol. 2019 Sep;234(9):16320-16327. doi: 10.1002/jcp.28297. Epub 2019 Feb 28.
• [17] Surfen, a proteoglycan binding agent, reduces inflammation but inhibits remyelination in murine models of Multiple Sclerosis.Acta Neuropathol Commun. 2018 Jan 4;6(1):4. doi: 10.1186/s40478-017-0506-9.
• [18] Endothelial heparan sulfate deficiency reduces inflammation and fibrosis in murine diabetic nephropathy.Lab Invest. 2018 Apr;98(4):427-438. doi: 10.1038/s41374-017-0015-2. Epub 2018 Jan 12.
• [19] 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.
• [20] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [21] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [22] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [23] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [24] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [25] Folate deficiency in normal human fibroblasts leads to altered expression of genes primarily linked to cell signaling, the cytoskeleton and extracellular matrix. J Nutr Biochem. 2007 Aug;18(8):541-52. doi: 10.1016/j.jnutbio.2006.11.002. Epub 2007 Feb 22.
• [26] 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.
• [27] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [28] 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.
• [29] Bisphenol A Exposure Changes the Transcriptomic and Proteomic Dynamics of Human Retinoblastoma Y79 Cells. Genes (Basel). 2021 Feb 11;12(2):264. doi: 10.3390/genes12020264.
• [30] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.