Details of Drug Off-Target (DOT)

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

• DOT Name: Heparan-alpha-glucosaminide N-acetyltransferase (HGSNAT)
• Synonyms: EC 2.3.1.78; Transmembrane protein 76
• Gene Name: HGSNAT
• Related Disease:
  Inherited retinal dystrophy
  Mucopolysaccharidosis type 3C
  Mucopolysaccharidosis type IIIA
  Mucopolysaccharidosis type 3A
  Retinitis pigmentosa 73
  Retinitis pigmentosa
  Mucopolysaccharidosis
  Mucopolysaccharidosis type 3D
• UniProt ID: HGNAT_HUMAN
• EC Number: 2.3.1.78
• Pfam ID: PF07786
• Sequence:
  MTGARASAAEQRRAGRSGQARAAERAAGMSGAGRALAALLLAASVLSAALLAPGGSSGRD
  AQAAPPRDLDKKRHAELKMDQALLLIHNELLWTNLTVYWKSECCYHCLFQVLVNVPQSPK
  AGKPSAAAASVSTQHGSILQLNDTLEEKEVCRLEYRFGEFGNYSLLVKNIHNGVSEIACD
  LAVNEDPVDSNLPVSIAFLIGLAVIIVISFLRLLLSLDDFNNWISKAISSRETDRLINSE
  LGSPSRTDPLDGDVQPATWRLSALPPRLRSVDTFRGIALILMVFVNYGGGKYWYFKHASW
  NGLTVADLVFPWFVFIMGSSIFLSMTSILQRGCSKFRLLGKIAWRSFLLICIGIIIVNPN
  YCLGPLSWDKVRIPGVLQRLGVTYFVVAVLELLFAKPVPEHCASERSCLSLRDITSSWPQ
  WLLILVLEGLWLGLTFLLPVPGCPTGYLGPGGIGDFGKYPNCTGGAAGYIDRLLLGDDHL
  YQHPSSAVLYHTEVAYDPEGILGTINSIVMAFLGVQAGKILLYYKARTKDILIRFTAWCC
  ILGLISVALTKVSENEGFIPVNKNLWSLSYVTTLSSFAFFILLVLYPVVDVKGLWTGTPF
  FYPGMNSILVYVGHEVFENYFPFQWKLKDNQSHKEHLTQNIVATALWVLIAYILYRKKIF
  WKI
• Function: Lysosomal acetyltransferase that acetylates the non-reducing terminal alpha-glucosamine residue of intralysosomal heparin or heparan sulfate, converting it into a substrate for luminal alpha-N-acetyl glucosaminidase.
• Tissue Specificity: Widely expressed, with highest level in leukocytes, heart, liver, skeletal muscle, lung, placenta and liver.
• KEGG Pathway:
  Glycosaminoglycan degradation (hsa00531)
  Metabolic pathways (hsa01100)
  Lysosome (hsa04142)
• Reactome Pathway:
  MPS IIIC - Sanfilippo syndrome C (R-HSA-2206291)
  Neutrophil degranulation (R-HSA-6798695)
  HS-GAG degradation (R-HSA-2024096)

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Inherited retinal dystrophy	DISGGL77	Definitive	Genetic Variation	[1]
Mucopolysaccharidosis type 3C	DISH5D5W	Definitive	Autosomal recessive	[2]
Mucopolysaccharidosis type IIIA	DISP7DR6	Definitive	Autosomal recessive	[2]
Mucopolysaccharidosis type 3A	DIS2TLNF	Strong	Genetic Variation	[3]
Retinitis pigmentosa 73	DISNXFKB	Strong	Autosomal recessive	[4]
Retinitis pigmentosa	DISCGPY8	Supportive	Autosomal dominant	[4]
Mucopolysaccharidosis	DISB083T	Limited	Genetic Variation	[3]
Mucopolysaccharidosis type 3D	DISQUYLN	Limited	Biomarker	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Heparan-alpha-glucosaminide N-acetyltransferase (HGSNAT).	[6]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Heparan-alpha-glucosaminide N-acetyltransferase (HGSNAT).	[7]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Heparan-alpha-glucosaminide N-acetyltransferase (HGSNAT).	[8]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Heparan-alpha-glucosaminide N-acetyltransferase (HGSNAT).	[9]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Heparan-alpha-glucosaminide N-acetyltransferase (HGSNAT).	[10]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Heparan-alpha-glucosaminide N-acetyltransferase (HGSNAT).	[11]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Heparan-alpha-glucosaminide N-acetyltransferase (HGSNAT).	[12]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Heparan-alpha-glucosaminide N-acetyltransferase (HGSNAT).	[13]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Heparan-alpha-glucosaminide N-acetyltransferase (HGSNAT).	[14]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Heparan-alpha-glucosaminide N-acetyltransferase (HGSNAT).	[15]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Heparan-alpha-glucosaminide N-acetyltransferase (HGSNAT).	[6]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Heparan-alpha-glucosaminide N-acetyltransferase (HGSNAT).	[16]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Heparan-alpha-glucosaminide N-acetyltransferase (HGSNAT).	[17]

References

• [1] Sanfilippo syndrome type C: mutation spectrum in the heparan sulfate acetyl-CoA: alpha-glucosaminide N-acetyltransferase (HGSNAT) gene.Hum Mutat. 2009 Jun;30(6):918-25. doi: 10.1002/humu.20986.
• [2] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [3] How close are we to therapies for Sanfilippo disease?.Metab Brain Dis. 2018 Feb;33(1):1-10. doi: 10.1007/s11011-017-0111-4. Epub 2017 Sep 18.
• [4] Non-syndromic retinitis pigmentosa due to mutations in the mucopolysaccharidosis type IIIC gene, heparan-alpha-glucosaminide N-acetyltransferase (HGSNAT). Hum Mol Genet. 2015 Jul 1;24(13):3742-51. doi: 10.1093/hmg/ddv118. Epub 2015 Apr 9.
• [5] Glycosaminoglycans and mucopolysaccharidosis type III.Front Biosci (Landmark Ed). 2016 Jun 1;21(7):1393-409. doi: 10.2741/4463.
• [6] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [7] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [8] 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.
• [9] 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.
• [10] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [11] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [12] 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.
• [13] 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.
• [14] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [15] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [16] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [17] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.