Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTM0709Q)

• DOT Name: Alpha-N-acetylglucosaminidase (NAGLU)
• Synonyms: EC 3.2.1.50; N-acetyl-alpha-glucosaminidase; NAG
• Gene Name: NAGLU
• Related Disease:
  Mucopolysaccharidosis type 3B
  Charcot-Marie-Tooth disease axonal type 2V
• UniProt ID: ANAG_HUMAN
• PDB ID: 4XWH
• EC Number: 3.2.1.50
• Pfam ID: PF05089 ; PF12972 ; PF12971
• Sequence:
  MEAVAVAAAVGVLLLAGAGGAAGDEAREAAAVRALVARLLGPGPAADFSVSVERALAAKP
  GLDTYSLGGGGAARVRVRGSTGVAAAAGLHRYLRDFCGCHVAWSGSQLRLPRPLPAVPGE
  LTEATPNRYRYYQNVCTQSYSFVWWDWARWEREIDWMALNGINLALAWSGQEAIWQRVYL
  ALGLTQAEINEFFTGPAFLAWGRMGNLHTWDGPLPPSWHIKQLYLQHRVLDQMRSFGMTP
  VLPAFAGHVPEAVTRVFPQVNVTKMGSWGHFNCSYSCSFLLAPEDPIFPIIGSLFLRELI
  KEFGTDHIYGADTFNEMQPPSSEPSYLAAATTAVYEAMTAVDTEAVWLLQGWLFQHQPQF
  WGPAQIRAVLGAVPRGRLLVLDLFAESQPVYTRTASFQGQPFIWCMLHNFGGNHGLFGAL
  EAVNGGPEAARLFPNSTMVGTGMAPEGISQNEVVYSLMAELGWRKDPVPDLAAWVTSFAA
  RRYGVSHPDAGAAWRLLLRSVYNCSGEACRGHNRSPLVRRPSLQMNTSIWYNRSDVFEAW
  RLLLTSAPSLATSPAFRYDLLDLTRQAVQELVSLYYEEARSAYLSKELASLLRAGGVLAY
  ELLPALDEVLASDSRFLLGSWLEQARAAAVSEAEADFYEQNSRYQLTLWGPEGNILDYAN
  KQLAGLVANYYTPRWRLFLEALVDSVAQGIPFQQHQFDKNVFQLEQAFVLSKQRYPSQPR
  GDTVDLAKKIFLKYYPRWVAGSW
• Function: Involved in the degradation of heparan sulfate.
• Tissue Specificity: Liver, ovary, peripheral blood leukocytes, testis, prostate, spleen, colon, lung, placenta and kidney.
• KEGG Pathway:
  Glycosaminoglycan degradation (hsa00531)
  Metabolic pathways (hsa01100)
  Lysosome (hsa04142)
• Reactome Pathway:
  MPS IIIB - Sanfilippo syndrome B (R-HSA-2206282)
  HS-GAG degradation (R-HSA-2024096)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Mucopolysaccharidosis type 3B	DIS1RN28	Definitive	Autosomal recessive	[1]
Charcot-Marie-Tooth disease axonal type 2V	DISMD18Z	Supportive	Autosomal dominant	[2]

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 Alpha-N-acetylglucosaminidase (NAGLU).	[3]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Alpha-N-acetylglucosaminidase (NAGLU).	[14]

13 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 Alpha-N-acetylglucosaminidase (NAGLU).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Alpha-N-acetylglucosaminidase (NAGLU).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Alpha-N-acetylglucosaminidase (NAGLU).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Alpha-N-acetylglucosaminidase (NAGLU).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Alpha-N-acetylglucosaminidase (NAGLU).	[8]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Alpha-N-acetylglucosaminidase (NAGLU).	[9]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Alpha-N-acetylglucosaminidase (NAGLU).	[10]
Selenium	DM25CGV	Approved	Selenium increases the expression of Alpha-N-acetylglucosaminidase (NAGLU).	[11]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Alpha-N-acetylglucosaminidase (NAGLU).	[12]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Alpha-N-acetylglucosaminidase (NAGLU).	[13]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Alpha-N-acetylglucosaminidase (NAGLU).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Alpha-N-acetylglucosaminidase (NAGLU).	[16]
PP-242	DM2348V	Investigative	PP-242 decreases the expression of Alpha-N-acetylglucosaminidase (NAGLU).	[17]

References

• [1] 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.
• [2] Adult-onset painful axonal polyneuropathy caused by a dominant NAGLU mutation. Brain. 2015 Jun;138(Pt 6):1477-83. doi: 10.1093/brain/awv074. Epub 2015 Mar 28.
• [3] 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.
• [4] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [5] Constitutive gene expression predisposes morphogen-mediated cell fate responses of NT2/D1 and 27X-1 human embryonal carcinoma cells. Stem Cells. 2007 Mar;25(3):771-8. doi: 10.1634/stemcells.2006-0271. Epub 2006 Nov 30.
• [6] 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.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [9] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [10] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [11] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [12] 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.
• [13] 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.
• [14] 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.
• [15] 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.
• [16] 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.
• [17] Marine biogenics in sea spray aerosols interact with the mTOR signaling pathway. Sci Rep. 2019 Jan 24;9(1):675.