Details of Drug Off-Target (DOT)

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

• DOT Name: Alpha-N-acetylgalactosaminidase (NAGA)
• Synonyms: EC 3.2.1.49; Alpha-galactosidase B
• Gene Name: NAGA
• Related Disease:
  Alpha-N-acetylgalactosaminidase deficiency
  Alpha-N-acetylgalactosaminidase deficiency type 2
  Neurodegeneration with brain iron accumulation 2A
  Advanced cancer
  Alpha-N-acetylgalactosaminidase deficiency type 1
  Fabry disease
  Influenza
  Nervous system disease
  Trichomoniasis
  Aplasia cutis congenita
  Corpus callosum, agenesis of
  Alpha-N-acetylgalactosaminidase deficiency type 3
  Cardiomyopathy
• UniProt ID: NAGAB_HUMAN
• PDB ID: 3H53; 3H54; 3H55; 3IGU; 4DO4; 4DO5; 4DO6
• EC Number: 3.2.1.49
• Pfam ID: PF16499 ; PF17450
• Sequence:
  MLLKTVLLLGHVAQVLMLDNGLLQTPPMGWLAWERFRCNINCDEDPKNCISEQLFMEMAD
  RMAQDGWRDMGYTYLNIDDCWIGGRDASGRLMPDPKRFPHGIPFLADYVHSLGLKLGIYA
  DMGNFTCMGYPGTTLDKVVQDAQTFAEWKVDMLKLDGCFSTPEERAQGYPKMAAALNATG
  RPIAFSCSWPAYEGGLPPRVNYSLLADICNLWRNYDDIQDSWWSVLSILNWFVEHQDILQ
  PVAGPGHWNDPDMLLIGNFGLSLEQSRAQMALWTVLAAPLLMSTDLRTISAQNMDILQNP
  LMIKINQDPLGIQGRRIHKEKSLIEVYMRPLSNKASALVFFSCRTDMPYRYHSSLGQLNF
  TGSVIYEAQDVYSGDIISGLRDETNFTVIINPSGVVMWYLYPIKNLEMSQQ
• Function: Removes terminal alpha-N-acetylgalactosamine residues from glycolipids and glycopeptides. Required for the breakdown of glycolipids.
• KEGG Pathway:
  Glycosphingolipid biosynthesis - globo and isoglobo series (hsa00603)
  Metabolic pathways (hsa01100)
  Lysosome (hsa04142)
• BioCyc Pathway: MetaCyc:HS01993-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

13 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alpha-N-acetylgalactosaminidase deficiency	DISJZCJ4	Definitive	Autosomal recessive	[1]
Alpha-N-acetylgalactosaminidase deficiency type 2	DISEVTNF	Definitive	Autosomal recessive	[2]
Neurodegeneration with brain iron accumulation 2A	DIS9XEBF	Definitive	Altered Expression	[3]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[4]
Alpha-N-acetylgalactosaminidase deficiency type 1	DISG30VZ	Strong	Autosomal recessive	[5]
Fabry disease	DISUUQJF	Strong	Biomarker	[6]
Influenza	DIS3PNU3	Strong	Altered Expression	[7]
Nervous system disease	DISJ7GGT	Strong	Biomarker	[8]
Trichomoniasis	DIS9HBNL	Strong	Genetic Variation	[9]
Aplasia cutis congenita	DISMDAYM	moderate	Biomarker	[10]
Corpus callosum, agenesis of	DISO9P40	moderate	Biomarker	[10]
Alpha-N-acetylgalactosaminidase deficiency type 3	DIS2DYZ3	Supportive	Autosomal recessive	[11]
Cardiomyopathy	DISUPZRG	Limited	Genetic Variation	[12]

10 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 Alpha-N-acetylgalactosaminidase (NAGA).	[13]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Alpha-N-acetylgalactosaminidase (NAGA).	[14]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Alpha-N-acetylgalactosaminidase (NAGA).	[15]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Alpha-N-acetylgalactosaminidase (NAGA).	[16]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Alpha-N-acetylgalactosaminidase (NAGA).	[17]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Alpha-N-acetylgalactosaminidase (NAGA).	[18]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Alpha-N-acetylgalactosaminidase (NAGA).	[20]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Alpha-N-acetylgalactosaminidase (NAGA).	[21]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Alpha-N-acetylgalactosaminidase (NAGA).	[22]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of Alpha-N-acetylgalactosaminidase (NAGA).	[23]

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 Alpha-N-acetylgalactosaminidase (NAGA).	[19]

References

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• [2] Human alpha-N-acetylgalactosaminidase (alpha-NAGA) deficiency: new mutations and the paradox between genotype and phenotype. J Med Genet. 1996 Jun;33(6):458-64. doi: 10.1136/jmg.33.6.458.
• [3] Lysosomal alpha-N-acetylgalactosaminidase deficiency, the enzymatic defect in angiokeratoma corporis diffusum with glycopeptiduria.J Clin Invest. 1991 Aug;88(2):707-11. doi: 10.1172/JCI115357.
• [4] Is -N-acetylgalactosaminidase the key to curing cancer? A mini-review and hypothesis.J BUON. 2017 Nov-Dec;22(6):1372-1377.
• [5] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [6] Use of a modified alpha-N-acetylgalactosaminidase in the development of enzyme replacement therapy for Fabry disease.Am J Hum Genet. 2009 Nov;85(5):569-80. doi: 10.1016/j.ajhg.2009.09.016. Epub 2009 Oct 22.
• [7] Pathogenic significance of alpha-N-acetylgalactosaminidase activity found in the hemagglutinin of influenza virus.Microbes Infect. 2005 Apr;7(4):674-81. doi: 10.1016/j.micinf.2005.01.015. Epub 2005 Mar 22.
• [8] Structural and immunocytochemical studies on alpha-N-acetylgalactosaminidase deficiency (Schindler/Kanzaki disease).J Hum Genet. 2004;49(1):1-8. doi: 10.1007/s10038-003-0098-z. Epub 2003 Dec 19.
• [9] Sexually Transmitted Infections: A Novel Screening Strategy for Improving Women's Health in Vulnerable Populations.Int J Mol Sci. 2017 Jun 20;18(6):1311. doi: 10.3390/ijms18061311.
• [10] High-molecular-weight fibronectin synthesized by adenoid cystic carcinoma cells of salivary gland origin.Jpn J Cancer Res. 1999 Mar;90(3):308-19. doi: 10.1111/j.1349-7006.1999.tb00749.x.
• [11] Clinical Practice Guidelines for Rare Diseases: The Orphanet Database. PLoS One. 2017 Jan 18;12(1):e0170365. doi: 10.1371/journal.pone.0170365. eCollection 2017.
• [12] A new infantile case of alpha-N-acetylgalactosaminidase deficiency. Cardiomyopathy as a presenting symptom.J Inherit Metab Dis. 2007 Feb;30(1):108. doi: 10.1007/s10545-006-0470-1. Epub 2006 Dec 14.
• [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] 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.
• [15] 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.
• [16] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [17] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [18] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [19] 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.
• [20] 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.
• [21] Environmental pollutant induced cellular injury is reflected in exosomes from placental explants. Placenta. 2020 Jan 1;89:42-49. doi: 10.1016/j.placenta.2019.10.008. Epub 2019 Oct 17.
• [22] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [23] Ochratoxin a lowers mRNA levels of genes encoding for key proteins of liver cell metabolism. Cancer Genomics Proteomics. 2008 Nov-Dec;5(6):319-32.