Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTZBQD5Q)

• DOT Name: Peptide-N(4)-(N-acetyl-beta-glucosaminyl)asparagine amidase (NGLY1)
• Synonyms: PNGase; hPNGase; EC 3.5.1.52; N-glycanase 1; Peptide:N-glycanase
• Gene Name: NGLY1
• Related Disease:
  Amyotrophic lateral sclerosis
  Congenital disorder of deglycosylation
  Congenital disorder of deglycosylation 1
  Cytomegalovirus infection
  Obsolete NGLY1-deficiency
  Peripheral neuropathy
  Movement disorder
  Advanced cancer
  Gastric cancer
  Melanoma
  Neoplasm
  Stomach cancer
• UniProt ID: NGLY1_HUMAN
• PDB ID: 2CCQ; 2CM0
• EC Number: 3.5.1.52
• Pfam ID: PF04721 ; PF09409 ; PF01841
• Sequence:
  MAAAALGSSSGSASPAVAELCQNTPETFLEASKLLLTYADNILRNPNDEKYRSIRIGNTA
  FSTRLLPVRGAVECLFEMGFEEGETHLIFPKKASVEQLQKIRDLIAIERSSRLDGSNKSH
  KVKSSQQPAASTQLPTTPSSNPSGLNQHTRNRQGQSSDPPSASTVAADSAILEVLQSNIQ
  HVLVYENPALQEKALACIPVQELKRKSQEKLSRARKLDKGINISDEDFLLLELLHWFKEE
  FFHWVNNVLCSKCGGQTRSRDRSLLPSDDELKWGAKEVEDHYCDACQFSNRFPRYNNPEK
  LLETRCGRCGEWANCFTLCCRAVGFEARYVWDYTDHVWTEVYSPSQQRWLHCDACEDVCD
  KPLLYEIGWGKKLSYVIAFSKDEVVDVTWRYSCKHEEVIARRTKVKEALLRDTINGLNKQ
  RQLFLSENRRKELLQRIIVELVEFISPKTPKPGELGGRISGSVAWRVARGEMGLQRKETL
  FIPCENEKISKQLHLCYNIVKDRYVRVSNNNQTISGWENGVWKMESIFRKVETDWHMVYL
  ARKEGSSFAYISWKFECGSVGLKVDSISIRTSSQTFQTGTVEWKLRSDTAQVELTGDNSL
  HSYADFSGATEVILEAELSRGDGDVAWQHTQLFRQSLNDHEENCLEIIIKFSDL
• Function: Specifically deglycosylates the denatured form of N-linked glycoproteins in the cytoplasm and assists their proteasome-mediated degradation. Cleaves the beta-aspartyl-glucosamine (GlcNAc) of the glycan and the amide side chain of Asn, converting Asn to Asp. Prefers proteins containing high-mannose over those bearing complex type oligosaccharides. Can recognize misfolded proteins in the endoplasmic reticulum that are exported to the cytosol to be destroyed and deglycosylate them, while it has no activity toward native proteins. Deglycosylation is a prerequisite for subsequent proteasome-mediated degradation of some, but not all, misfolded glycoproteins.
• KEGG Pathway: Protein processing in endoplasmic reticulum (hsa04141)
• Reactome Pathway: N-glycan trimming in the ER and Calnexin/Calreticulin cycle (R-HSA-532668)

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Amyotrophic lateral sclerosis	DISF7HVM	Definitive	Altered Expression	[1]
Congenital disorder of deglycosylation	DISF7BSZ	Definitive	Biomarker	[2]
Congenital disorder of deglycosylation 1	DISYOKRV	Definitive	Autosomal recessive	[3]
Cytomegalovirus infection	DISCEMGC	Strong	Biomarker	[4]
Obsolete NGLY1-deficiency	DISWVW9F	Strong	Autosomal recessive	[5]
Peripheral neuropathy	DIS7KN5G	Strong	Genetic Variation	[6]
Movement disorder	DISOJJ2D	moderate	CausalMutation	[7]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[8]
Gastric cancer	DISXGOUK	Limited	Genetic Variation	[9]
Melanoma	DIS1RRCY	Limited	Biomarker	[8]
Neoplasm	DISZKGEW	Limited	Biomarker	[8]
Stomach cancer	DISKIJSX	Limited	Genetic Variation	[9]

8 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 Peptide-N(4)-(N-acetyl-beta-glucosaminyl)asparagine amidase (NGLY1).	[10]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Peptide-N(4)-(N-acetyl-beta-glucosaminyl)asparagine amidase (NGLY1).	[11]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Peptide-N(4)-(N-acetyl-beta-glucosaminyl)asparagine amidase (NGLY1).	[12]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Peptide-N(4)-(N-acetyl-beta-glucosaminyl)asparagine amidase (NGLY1).	[13]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Peptide-N(4)-(N-acetyl-beta-glucosaminyl)asparagine amidase (NGLY1).	[14]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Peptide-N(4)-(N-acetyl-beta-glucosaminyl)asparagine amidase (NGLY1).	[15]
[3H]methyltrienolone	DMTSGOW	Investigative	[3H]methyltrienolone increases the expression of Peptide-N(4)-(N-acetyl-beta-glucosaminyl)asparagine amidase (NGLY1).	[17]
Forskolin	DM6ITNG	Investigative	Forskolin increases the expression of Peptide-N(4)-(N-acetyl-beta-glucosaminyl)asparagine amidase (NGLY1).	[17]

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 Peptide-N(4)-(N-acetyl-beta-glucosaminyl)asparagine amidase (NGLY1).	[16]

References

• [1] HR23B pathology preferentially co-localizes with p62, pTDP-43 and poly-GA in C9ORF72-linked frontotemporal dementia and amyotrophic lateral sclerosis.Acta Neuropathol Commun. 2019 Mar 13;7(1):39. doi: 10.1186/s40478-019-0694-6.
• [2] Liver-specific deletion of Ngly1 causes abnormal nuclear morphology and lipid metabolism under food stress.Biochim Biophys Acta Mol Basis Dis. 2020 Mar 1;1866(3):165588. doi: 10.1016/j.bbadis.2019.165588. Epub 2019 Nov 13.
• [3] 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.
• [4] Blocking cellular N-glycosylation suppresses human cytomegalovirus entry in human fibroblasts.Microb Pathog. 2020 Jan;138:103776. doi: 10.1016/j.micpath.2019.103776. Epub 2019 Oct 7.
• [5] Mutations in NGLY1 cause an inherited disorder of the endoplasmic reticulum-associated degradation pathway. Genet Med. 2014 Oct;16(10):751-8. doi: 10.1038/gim.2014.22. Epub 2014 Mar 20.
• [6] NGLY1 mutation causes neuromotor impairment, intellectual disability, and neuropathy.Eur J Med Genet. 2015 Jan;58(1):39-43. doi: 10.1016/j.ejmg.2014.08.008. Epub 2014 Sep 9.
• [7] Prospective phenotyping of NGLY1-CDDG, the first congenital disorder of deglycosylation.Genet Med. 2017 Feb;19(2):160-168. doi: 10.1038/gim.2016.75. Epub 2016 Jul 7.
• [8] Stress and interferon signalling-mediated apoptosis contributes to pleiotropic anticancer responses induced by targeting NGLY1.Br J Cancer. 2018 Dec;119(12):1538-1551. doi: 10.1038/s41416-018-0265-9. Epub 2018 Nov 2.
• [9] Identification of N- and O-linked glycans recognized by AAL in saliva of patients with atrophic gastritis and gastric cancer.Cancer Biomark. 2018;22(4):669-681. doi: 10.3233/CBM-171087.
• [10] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [11] 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.
• [12] 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.
• [13] 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.
• [14] 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.
• [15] 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.
• [16] 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.
• [17] Identification of genes targeted by the androgen and PKA signaling pathways in prostate cancer cells. Oncogene. 2006 Nov 23;25(55):7311-23.