Details of Drug Off-Target (DOT)

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

• DOT Name: UDP-N-acetylglucosamine--dolichyl-phosphate N-acetylglucosaminephosphotransferase (DPAGT1)
• Synonyms: EC 2.7.8.15; GlcNAc-1-P transferase; G1PT; GPT; N-acetylglucosamine-1-phosphate transferase
• Gene Name: DPAGT1
• Related Disease:
  Colorectal carcinoma
  Colorectal neoplasm
  Congenital myasthenic syndrome 13
  Obsolete hematopoietic stem cell kinetics, control of
  Tuberculosis
  Congenital disorder of glycosylation
  Congenital myasthenic syndrome
  Cutaneous leishmaniasis
  Developmental and epileptic encephalopathy, 36
  DPAGT1-congenital disorder of glycosylation
  Gastric cancer
  Gastric neoplasm
  Hepatocellular carcinoma
  Hereditary diffuse gastric adenocarcinoma
  Mucolipidosis
  Oral cancer
  Squamous cell carcinoma
  Arthrogryposis
  Ebola virus infection
  Fetal akinesia deformation sequence 1
  High blood pressure
  Neoplasm
  Obsolete congenital myasthenic syndromes with glycosylation defect
  Intellectual disability
  Leishmaniasis
  LambertEaton myasthenic syndrome
  Myopathy
• UniProt ID: GPT_HUMAN
• PDB ID: 5LEV; 5O5E; 6BW5; 6BW6; 6FM9; 6FWZ; 6JQ3
• EC Number: 2.7.8.15
• Pfam ID: PF21383 ; PF00953
• Sequence:
  MWAFSELPMPLLINLIVSLLGFVATVTLIPAFRGHFIAARLCGQDLNKTSRQQIPESQGV
  ISGAVFLIILFCFIPFPFLNCFVKEQCKAFPHHEFVALIGALLAICCMIFLGFADDVLNL
  RWRHKLLLPTAASLPLLMVYFTNFGNTTIVVPKPFRPILGLHLDLGILYYVYMGLLAVFC
  TNAINILAGINGLEAGQSLVISASIIVFNLVELEGDCRDDHVFSLYFMIPFFFTTLGLLY
  HNWYPSRVFVGDTFCYFAGMTFAVVGILGHFSKTMLLFFMPQVFNFLYSLPQLLHIIPCP
  RHRIPRLNIKTGKLEMSYSKFKTKSLSFLGTFILKVAESLQLVTVHQSETEDGEFTECNN
  MTLINLLLKVLGPIHERNLTLLLLLLQILGSAITFSIRYQLVRLFYDV
• Function: Catalyzes the initial step of dolichol-linked oligosaccharide biosynthesis in N-linked protein glycosylation pathway: transfers GlcNAc-1-P from UDP-GlcNAc onto the carrier lipid dolichyl phosphate (P-dolichol), yielding GlcNAc-P-P-dolichol.
• KEGG Pathway:
  N-Glycan biosynthesis (hsa00510)
  Metabolic pathways (hsa01100)
• Reactome Pathway:
  Defective DPAGT1 causes CDG-1j, CMSTA2 (R-HSA-4549356)
  Biosynthesis of the N-glycan precursor (dolichol lipid-linked oligosaccharide, LLO) and transfer to a nascent protein (R-HSA-446193)

Molecular Interaction Atlas (MIA) of This DOT

27 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Colorectal carcinoma	DIS5PYL0	Definitive	Biomarker	[1]
Colorectal neoplasm	DISR1UCN	Definitive	Biomarker	[1]
Congenital myasthenic syndrome 13	DIS8C9AF	Definitive	Autosomal recessive	[2]
Obsolete hematopoietic stem cell kinetics, control of	DISGEGEG	Definitive	Autosomal recessive	[3]
Tuberculosis	DIS2YIMD	Definitive	Biomarker	[4]
Congenital disorder of glycosylation	DIS400QP	Strong	Genetic Variation	[5]
Congenital myasthenic syndrome	DISJLG2T	Strong	Genetic Variation	[6]
Cutaneous leishmaniasis	DISRK7TS	Strong	Genetic Variation	[7]
Developmental and epileptic encephalopathy, 36	DISG4MY5	Strong	Biomarker	[8]
DPAGT1-congenital disorder of glycosylation	DISXWRLX	Strong	Autosomal recessive	[9]
Gastric cancer	DISXGOUK	Strong	Biomarker	[10]
Gastric neoplasm	DISOKN4Y	Strong	Biomarker	[10]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[11]
Hereditary diffuse gastric adenocarcinoma	DISUIBYS	Strong	Biomarker	[10]
Mucolipidosis	DISOZ8DI	Strong	Genetic Variation	[12]
Oral cancer	DISLD42D	Strong	Biomarker	[13]
Squamous cell carcinoma	DISQVIFL	Strong	Biomarker	[13]
Arthrogryposis	DISC81CM	moderate	Biomarker	[14]
Ebola virus infection	DISJAVM1	moderate	Biomarker	[15]
Fetal akinesia deformation sequence 1	DISKDI9L	moderate	Biomarker	[14]
High blood pressure	DISY2OHH	moderate	Altered Expression	[16]
Neoplasm	DISZKGEW	moderate	Altered Expression	[11]
Obsolete congenital myasthenic syndromes with glycosylation defect	DISIGACA	Supportive	Autosomal recessive	[17]
Intellectual disability	DISMBNXP	Disputed	Genetic Variation	[18]
Leishmaniasis	DISABTW7	Disputed	Biomarker	[19]
LambertEaton myasthenic syndrome	DISN0Q7Q	Limited	Biomarker	[18]
Myopathy	DISOWG27	Limited	Genetic Variation	[20]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Fluorouracil	DMUM7HZ	Approved	UDP-N-acetylglucosamine--dolichyl-phosphate N-acetylglucosaminephosphotransferase (DPAGT1) affects the response to substance of Fluorouracil.	[32]

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 UDP-N-acetylglucosamine--dolichyl-phosphate N-acetylglucosaminephosphotransferase (DPAGT1).	[21]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of UDP-N-acetylglucosamine--dolichyl-phosphate N-acetylglucosaminephosphotransferase (DPAGT1).	[28]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of UDP-N-acetylglucosamine--dolichyl-phosphate N-acetylglucosaminephosphotransferase (DPAGT1).	[22]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of UDP-N-acetylglucosamine--dolichyl-phosphate N-acetylglucosaminephosphotransferase (DPAGT1).	[23]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of UDP-N-acetylglucosamine--dolichyl-phosphate N-acetylglucosaminephosphotransferase (DPAGT1).	[24]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of UDP-N-acetylglucosamine--dolichyl-phosphate N-acetylglucosaminephosphotransferase (DPAGT1).	[25]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of UDP-N-acetylglucosamine--dolichyl-phosphate N-acetylglucosaminephosphotransferase (DPAGT1).	[26]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of UDP-N-acetylglucosamine--dolichyl-phosphate N-acetylglucosaminephosphotransferase (DPAGT1).	[27]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of UDP-N-acetylglucosamine--dolichyl-phosphate N-acetylglucosaminephosphotransferase (DPAGT1).	[29]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of UDP-N-acetylglucosamine--dolichyl-phosphate N-acetylglucosaminephosphotransferase (DPAGT1).	[30]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of UDP-N-acetylglucosamine--dolichyl-phosphate N-acetylglucosaminephosphotransferase (DPAGT1).	[31]

References

• [1] Highly Expressed Genes in Rapidly Proliferating Tumor Cells as New Targets for Colorectal Cancer Treatment.Clin Cancer Res. 2015 Aug 15;21(16):3695-704. doi: 10.1158/1078-0432.CCR-14-2457. Epub 2015 May 5.
• [2] Mutations in DPAGT1 cause a limb-girdle congenital myasthenic syndrome with tubular aggregates. Am J Hum Genet. 2012 Jul 13;91(1):193-201. doi: 10.1016/j.ajhg.2012.05.022. Epub 2012 Jun 27.
• [3] Flexible and scalable diagnostic filtering of genomic variants using G2P with Ensembl VEP. Nat Commun. 2019 May 30;10(1):2373. doi: 10.1038/s41467-019-10016-3.
• [4] Down-regulation of N-acetylglucosamine-1-phosphate transferase (WecA) enhanced the sensitivity of Mycobacterium smegmatis against rifampin.J Appl Microbiol. 2016 Oct;121(4):966-72. doi: 10.1111/jam.13228. Epub 2016 Aug 21.
• [5] Congenital glycosylation disorder: a novel presentation of coexisting anterior and posterior segment pathology and its implications in pediatric cataract management.J AAPOS. 2019 Oct;23(5):297-300. doi: 10.1016/j.jaapos.2019.05.004. Epub 2019 May 30.
• [6] Structures of DPAGT1 Explain Glycosylation Disease Mechanisms and Advance TB Antibiotic Design.Cell. 2018 Nov 1;175(4):1045-1058.e16. doi: 10.1016/j.cell.2018.10.037.
• [7] Genetic polymorphism in Leishmania infantum isolates from human and animals determined by nagt PCR-RFLP.Infect Dis Poverty. 2018 Jun 14;7(1):54. doi: 10.1186/s40249-018-0439-y.
• [8] A compound heterozygous mutation in DPAGT1 results in a congenital disorder of glycosylation with a relatively mild phenotype.Eur J Hum Genet. 2013 Aug;21(8):844-9. doi: 10.1038/ejhg.2012.257. Epub 2012 Dec 19.
• [9] Deficiency of UDP-GlcNAc:Dolichol Phosphate N-Acetylglucosamine-1 Phosphate Transferase (DPAGT1) causes a novel congenital disorder of Glycosylation Type Ij. Hum Mutat. 2003 Aug;22(2):144-50. doi: 10.1002/humu.10239.
• [10] A gene expression signature of acquired chemoresistance to cisplatin and fluorouracil combination chemotherapy in gastric cancer patients.PLoS One. 2011 Feb 18;6(2):e16694. doi: 10.1371/journal.pone.0016694.
• [11] Dysregulation of the miR-325-3p/DPAGT1 axis supports HBV-positive HCC chemoresistance.Biochem Biophys Res Commun. 2019 Nov 5;519(2):358-365. doi: 10.1016/j.bbrc.2019.08.116. Epub 2019 Sep 10.
• [12] Molecular characterization of 22 novel UDP-N-acetylglucosamine-1-phosphate transferase alpha- and beta-subunit (GNPTAB) gene mutations causing mucolipidosis types IIalpha/beta and IIIalpha/beta in 46 patients.Hum Mutat. 2009 Nov;30(11):E956-73. doi: 10.1002/humu.21099.
• [13] Aberrant amplification of the crosstalk between canonical Wnt signaling and N-glycosylation gene DPAGT1 promotes oral cancer.Oral Oncol. 2012 Jun;48(6):523-9. doi: 10.1016/j.oraloncology.2012.01.010. Epub 2012 Feb 15.
• [14] Fetal akinesia deformation sequence due to a congenital disorder of glycosylation.Am J Med Genet A. 2015 Oct;167A(10):2411-7. doi: 10.1002/ajmg.a.37184. Epub 2015 May 31.
• [15] A genome-wide CRISPR screen identifies N-acetylglucosamine-1-phosphate transferase as a potential antiviral target for Ebola virus. Nat Commun. 2019 Jan 17;10(1):285.
• [16] Urinary angiotensinogen level is correlated with blood pressure level and proteinuria in patients with masked hypertension.Clin Exp Hypertens. 2018;40(7):644-649. doi: 10.1080/10641963.2017.1416122. Epub 2018 Feb 8.
• [17] Congenital myasthenic syndromes due to mutations in ALG2 and ALG14. Brain. 2013 Mar;136(Pt 3):944-56. doi: 10.1093/brain/awt010. Epub 2013 Feb 11.
• [18] DPAGT1 myasthenia and myopathy: genetic, phenotypic, and expression studies.Neurology. 2014 May 20;82(20):1822-30. doi: 10.1212/WNL.0000000000000435. Epub 2014 Apr 23.
• [19] Identification and phylogenetic relationship of Iranian strains of various Leishmania species isolated from cutaneous and visceral cases of leishmaniasis based on N-acetylglucosamine-1-phosphate transferase gene.Infect Genet Evol. 2014 Aug;26:203-12. doi: 10.1016/j.meegid.2014.05.026. Epub 2014 Jun 7.
• [20] Tubular Aggregates and Cylindrical Spirals Have Distinct Immunohistochemical Signatures.J Neuropathol Exp Neurol. 2016 Dec;75(12):1171-1178. doi: 10.1093/jnen/nlw096.
• [21] 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.
• [22] 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.
• [23] 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.
• [24] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [25] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [26] Chronic occupational exposure to arsenic induces carcinogenic gene signaling networks and neoplastic transformation in human lung epithelial cells. Toxicol Appl Pharmacol. 2012 Jun 1;261(2):204-16.
• [27] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [28] 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.
• [29] 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.
• [30] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [31] 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.
• [32] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.