Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTYO6ONR)

• DOT Name: N-acetylglucosamine-1-phosphotransferase subunit gamma (GNPTG)
• Synonyms: GlcNAc-1-phosphotransferase subunit gamma; UDP-N-acetylglucosamine-1-phosphotransferase subunit gamma
• Gene Name: GNPTG
• Related Disease:
  GNPTG-mucolipidosis
  Morquio syndrome
  Mucolipidosis type III, alpha/beta
  Retinitis pigmentosa
  Lysosomal storage disease
  Mucolipidosis type II
• UniProt ID: GNPTG_HUMAN
• Pfam ID: PF07915
• Sequence:
  MAAGLARLLLLLGLSAGGPAPAGAAKMKVVEEPNAFGVNNPFLPQASRLQAKRDPSPVSG
  PVHLFRLSGKCFSLVESTYKYEFCPFHNVTQHEQTFRWNAYSGILGIWHEWEIANNTFTG
  MWMRDGDACRSRSRQSKVELACGKSNRLAHVSEPSTCVYALTFETPLVCHPHALLVYPTL
  PEALQRQWDQVEQDLADELITPQGHEKLLRTLFEDAGYLKTPEENEPTQLEGGPDSLGFE
  TLENCRKAHKELSKEIKRLKGLLTQHGIPYTRPTETSNLEHLGHETPRAKSPEQLRGDPG
  LRGSL
• Function: Non-catalytic subunit of the N-acetylglucosamine-1-phosphotransferase complex, an enzyme that catalyzes the formation of mannose 6-phosphate (M6P) markers on high mannose type oligosaccharides in the Golgi apparatus. Binds and presents the high mannose glycans of the acceptor to the catalytic alpha and beta subunits (GNPTAB). Enhances the rate of N-acetylglucosamine-1-phosphate transfer to the oligosaccharides of acid hydrolase acceptors.
• Tissue Specificity: Widely expressed.
• KEGG Pathway: Lysosome (hsa04142)

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
GNPTG-mucolipidosis	DIS1K7GJ	Definitive	Autosomal recessive	[1]
Morquio syndrome	DIS2Y2P2	Strong	Genetic Variation	[2]
Mucolipidosis type III, alpha/beta	DISU1TGJ	Strong	Biomarker	[3]
Retinitis pigmentosa	DISCGPY8	Strong	Genetic Variation	[2]
Lysosomal storage disease	DIS6QM6U	moderate	Genetic Variation	[4]
Mucolipidosis type II	DISUNVXN	Limited	Biomarker	[5]

3 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 N-acetylglucosamine-1-phosphotransferase subunit gamma (GNPTG).	[6]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the methylation of N-acetylglucosamine-1-phosphotransferase subunit gamma (GNPTG).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of N-acetylglucosamine-1-phosphotransferase subunit gamma (GNPTG).	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of N-acetylglucosamine-1-phosphotransferase subunit gamma (GNPTG).	[8]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of N-acetylglucosamine-1-phosphotransferase subunit gamma (GNPTG).	[9]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of N-acetylglucosamine-1-phosphotransferase subunit gamma (GNPTG).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of N-acetylglucosamine-1-phosphotransferase subunit gamma (GNPTG).	[12]

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] Using next-generation sequencing for the diagnosis of rare disorders: a family with retinitis pigmentosa and skeletal abnormalities.J Pathol. 2011 Sep;225(1):12-8. doi: 10.1002/path.2941.
• [3] Mucolipidosis III GNPTG Missense Mutations Cause Misfolding of the Subunit of GlcNAc-1-Phosphotransferase.Hum Mutat. 2016 Jul;37(7):623-6. doi: 10.1002/humu.22993. Epub 2016 Apr 22.
• [4] The lysosomal storage disorders mucolipidosis type II, type III alpha/beta, and type III gamma: Update on GNPTAB and GNPTG mutations.Hum Mutat. 2019 Jul;40(7):842-864. doi: 10.1002/humu.23748. Epub 2019 Apr 13.
• [5] Mucolipidosis types II and III and non-syndromic stuttering are associated with different variants in the same genes.Eur J Hum Genet. 2016 Apr;24(4):529-34. doi: 10.1038/ejhg.2015.154. Epub 2015 Jul 1.
• [6] 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.
• [7] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [8] 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.
• [9] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [10] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [11] 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.
• [12] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.