Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT2Z03OB)

• DOT Name: N-acetylglucosamine-1-phosphotransferase subunits alpha/beta (GNPTAB)
• Synonyms: EC 2.7.8.17; GlcNAc-1-phosphotransferase subunits alpha/beta; Stealth protein GNPTAB; UDP-N-acetylglucosamine-1-phosphotransferase subunits alpha/beta
• Gene Name: GNPTAB
• Related Disease:
  Autism
  GNPTAB-mucolipidosis
  Mucolipidosis
  Mucolipidosis type II
  Mucolipidosis type III, alpha/beta
  Arrhythmogenic right ventricular cardiomyopathy
  Cardiac failure
  Cardiomyopathy
  Congestive heart failure
  Lysosomal storage disease
  Metabolic disorder
  Ebola virus infection
  Osteochondrodysplasia
  Skeletal dysplasia
  Advanced cancer
  Clear cell renal carcinoma
  Neoplasm
• UniProt ID: GNPTA_HUMAN
• PDB ID: 2N6D; 7S05; 7S06
• EC Number: 2.7.8.17
• Pfam ID: PF06464 ; PF18440 ; PF00066 ; PF17101 ; PF11380 ; PF17102 ; PF17103
• Sequence:
  MLFKLLQRQTYTCLSHRYGLYVCFLGVVVTIVSAFQFGEVVLEWSRDQYHVLFDSYRDNI
  AGKSFQNRLCLPMPIDVVYTWVNGTDLELLKELQQVREQMEEEQKAMREILGKNTTEPTK
  KSEKQLECLLTHCIKVPMLVLDPALPANITLKDLPSLYPSFHSASDIFNVAKPKNPSTNV
  SVVVFDSTKDVEDAHSGLLKGNSRQTVWRGYLTTDKEVPGLVLMQDLAFLSGFPPTFKET
  NQLKTKLPENLSSKVKLLQLYSEASVALLKLNNPKDFQELNKQTKKNMTIDGKELTISPA
  YLLWDLSAISQSKQDEDISASRFEDNEELRYSLRSIERHAPWVRNIFIVTNGQIPSWLNL
  DNPRVTIVTHQDVFRNLSHLPTFSSPAIESHIHRIEGLSQKFIYLNDDVMFGKDVWPDDF
  YSHSKGQKVYLTWPVPNCAEGCPGSWIKDGYCDKACNNSACDWDGGDCSGNSGGSRYIAG
  GGGTGSIGVGQPWQFGGGINSVSYCNQGCANSWLADKFCDQACNVLSCGFDAGDCGQDHF
  HELYKVILLPNQTHYIIPKGECLPYFSFAEVAKRGVEGAYSDNPIIRHASIANKWKTIHL
  IMHSGMNATTIHFNLTFQNTNDEEFKMQITVEVDTREGPKLNSTAQKGYENLVSPITLLP
  EAEILFEDIPKEKRFPKFKRHDVNSTRRAQEEVKIPLVNISLLPKDAQLSLNTLDLQLEH
  GDITLKGYNLSKSALLRSFLMNSQHAKIKNQAIITDETNDSLVAPQEKQVHKSILPNSLG
  VSERLQRLTFPAVSVKVNGHDQGQNPPLDLETTARFRVETHTQKTIGGNVTKEKPPSLIV
  PLESQMTKEKKITGKEKENSRMEENAENHIGVTEVLLGRKLQHYTDSYLGFLPWEKKKYF
  QDLLDEEESLKTQLAYFTDSKNTGRQLKDTFADSLRYVNKILNSKFGFTSRKVPAHMPHM
  IDRIVMQELQDMFPEEFDKTSFHKVRHSEDMQFAFSYFYYLMSAVQPLNISQVFDEVDTD
  QSGVLSDREIRTLATRIHELPLSLQDLTGLEHMLINCSKMLPADITQLNNIPPTQESYYD
  PNLPPVTKSLVTNCKPVTDKIHKAYKDKNKYRFEIMGEEEIAFKMIRTNVSHVVGQLDDI
  RKNPRKFVCLNDNIDHNHKDAQTVKAVLRDFYESMFPIPSQFELPREYRNRFLHMHELQE
  WRAYRDKLKFWTHCVLATLIMFTIFSFFAEQLIALKRKIFPRRRIHKEASPNRIRV
• Function: Catalyzes the formation of mannose 6-phosphate (M6P) markers on high mannose type oligosaccharides in the Golgi apparatus. M6P residues are required to bind to the M6P receptors (MPR), which mediate the vesicular transport of lysosomal enzymes to the endosomal/prelysosomal compartment.
• Tissue Specificity: Expressed in the heart, whole brain, placenta, lung, liver, skeletal muscle, kidney and pancreas.
• KEGG Pathway: Lysosome (hsa04142)

Molecular Interaction Atlas (MIA) of This DOT

17 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autism	DISV4V1Z	Definitive	CausalMutation	[1]
GNPTAB-mucolipidosis	DISBFVOW	Definitive	Autosomal recessive	[2]
Mucolipidosis	DISOZ8DI	Definitive	Autosomal recessive	[2]
Mucolipidosis type II	DISUNVXN	Definitive	Autosomal recessive	[3]
Mucolipidosis type III, alpha/beta	DISU1TGJ	Definitive	Autosomal recessive	[4]
Arrhythmogenic right ventricular cardiomyopathy	DIS3V2BE	Strong	Altered Expression	[5]
Cardiac failure	DISDC067	Strong	Biomarker	[6]
Cardiomyopathy	DISUPZRG	Strong	Altered Expression	[5]
Congestive heart failure	DIS32MEA	Strong	Biomarker	[6]
Lysosomal storage disease	DIS6QM6U	Strong	Genetic Variation	[7]
Metabolic disorder	DIS71G5H	Strong	Genetic Variation	[8]
Ebola virus infection	DISJAVM1	moderate	Biomarker	[9]
Osteochondrodysplasia	DIS9SPWW	moderate	Genetic Variation	[10]
Skeletal dysplasia	DIS5Z8U6	moderate	Genetic Variation	[10]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[11]
Clear cell renal carcinoma	DISBXRFJ	Limited	Biomarker	[11]
Neoplasm	DISZKGEW	Limited	Biomarker	[11]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	N-acetylglucosamine-1-phosphotransferase subunits alpha/beta (GNPTAB) affects the response to substance of Doxorubicin.	[23]
Vinblastine	DM5TVS3	Approved	N-acetylglucosamine-1-phosphotransferase subunits alpha/beta (GNPTAB) affects the response to substance of Vinblastine.	[23]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of N-acetylglucosamine-1-phosphotransferase subunits alpha/beta (GNPTAB).	[12]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of N-acetylglucosamine-1-phosphotransferase subunits alpha/beta (GNPTAB).	[13]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of N-acetylglucosamine-1-phosphotransferase subunits alpha/beta (GNPTAB).	[14]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of N-acetylglucosamine-1-phosphotransferase subunits alpha/beta (GNPTAB).	[15]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of N-acetylglucosamine-1-phosphotransferase subunits alpha/beta (GNPTAB).	[16]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol decreases the expression of N-acetylglucosamine-1-phosphotransferase subunits alpha/beta (GNPTAB).	[17]
Ethanol	DMDRQZU	Approved	Ethanol increases the expression of N-acetylglucosamine-1-phosphotransferase subunits alpha/beta (GNPTAB).	[18]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of N-acetylglucosamine-1-phosphotransferase subunits alpha/beta (GNPTAB).	[19]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of N-acetylglucosamine-1-phosphotransferase subunits alpha/beta (GNPTAB).	[20]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of N-acetylglucosamine-1-phosphotransferase subunits alpha/beta (GNPTAB).	[21]

1 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of N-acetylglucosamine-1-phosphotransferase subunits alpha/beta (GNPTAB).	[22]

References

• [1] Pitfalls in the prenatal diagnosis of mucolipidosis II alpha/beta: A case report.Meta Gene. 2014 Jun 1;2:403-6. doi: 10.1016/j.mgene.2014.03.003. eCollection 2014 Dec.
• [2] 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.
• [3] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [4] Mucolipidosis II (I-cell disease) and mucolipidosis IIIA (classical pseudo-hurler polydystrophy) are caused by mutations in the GlcNAc-phosphotransferase alpha / beta -subunits precursor gene. Am J Hum Genet. 2006 Mar;78(3):451-63. doi: 10.1086/500849. Epub 2006 Jan 24.
• [5] Intercalated discs: cellular adhesion and signaling in heart health and diseases.Heart Fail Rev. 2019 Jan;24(1):115-132. doi: 10.1007/s10741-018-9743-7.
• [6] Outcomes following implantable cardioverter-defibrillator generator replacement in patients with recovered left ventricular systolic function: The National Cardiovascular Data Registry.Heart Rhythm. 2019 May;16(5):733-740. doi: 10.1016/j.hrthm.2018.11.005. Epub 2018 Nov 7.
• [7] Combined in vitro and in silico analyses of missense mutations in GNPTAB provide new insights into the molecular bases of mucolipidosis II and III alpha/beta.Hum Mutat. 2020 Jan;41(1):133-139. doi: 10.1002/humu.23928. Epub 2019 Oct 14.
• [8] A novel splice site mutation in the GNPTAB gene in an Iranian patient with mucolipidosis II /.J Pediatr Endocrinol Metab. 2016 Aug 1;29(8):991-3. doi: 10.1515/jpem-2016-0032.
• [9] 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.
• [10] Prenatal skeletal dysplasia phenotype in severe MLII alpha/beta with novel GNPTAB mutation.Gene. 2014 Jun 1;542(2):266-8. doi: 10.1016/j.gene.2014.03.053. Epub 2014 Mar 28.
• [11] Transforming growth factor- promotes aggressiveness and invasion of clear cell renal cell carcinoma.Oncotarget. 2016 Jun 14;7(24):35917-35931. doi: 10.18632/oncotarget.9177.
• [12] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [13] 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.
• [14] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [15] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [16] 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.
• [17] Identification of biomarkers and outcomes of endocrine disruption in human ovarian cortex using In Vitro Models. Toxicology. 2023 Feb;485:153425. doi: 10.1016/j.tox.2023.153425. Epub 2023 Jan 5.
• [18] Gene expression signatures after ethanol exposure in differentiating embryoid bodies. Toxicol In Vitro. 2018 Feb;46:66-76.
• [19] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [20] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [21] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [22] Expression and DNA methylation changes in human breast epithelial cells after bisphenol A exposure. Int J Oncol. 2012 Jul;41(1):369-77.
• [23] 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.