Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT0ZW5FM)

• DOT Name: Alpha-1,3-mannosyl-glycoprotein 4-beta-N-acetylglucosaminyltransferase A (MGAT4A)
• Synonyms: EC 2.4.1.145; N-glycosyl-oligosaccharide-glycoprotein N-acetylglucosaminyltransferase IVa; GlcNAc-T IVa; GnT-IVa; N-acetylglucosaminyltransferase IVa; UDP-N-acetylglucosamine: alpha-1,3-D-mannoside beta-1,4-N-acetylglucosaminyltransferase IVa
• Gene Name: MGAT4A
• Related Disease:
  Metabolic disorder
  Advanced cancer
  Choriocarcinoma
  Colorectal neoplasm
  Gestational trophoblastic neoplasia
  Hypoplastic left heart syndrome 1
  Pancreatic tumour
  Bipolar disorder
  Non-insulin dependent diabetes
• UniProt ID: MGT4A_HUMAN
• PDB ID: 7XTL
• EC Number: 2.4.1.145
• Pfam ID: PF04666
• Sequence:
  MRLRNGTVATALAFITSFLTLSWYTTWQNGKEKLIAYQREFLALKERLRIAEHRISQRSS
  ELNTIVQQFKRVGAETNGSKDALNKFSDNTLKLLKELTSKKSLQVPSIYYHLPHLLKNEG
  SLQPAVQIGNGRTGVSIVMGIPTVKREVKSYLIETLHSLIDNLYPEEKLDCVIVVFIGET
  DIDYVHGVVANLEKEFSKEISSGLVEVISPPESYYPDLTNLKETFGDSKERVRWRTKQNL
  DYCFLMMYAQEKGIYYIQLEDDIIVKQNYFNTIKNFALQLSSEEWMILEFSQLGFIGKMF
  QAPDLTLIVEFIFMFYKEKPIDWLLDHILWVKVCNPEKDAKHCDRQKANLRIRFRPSLFQ
  HVGLHSSLSGKIQKLTDKDYMKPLLLKIHVNPPAEVSTSLKVYQGHTLEKTYMGEDFFWA
  ITPIAGDYILFKFDKPVNVESYLFHSGNQEHPGDILLNTTVEVLPFKSEGLEISKETKDK
  RLEDGYFRIGKFENGVAEGMVDPSLNPISAFRLSVIQNSAVWAILNEIHIKKATN
• Function: Glycosyltransferase that catalyze the transfer of GlcNAc from UDP-GlcNAc to the GlcNAcbeta1-2Manalpha1-3 arm of the core structure of N-linked glycans through a beta1-4 linkage and participates in the production of tri- and tetra-antennary N-linked sugar chains. Involved in glucose transport by mediating SLC2A2/GLUT2 glycosylation, thereby controlling cell-surface expression of SLC2A2 in pancreatic beta cells.
• Tissue Specificity: Expressed in pancreas, spleen, thymus, prostate, small intestine, peripheral blood leukocytes and lymph node. Strongly overexpressed in choriocarcinoma cancer cell lines. Down-regulated in pancreatic cancer.
• KEGG Pathway:
  N-Glycan biosynthesis (hsa00510)
  Various types of N-glycan biosynthesis (hsa00513)
  Metabolic pathways (hsa01100)
• Reactome Pathway:
  Post-translational protein phosphorylation (R-HSA-8957275)
  Maturation of spike protein (R-HSA-9694548)
  N-Glycan antennae elongation (R-HSA-975577)
  Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) (R-HSA-381426)
• BioCyc Pathway: MetaCyc:HS01024-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Metabolic disorder	DIS71G5H	Definitive	Altered Expression	[1]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[2]
Choriocarcinoma	DISDBVNL	Strong	Altered Expression	[2]
Colorectal neoplasm	DISR1UCN	Strong	Biomarker	[3]
Gestational trophoblastic neoplasia	DIS4EJNA	Strong	Altered Expression	[2]
Hypoplastic left heart syndrome 1	DISW3OY8	Strong	Genetic Variation	[4]
Pancreatic tumour	DIS3U0LK	Strong	Altered Expression	[5]
Bipolar disorder	DISAM7J2	moderate	Genetic Variation	[6]
Non-insulin dependent diabetes	DISK1O5Z	Limited	Altered Expression	[7]

2 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 Alpha-1,3-mannosyl-glycoprotein 4-beta-N-acetylglucosaminyltransferase A (MGAT4A).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Alpha-1,3-mannosyl-glycoprotein 4-beta-N-acetylglucosaminyltransferase A (MGAT4A).	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Alpha-1,3-mannosyl-glycoprotein 4-beta-N-acetylglucosaminyltransferase A (MGAT4A).	[9]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Alpha-1,3-mannosyl-glycoprotein 4-beta-N-acetylglucosaminyltransferase A (MGAT4A).	[10]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Alpha-1,3-mannosyl-glycoprotein 4-beta-N-acetylglucosaminyltransferase A (MGAT4A).	[11]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Alpha-1,3-mannosyl-glycoprotein 4-beta-N-acetylglucosaminyltransferase A (MGAT4A).	[12]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Alpha-1,3-mannosyl-glycoprotein 4-beta-N-acetylglucosaminyltransferase A (MGAT4A).	[13]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Alpha-1,3-mannosyl-glycoprotein 4-beta-N-acetylglucosaminyltransferase A (MGAT4A).	[14]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Alpha-1,3-mannosyl-glycoprotein 4-beta-N-acetylglucosaminyltransferase A (MGAT4A).	[15]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Alpha-1,3-mannosyl-glycoprotein 4-beta-N-acetylglucosaminyltransferase A (MGAT4A).	[16]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Alpha-1,3-mannosyl-glycoprotein 4-beta-N-acetylglucosaminyltransferase A (MGAT4A).	[18]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Alpha-1,3-mannosyl-glycoprotein 4-beta-N-acetylglucosaminyltransferase A (MGAT4A).	[19]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Alpha-1,3-mannosyl-glycoprotein 4-beta-N-acetylglucosaminyltransferase A (MGAT4A).	[20]

References

• [1] Pathway to diabetes through attenuation of pancreatic beta cell glycosylation and glucose transport.Nat Med. 2011 Aug 14;17(9):1067-75. doi: 10.1038/nm.2414.
• [2] N-acetylglucosaminyltransferase IVa promotes invasion of choriocarcinoma.Oncol Rep. 2017 Jul;38(1):440-448. doi: 10.3892/or.2017.5661. Epub 2017 May 23.
• [3] Metastatic transcriptional pattern revealed by gene expression profiling in primary colorectal carcinoma.Int J Cancer. 2005 Jun 10;115(2):256-62. doi: 10.1002/ijc.20883.
• [4] Genome-Wide Association Studies and Meta-Analyses for Congenital Heart Defects.Circ Cardiovasc Genet. 2017 Jun;10(3):e001449. doi: 10.1161/CIRCGENETICS.116.001449.
• [5] Aberrant expression of N-acetylglucosaminyltransferase-IVa and IVb (GnT-IVa and b) in pancreatic cancer.Biochem Biophys Res Commun. 2006 Mar 10;341(2):478-82. doi: 10.1016/j.bbrc.2005.12.208. Epub 2006 Jan 11.
• [6] Genome-wide association of bipolar disorder suggests an enrichment of replicable associations in regions near genes.PLoS Genet. 2011 Jun;7(6):e1002134. doi: 10.1371/journal.pgen.1002134. Epub 2011 Jun 30.
• [7] The transcription of MGAT4A glycosyl transferase is increased in white cells of peripheral blood of type 2 diabetes patients.BMC Genet. 2007 Oct 22;8:73. doi: 10.1186/1471-2156-8-73.
• [8] 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.
• [9] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [10] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [11] Toxicogenomics-based prediction of acetaminophen-induced liver injury using human hepatic cell systems. Toxicol Lett. 2016 Jan 5;240(1):50-9.
• [12] 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.
• [13] Persistent and non-persistent changes in gene expression result from long-term estrogen exposure of MCF-7 breast cancer cells. J Steroid Biochem Mol Biol. 2011 Feb;123(3-5):140-50.
• [14] 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.
• [15] Single-cell Transcriptome Mapping Identifies Common and Cell-type Specific Genes Affected by Acute Delta9-tetrahydrocannabinol in Humans. Sci Rep. 2020 Feb 26;10(1):3450. doi: 10.1038/s41598-020-59827-1.
• [16] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [17] 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.
• [18] 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.
• [19] 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.
• [20] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.