Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTXI5X4T)

• DOT Name: Beta-1,4-mannosyl-glycoprotein 4-beta-N-acetylglucosaminyltransferase (MGAT3)
• Synonyms: EC 2.4.1.144; N-glycosyl-oligosaccharide-glycoprotein N-acetylglucosaminyltransferase III; GNT-III; GlcNAc-T III; N-acetylglucosaminyltransferase III
• Gene Name: MGAT3
• Related Disease:
  Advanced cancer
  Alzheimer disease
  Brachydactyly type C
  Breast cancer
  Choriocarcinoma
  Epithelial ovarian cancer
  Hepatitis B virus infection
  Hepatocellular carcinoma
  Inflammatory bowel disease
  Neoplasm
  Obesity
  Ovarian cancer
  Ovarian neoplasm
  Breast carcinoma
  Metastatic malignant neoplasm
• UniProt ID: MGAT3_HUMAN
• EC Number: 2.4.1.144
• Pfam ID: PF04724
• Sequence:
  MKMRRYKLFLMFCMAGLCLISFLHFFKTLSYVTFPRELASLSPNLVSSFFWNNAPVTPQA
  SPEPGGPDLLRTPLYSHSPLLQPLPPSKAAEELHRVDLVLPEDTTEYFVRTKAGGVCFKP
  GTKMLERPPPGRPEEKPEGANGSSARRPPRYLLSARERTGGRGARRKWVECVCLPGWHGP
  SCGVPTVVQYSNLPTKERLVPREVPRRVINAINVNHEFDLLDVRFHELGDVVDAFVVCES
  NFTAYGEPRPLKFREMLTNGTFEYIRHKVLYVFLDHFPPGGRQDGWIADDYLRTFLTQDG
  VSRLRNLRPDDVFIIDDADEIPARDGVLFLKLYDGWTEPFAFHMRKSLYGFFWKQPGTLE
  VVSGCTVDMLQAVYGLDGIRLRRRQYYTMPNFRQYENRTGHILVQWSLGSPLHFAGWHCS
  WCFTPEGIYFKLVSAQNGDFPRWGDYEDKRDLNYIRGLIRTGGWFDGTQQEYPPADPSEH
  MYAPKYLLKNYDRFHYLLDNPYQEPRSTAAGGWRHRGPEGRPPARGKLDEAEV
• Function: It is involved in the regulation of the biosynthesis and biological function of glycoprotein oligosaccharides. Catalyzes the addition of N-acetylglucosamine in beta 1-4 linkage to the beta-linked mannose of the trimannosyl core of N-linked sugar chains, called bisecting N-acetylglucosamine (GlcNAc). It is one of the most important enzymes involved in the regulation of the biosynthesis of glycoprotein oligosaccharides. The addition of this bisecting GlcNAc residue alters not only the composition, but also the conformation of the N-glycan. The introduction of the bisecting GlcNAc residue results in the suppression of further processing and elongation of N-glycans, precluding the formation of beta-1,6 GlcNAc branching, catalyzed by MGAT5 since it is unable to use the bisected oligosaccharide as a substrate. Addition of bisecting N-acetylglucosamine to CDH1/E-cadherin modulates CDH1 cell membrane location. Inhibits NeuAc-alpha-2,3-Gal-beta-1,4-GlcNAc- formation which modulates sialylation levels and plays a role in cell migration regulation. In brain, addition of bisecting N-acetylglucosamine to BACE1 blocks its lysosomal targeting in response to oxidative stress and further degradation which increases its location to early endosome and the APP cleavage.
• KEGG Pathway:
  N-Glycan biosynthesis (hsa00510)
  Metabolic pathways (hsa01100)
• Reactome Pathway: Reactions specific to the hybrid N-glycan synthesis pathway (R-HSA-975574)
• BioCyc Pathway: MetaCyc:HS05168-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

15 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[1]
Alzheimer disease	DISF8S70	Strong	Biomarker	[2]
Brachydactyly type C	DISZ8FTZ	Strong	Altered Expression	[3]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[4]
Choriocarcinoma	DISDBVNL	Strong	Altered Expression	[5]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[1]
Hepatitis B virus infection	DISLQ2XY	Strong	Altered Expression	[6]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[7]
Inflammatory bowel disease	DISGN23E	Strong	Altered Expression	[8]
Neoplasm	DISZKGEW	Strong	Biomarker	[9]
Obesity	DIS47Y1K	Strong	Biomarker	[10]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[1]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[1]
Breast carcinoma	DIS2UE88	Limited	Altered Expression	[9]
Metastatic malignant neoplasm	DIS86UK6	Limited	Biomarker	[11]

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 Beta-1,4-mannosyl-glycoprotein 4-beta-N-acetylglucosaminyltransferase (MGAT3).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Beta-1,4-mannosyl-glycoprotein 4-beta-N-acetylglucosaminyltransferase (MGAT3).	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Beta-1,4-mannosyl-glycoprotein 4-beta-N-acetylglucosaminyltransferase (MGAT3).	[13]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Beta-1,4-mannosyl-glycoprotein 4-beta-N-acetylglucosaminyltransferase (MGAT3).	[14]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Beta-1,4-mannosyl-glycoprotein 4-beta-N-acetylglucosaminyltransferase (MGAT3).	[15]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Beta-1,4-mannosyl-glycoprotein 4-beta-N-acetylglucosaminyltransferase (MGAT3).	[16]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Beta-1,4-mannosyl-glycoprotein 4-beta-N-acetylglucosaminyltransferase (MGAT3).	[17]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Beta-1,4-mannosyl-glycoprotein 4-beta-N-acetylglucosaminyltransferase (MGAT3).	[18]
DTI-015	DMXZRW0	Approved	DTI-015 decreases the expression of Beta-1,4-mannosyl-glycoprotein 4-beta-N-acetylglucosaminyltransferase (MGAT3).	[19]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Beta-1,4-mannosyl-glycoprotein 4-beta-N-acetylglucosaminyltransferase (MGAT3).	[21]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Beta-1,4-mannosyl-glycoprotein 4-beta-N-acetylglucosaminyltransferase (MGAT3).	[22]

References

• [1] The glycosyltransferase GnT-III activates Notch signaling and drives stem cell expansion to promote the growth and invasion of ovarian cancer.J Biol Chem. 2017 Sep 29;292(39):16351-16359. doi: 10.1074/jbc.M117.783936. Epub 2017 Aug 23.
• [2] An aberrant sugar modification of BACE1 blocks its lysosomal targeting in Alzheimer's disease.EMBO Mol Med. 2015 Feb;7(2):175-89. doi: 10.15252/emmm.201404438.
• [3] Curcumin and Novel Synthetic Analogs in Cell-Based Studies of Alzheimer's Disease.Front Pharmacol. 2018 Dec 3;9:1404. doi: 10.3389/fphar.2018.01404. eCollection 2018.
• [4] Epigenetic activation of MGAT3 and corresponding bisecting GlcNAc shortens the survival of cancer patients.Oncotarget. 2016 Aug 9;7(32):51674-51686. doi: 10.18632/oncotarget.10543.
• [5] Unusually high expression of N-acetylglucosaminyltransferase-IVa in human choriocarcinoma cell lines: a possible enzymatic basis of the formation of abnormal biantennary sugar chain.Cancer Res. 1999 Aug 15;59(16):3949-53.
• [6] Transfection of N-acetylglucosaminyltransferase III gene suppresses expression of hepatitis B virus in a human hepatoma cell line, HB611.J Biol Chem. 1995 Nov 24;270(47):28311-5. doi: 10.1074/jbc.270.47.28311.
• [7] Opposing changes in N-acetylglucosaminyltransferase-V and -III during the cell cycle and all-trans retinoic acid treatment of hepatocarcinoma cell line.Biochim Biophys Acta. 2000 Feb 28;1495(3):297-307. doi: 10.1016/s0167-4889(99)00157-3.
• [8] Promoter methylation of the MGAT3 and BACH2 genes correlates with the composition of the immunoglobulin G glycome in inflammatory bowel disease.Clin Epigenetics. 2018 Jun 4;10:75. doi: 10.1186/s13148-018-0507-y. eCollection 2018.
• [9] Bisected, complex N-glycans and galectins in mouse mammary tumor progression and human breast cancer.Glycobiology. 2013 Dec;23(12):1477-90. doi: 10.1093/glycob/cwt075. Epub 2013 Sep 13.
• [10] Hyperexpression of N-acetylglucosaminyltransferase-III in liver tissues of transgenic mice causes fatty body and obesity through severe accumulation of Apo A-I and Apo B.Arch Biochem Biophys. 2004 Jun 1;426(1):18-31. doi: 10.1016/j.abb.2003.12.039.
• [11] Reduced N-acetylglucosaminyltransferase III expression via Smad3 and Erk signaling in TGF-1-induced HCC EMT model.Discov Med. 2017 Jan;23(124):7-17.
• [12] 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.
• [13] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [14] 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.
• [15] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [16] Research resource: STR DNA profile and gene expression comparisons of human BG-1 cells and a BG-1/MCF-7 clonal variant. Mol Endocrinol. 2014 Dec;28(12):2072-81.
• [17] 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.
• [18] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [19] Gene expression profile induced by BCNU in human glioma cell lines with differential MGMT expression. J Neurooncol. 2005 Jul;73(3):189-98.
• [20] 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.
• [21] 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.
• [22] Comparative Analysis of Transcriptomic Changes including mRNA and microRNA Expression Induced by the Xenoestrogens Zearalenone and Bisphenol A in Human Ovarian Cells. Toxins (Basel). 2023 Feb 9;15(2):140. doi: 10.3390/toxins15020140.