Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTRUIMC4)

• DOT Name: N-acetyllactosaminide beta-1,6-N-acetylglucosaminyl-transferase (GCNT2)
• Synonyms: N-acetylglucosaminyltransferase; EC 2.4.1.150; I-branching enzyme; IGNT
• Gene Name: GCNT2
• Related Disease:
  Cataract 13 with adult I phenotype
  Tuberculosis
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Cataract
  Cervical cancer
  Cervical carcinoma
  Childhood acute lymphoblastic leukemia
  Colon cancer
  Colon carcinoma
  Colorectal carcinoma
  Esophageal squamous cell carcinoma
  Hereditary hyperferritinemia with congenital cataracts
  Kidney failure
  Neoplasm
  Total early-onset cataract
  Melanoma
  Gallbladder cancer
  Gallbladder carcinoma
• UniProt ID: GNT2A_HUMAN
• EC Number: 2.4.1.150
• Pfam ID: PF02485
• Sequence:
  MMGSWKHCLFSASLISALIFVFVYNTELWENKRFLRAALSNASLLAEACHQIFEGKVFYP
  TENALKTTLDEATCYEYMVRSHYVTETLSEEEAGFPLAYTVTIHKDFGTFERLFRAIYMP
  QNVYCVHLDQKATDAFKGAVKQLLSCFPNAFLASKKESVVYGGISRLQADLNCLEDLVAS
  EVPWKYVINTCGQDFPLKTNREIVQYLKGFKGKNITPGVLPPDHAVGRTKYVHQELLNHK
  NSYVIKTTKLKTPPPHDMVIYFGTAYVALTRDFANFVLQDQLALDLLSWSKDTYSPDEHF
  WVTLNRIPGVPGSMPNASWTGNLRAIKWSDMEDRHGGCHGHYVHGICIYGNGDLKWLVNS
  PSLFANKFELNTYPLTVECLELRHRERTLNQSETAIQPSWYF
• Function: Branching enzyme that converts linear into branched poly-N-acetyllactosaminoglycans. Introduces the blood group I antigen during embryonic development. It is closely associated with the development and maturation of erythroid cells; [Isoform C]: Determines the expression of the blood group I antigen in erythrocytes.
• Tissue Specificity: .Expressed in lens epithelium cells.; [Isoform C]: Expressed in reticulocytes.
• KEGG Pathway:
  Glycosphingolipid biosynthesis - lacto and neolacto series (hsa00601)
  Metabolic pathways (hsa01100)
• BioCyc Pathway: MetaCyc:HS03475-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

21 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cataract 13 with adult I phenotype	DISR86FN	Definitive	Autosomal recessive	[1]
Tuberculosis	DIS2YIMD	Definitive	Biomarker	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Breast cancer	DIS7DPX1	Strong	Biomarker	[4]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[4]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[4]
Cataract	DISUD7SL	Strong	Genetic Variation	[5]
Cervical cancer	DISFSHPF	Strong	Altered Expression	[6]
Cervical carcinoma	DIST4S00	Strong	Altered Expression	[6]
Childhood acute lymphoblastic leukemia	DISJ5D6U	Strong	Altered Expression	[7]
Colon cancer	DISVC52G	Strong	Biomarker	[8]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[8]
Colorectal carcinoma	DIS5PYL0	Strong	Genetic Variation	[9]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Biomarker	[10]
Hereditary hyperferritinemia with congenital cataracts	DISGL689	Strong	Genetic Variation	[11]
Kidney failure	DISOVQ9P	Strong	Biomarker	[12]
Neoplasm	DISZKGEW	Strong	Altered Expression	[6]
Total early-onset cataract	DISACMEZ	Supportive	Autosomal dominant	[5]
Melanoma	DIS1RRCY	Disputed	Altered Expression	[13]
Gallbladder cancer	DISXJUAF	Limited	Genetic Variation	[14]
Gallbladder carcinoma	DISD6ACL	Limited	Genetic Variation	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	N-acetyllactosaminide beta-1,6-N-acetylglucosaminyl-transferase (GCNT2) affects the response to substance of Cisplatin.	[29]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of N-acetyllactosaminide beta-1,6-N-acetylglucosaminyl-transferase (GCNT2).	[15]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of N-acetyllactosaminide beta-1,6-N-acetylglucosaminyl-transferase (GCNT2).	[16]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of N-acetyllactosaminide beta-1,6-N-acetylglucosaminyl-transferase (GCNT2).	[17]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of N-acetyllactosaminide beta-1,6-N-acetylglucosaminyl-transferase (GCNT2).	[18]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of N-acetyllactosaminide beta-1,6-N-acetylglucosaminyl-transferase (GCNT2).	[19]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of N-acetyllactosaminide beta-1,6-N-acetylglucosaminyl-transferase (GCNT2).	[20]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of N-acetyllactosaminide beta-1,6-N-acetylglucosaminyl-transferase (GCNT2).	[21]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of N-acetyllactosaminide beta-1,6-N-acetylglucosaminyl-transferase (GCNT2).	[22]
Bortezomib	DMNO38U	Approved	Bortezomib increases the expression of N-acetyllactosaminide beta-1,6-N-acetylglucosaminyl-transferase (GCNT2).	[23]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of N-acetyllactosaminide beta-1,6-N-acetylglucosaminyl-transferase (GCNT2).	[24]
Azacitidine	DMTA5OE	Approved	Azacitidine decreases the expression of N-acetyllactosaminide beta-1,6-N-acetylglucosaminyl-transferase (GCNT2).	[25]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of N-acetyllactosaminide beta-1,6-N-acetylglucosaminyl-transferase (GCNT2).	[26]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of N-acetyllactosaminide beta-1,6-N-acetylglucosaminyl-transferase (GCNT2).	[27]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of N-acetyllactosaminide beta-1,6-N-acetylglucosaminyl-transferase (GCNT2).	[28]

References

• [1] Molecular basis of the adult i phenotype and the gene responsible for the expression of the human blood group I antigen. Blood. 2001 Dec 15;98(13):3840-5. doi: 10.1182/blood.v98.13.3840.
• [2] Liver X receptor gene polymorphisms in tuberculosis: effect on susceptibility.PLoS One. 2014 May 1;9(5):e95954. doi: 10.1371/journal.pone.0095954. eCollection 2014.
• [3] I-branched carbohydrates as emerging effectors of malignant progression.Proc Natl Acad Sci U S A. 2019 Jul 9;116(28):13729-13737. doi: 10.1073/pnas.1900268116. Epub 2019 Jun 18.
• [4] Engagement of I-branching {beta}-1, 6-N-acetylglucosaminyltransferase 2 in breast cancer metastasis and TGF-{beta} signaling.Cancer Res. 2011 Jul 15;71(14):4846-56. doi: 10.1158/0008-5472.CAN-11-0414. Epub 2011 Jul 12.
• [5] An Alu repeat-mediated genomic GCNT2 deletion underlies congenital cataracts and adult i blood group. Hum Genet. 2012 Feb;131(2):209-16. doi: 10.1007/s00439-011-1062-1. Epub 2011 Jul 15.
• [6] CCAT-1 promotes proliferation and inhibits apoptosis of cervical cancer cells via the Wnt signaling pathway.Oncotarget. 2017 Jul 10;8(40):68059-68070. doi: 10.18632/oncotarget.19155. eCollection 2017 Sep 15.
• [7] The role of interleukin-15 polymorphisms in adult acute lymphoblastic leukemia.PLoS One. 2010 Oct 25;5(10):e13626. doi: 10.1371/journal.pone.0013626.
• [8] Downregulation of miR-199a/b-5p is associated with GCNT2 induction upon epithelial-mesenchymal transition in colon cancer.FEBS Lett. 2017 Jul;591(13):1902-1917. doi: 10.1002/1873-3468.12685. Epub 2017 Jun 10.
• [9] Aberrant methylation of GCNT2 is tightly related to lymph node metastasis of primary CRC.Anticancer Res. 2015 Mar;35(3):1411-21.
• [10] GCNT2 induces epithelial-mesenchymal transition and promotes migration and invasion in esophageal squamous cell carcinoma cells.Cell Biochem Funct. 2019 Jan;37(1):42-51. doi: 10.1002/cbf.3371. Epub 2018 Dec 21.
• [11] Hematologic biomarkers in childhood cataracts.Mol Vis. 2011 Apr 24;17:1011-5.
• [12] Low contrast material dose coronary computed tomographic angiography using a dual-layer spectral detector system in patients at risk for contrast-induced nephropathy.Br J Radiol. 2019 Feb;92(1094):20180215. doi: 10.1259/bjr.20180215. Epub 2018 Nov 14.
• [13] Loss of GCNT2/I-branched glycans enhances melanoma growth and survival.Nat Commun. 2018 Aug 22;9(1):3368. doi: 10.1038/s41467-018-05795-0.
• [14] Association of genetic variants of cancer stem cell gene CD44 haplotypes with gallbladder cancer susceptibility in North Indian population.Tumour Biol. 2014 Mar;35(3):2583-9. doi: 10.1007/s13277-013-1340-8. Epub 2013 Nov 5.
• [15] 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.
• [16] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [17] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [18] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [19] 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.
• [20] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [21] 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.
• [22] 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.
• [23] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [24] Cytosine arabinoside induces ectoderm and inhibits mesoderm expression in human embryonic stem cells during multilineage differentiation. Br J Pharmacol. 2011 Apr;162(8):1743-56.
• [25] The effect of DNA methylation inhibitor 5-Aza-2'-deoxycytidine on human endometrial stromal cells. Hum Reprod. 2010 Nov;25(11):2859-69.
• [26] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [27] 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.
• [28] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [29] 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.