Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTZZ5386)

• DOT Name: Polypeptide N-acetylgalactosaminyltransferase 2 (GALNT2)
• Synonyms: EC 2.4.1.41; Polypeptide GalNAc transferase 2; GalNAc-T2; pp-GaNTase 2; Protein-UDP acetylgalactosaminyltransferase 2; UDP-GalNAc:polypeptide N-acetylgalactosaminyltransferase 2
• Gene Name: GALNT2
• Related Disease:
  Crohn disease
  Advanced cancer
  Congenital disorder of glycosylation, type iit
  Coronary heart disease
  Gastric adenocarcinoma
  Gastric cancer
  Glioma
  Hepatocellular carcinoma
  Hyperalphalipoproteinemia
  Hyperlipidemia
  Hypochondroplasia
  Malignant glioma
  Renal cell carcinoma
  Squamous cell carcinoma
  Stomach cancer
  Acute myelogenous leukaemia
  Coronary atherosclerosis
  High blood pressure
  Neoplasm
  Stroke
  Hyperglycemia
  Non-insulin dependent diabetes
  Obesity
  Schizophrenia
• UniProt ID: GALT2_HUMAN
• PDB ID: 2FFU; 2FFV; 4D0T; 4D0Z; 4D11; 5AJN; 5AJO; 5AJP; 5FV9; 5NDF; 6E7I; 6EGS; 6NQT
• EC Number: 2.4.1.41
• Pfam ID: PF00535 ; PF00652
• Sequence:
  MRRRSRMLLCFAFLWVLGIAYYMYSGGGSALAGGAGGGAGRKEDWNEIDPIKKKDLHHSN
  GEEKAQSMETLPPGKVRWPDFNQEAYVGGTMVRSGQDPYARNKFNQVESDKLRMDRAIPD
  TRHDQCQRKQWRVDLPATSVVITFHNEARSALLRTVVSVLKKSPPHLIKEIILVDDYSND
  PEDGALLGKIEKVRVLRNDRREGLMRSRVRGADAAQAKVLTFLDSHCECNEHWLEPLLER
  VAEDRTRVVSPIIDVINMDNFQYVGASADLKGGFDWNLVFKWDYMTPEQRRSRQGNPVAP
  IKTPMIAGGLFVMDKFYFEELGKYDMMMDVWGGENLEISFRVWQCGGSLEIIPCSRVGHV
  FRKQHPYTFPGGSGTVFARNTRRAAEVWMDEYKNFYYAAVPSARNVPYGNIQSRLELRKK
  LSCKPFKWYLENVYPELRVPDHQDIAFGALQQGTNCLDTLGHFADGVVGVYECHNAGGNQ
  EWALTKEKSVKHMDLCLTVVDRAPGSLIKLQGCRENDSRQKWEQIEGNSKLRHVGSNLCL
  DSRTAKSGGLSVEVCGPALSQQWKFTLNLQQ
• Function: Catalyzes the initial reaction in O-linked oligosaccharide biosynthesis, the transfer of an N-acetyl-D-galactosamine residue to a serine or threonine residue on the protein receptor. Has a broad spectrum of substrates for peptides such as EA2, Muc5AC, Muc1a, Muc1b. Probably involved in O-linked glycosylation of the immunoglobulin A1 (IgA1) hinge region. Involved in O-linked glycosylation of APOC-III, ANGPTL3 and PLTP. It participates in the regulation of HDL-C metabolism.
• Tissue Specificity: Detected in urine (at protein level) . Widely expressed.
• KEGG Pathway:
  Mucin type O-glycan biosynthesis (hsa00512)
  Other types of O-glycan biosynthesis (hsa00514)
  Metabolic pathways (hsa01100)
• Reactome Pathway:
  O-linked glycosylation of mucins (R-HSA-913709)
  COPI-independent Golgi-to-ER retrograde traffic (R-HSA-6811436)

Molecular Interaction Atlas (MIA) of This DOT

24 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Crohn disease	DIS2C5Q8	Definitive	Altered Expression	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Congenital disorder of glycosylation, type iit	DIST2DH9	Strong	Autosomal recessive	[3]
Coronary heart disease	DIS5OIP1	Strong	Genetic Variation	[4]
Gastric adenocarcinoma	DISWWLTC	Strong	Biomarker	[5]
Gastric cancer	DISXGOUK	Strong	Biomarker	[6]
Glioma	DIS5RPEH	Strong	Biomarker	[2]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[7]
Hyperalphalipoproteinemia	DISPUX00	Strong	Biomarker	[8]
Hyperlipidemia	DIS61J3S	Strong	Genetic Variation	[9]
Hypochondroplasia	DISHNE51	Strong	Genetic Variation	[9]
Malignant glioma	DISFXKOV	Strong	Biomarker	[10]
Renal cell carcinoma	DISQZ2X8	Strong	Biomarker	[11]
Squamous cell carcinoma	DISQVIFL	Strong	Biomarker	[12]
Stomach cancer	DISKIJSX	Strong	Biomarker	[6]
Acute myelogenous leukaemia	DISCSPTN	moderate	Genetic Variation	[13]
Coronary atherosclerosis	DISKNDYU	moderate	Posttranslational Modification	[14]
High blood pressure	DISY2OHH	moderate	Genetic Variation	[15]
Neoplasm	DISZKGEW	moderate	Biomarker	[2]
Stroke	DISX6UHX	moderate	Genetic Variation	[16]
Hyperglycemia	DIS0BZB5	Limited	Biomarker	[17]
Non-insulin dependent diabetes	DISK1O5Z	Limited	Altered Expression	[17]
Obesity	DIS47Y1K	Limited	Altered Expression	[17]
Schizophrenia	DISSRV2N	Limited	Genetic Variation	[18]

8 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 Polypeptide N-acetylgalactosaminyltransferase 2 (GALNT2).	[19]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Polypeptide N-acetylgalactosaminyltransferase 2 (GALNT2).	[20]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Polypeptide N-acetylgalactosaminyltransferase 2 (GALNT2).	[21]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Polypeptide N-acetylgalactosaminyltransferase 2 (GALNT2).	[22]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Polypeptide N-acetylgalactosaminyltransferase 2 (GALNT2).	[23]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Polypeptide N-acetylgalactosaminyltransferase 2 (GALNT2).	[24]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Polypeptide N-acetylgalactosaminyltransferase 2 (GALNT2).	[25]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Polypeptide N-acetylgalactosaminyltransferase 2 (GALNT2).	[27]

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 decreases the methylation of Polypeptide N-acetylgalactosaminyltransferase 2 (GALNT2).	[26]

References

• [1] TLE1 modifies the effects of NOD2 in the pathogenesis of Crohn's disease.Gastroenterology. 2011 Sep;141(3):972-981.e1-2. doi: 10.1053/j.gastro.2011.05.043. Epub 2011 May 27.
• [2] Mucin O-glycosylating enzyme GALNT2 facilitates the malignant character of glioma by activating the EGFR/PI3K/Akt/mTOR axis.Clin Sci (Lond). 2019 May 21;133(10):1167-1184. doi: 10.1042/CS20190145. Print 2019 May 31.
• [3] 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.
• [4] Identification of 64 Novel Genetic Loci Provides an Expanded View on the Genetic Architecture of Coronary Artery Disease.Circ Res. 2018 Feb 2;122(3):433-443. doi: 10.1161/CIRCRESAHA.117.312086. Epub 2017 Dec 6.
• [5] The O-glycosylating enzyme GALNT2 suppresses the malignancy of gastric adenocarcinoma by reducing EGFR activities.Am J Cancer Res. 2018 Sep 1;8(9):1739-1751. eCollection 2018.
• [6] Polypeptide N-acetylgalactosaminyltransferase 2 regulates cellular metastasis-associated behavior in gastric cancer. Int J Mol Med. 2012 Dec;30(6):1267-74.
• [7] Mucin glycosylating enzyme GALNT2 regulates the malignant character of hepatocellular carcinoma by modifying the EGF receptor.Cancer Res. 2011 Dec 1;71(23):7270-9. doi: 10.1158/0008-5472.CAN-11-1161. Epub 2011 Oct 11.
• [8] Segregation of LIPG, CETP, and GALNT2 mutations in Caucasian families with extremely high HDL cholesterol.PLoS One. 2012;7(8):e37437. doi: 10.1371/journal.pone.0037437. Epub 2012 Aug 27.
• [9] Association of the variants and haplotypes in the DOCK7, PCSK9 and GALNT2 genes and the risk of hyperlipidaemia.J Cell Mol Med. 2016 Feb;20(2):243-65. doi: 10.1111/jcmm.12713. Epub 2015 Oct 23.
• [10] regulation of the invasion and metastasis of human glioma cells by polypeptide N-acetylgalactosaminyltransferase 2.Mol Med Rep. 2011 Nov-Dec;4(6):1299-305. doi: 10.3892/mmr.2011.569. Epub 2011 Aug 22.
• [11] Roles of GalNAc-disialyl Lactotetraosyl Antigens in Renal Cancer Cells.Sci Rep. 2018 May 4;8(1):7017. doi: 10.1038/s41598-018-25521-6.
• [12] Expression of polypeptide GalNAc-transferases in stratified epithelia and squamous cell carcinomas: immunohistological evaluation using monoclonal antibodies to three members of the GalNAc-transferase family.Glycobiology. 1999 Jan;9(1):43-52. doi: 10.1093/glycob/9.1.43.
• [13] Genome-wide haplotype association study identify the FGFR2 gene as a risk gene for acute myeloid leukemia.Oncotarget. 2017 Jan 31;8(5):7891-7899. doi: 10.18632/oncotarget.13631.
• [14] A preliminary study of the relationship between promoter methylation of the ABCG1, GALNT2 and HMGCR genes and coronary heart disease. PLoS One. 2014 Aug 1;9(8):e102265.
• [15] Phenome-wide association study (PheWAS) for detection of pleiotropy within the Population Architecture using Genomics and Epidemiology (PAGE) Network.PLoS Genet. 2013;9(1):e1003087. doi: 10.1371/journal.pgen.1003087. Epub 2013 Jan 31.
• [16] Triglyceride level modifying functional variants of GALTN2 and MLXIPL in patients with ischaemic stroke.Eur J Neurol. 2010 Aug;17(8):1033-9. doi: 10.1111/j.1468-1331.2010.02957.x. Epub 2010 Feb 10.
• [17] GALNT2 expression is reduced in patients with Type 2 diabetes: possible role of hyperglycemia.PLoS One. 2013 Jul 22;8(7):e70159. doi: 10.1371/journal.pone.0070159. Print 2013.
• [18] Genome-wide association study of schizophrenia in Ashkenazi Jews.Am J Med Genet B Neuropsychiatr Genet. 2015 Dec;168(8):649-59. doi: 10.1002/ajmg.b.32349. Epub 2015 Jul 21.
• [19] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [20] 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.
• [21] 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.
• [22] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [23] 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.
• [24] 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.
• [25] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [26] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [27] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.