Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT7M67WT)

• DOT Name: Polypeptide N-acetylgalactosaminyltransferase 3 (GALNT3)
• Synonyms: EC 2.4.1.41; Polypeptide GalNAc transferase 3; GalNAc-T3; pp-GaNTase 3; Protein-UDP acetylgalactosaminyltransferase 3; UDP-GalNAc:polypeptide N-acetylgalactosaminyltransferase 3
• Gene Name: GALNT3
• Related Disease:
  Autosomal recessive hypophosphatemic rickets
  Coronary atherosclerosis
  Lung adenocarcinoma
  Lung carcinoma
  Melanoma
  Tumoral calcinosis, hyperphosphatemic, familial, 1
  Adenocarcinoma
  Benign prostatic hyperplasia
  CHARGE syndrome
  Chondrocalcinosis
  Chronic kidney disease
  Chronic renal failure
  Colorectal carcinoma
  End-stage renal disease
  Endometriosis
  Epithelial ovarian cancer
  Familial tumoral calcinosis
  Hoyeraal-Hreidarsson syndrome
  Hyperostosis
  Hypotrichosis 1
  Lung neoplasm
  Matthew-Wood syndrome
  Metabolic disorder
  Neoplasm
  Obsolete tumoral calcinosis, hyperphosphatemic, familial, 1
  Pancreatic cancer
  Prostate carcinoma
  Prostate neoplasm
  Renal cell carcinoma
  Squamous cell carcinoma
  Advanced cancer
  Calcinosis
  Hypotrichosis simplex
  Ovarian neoplasm
  Type-1 diabetes
  Type-1/2 diabetes
  Carcinoma
  Coronary heart disease
  Gallbladder carcinoma
  Hyperphosphatemia
  Osteoporosis
  Prostate cancer
  Stroke
• UniProt ID: GALT3_HUMAN
• EC Number: 2.4.1.41
• Pfam ID: PF00535 ; PF00652
• Sequence:
  MAHLKRLVKLHIKRHYHKKFWKLGAVIFFFIIVLVLMQREVSVQYSKEESRMERNMKNKN
  KMLDLMLEAVNNIKDAMPKMQIGAPVRQNIDAGERPCLQGYYTAAELKPVLDRPPQDSNA
  PGASGKAFKTTNLSVEEQKEKERGEAKHCFNAFASDRISLHRDLGPDTRPPECIEQKFKR
  CPPLPTTSVIIVFHNEAWSTLLRTVHSVLYSSPAILLKEIILVDDASVDEYLHDKLDEYV
  KQFSIVKIVRQRERKGLITARLLGATVATAETLTFLDAHCECFYGWLEPLLARIAENYTA
  VVSPDIASIDLNTFEFNKPSPYGSNHNRGNFDWSLSFGWESLPDHEKQRRKDETYPIKTP
  TFAGGLFSISKEYFEYIGSYDEEMEIWGGENIEMSFRVWQCGGQLEIMPCSVVGHVFRSK
  SPHSFPKGTQVIARNQVRLAEVWMDEYKEIFYRRNTDAAKIVKQKAFGDLSKRFEIKHRL
  QCKNFTWYLNNIYPEVYVPDLNPVISGYIKSVGQPLCLDVGENNQGGKPLIMYTCHGLGG
  NQYFEYSAQHEIRHNIQKELCLHAAQGLVQLKACTYKGHKTVVTGEQIWEIQKDQLLYNP
  FLKMCLSANGEHPSLVSCNPSDPLQKWILSQND
• 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 activity toward HIV envelope glycoprotein gp120, EA2, MUC2, MUC1A and MUC5AC. Probably glycosylates fibronectin in vivo. Glycosylates FGF23.
• Tissue Specificity: Expressed in organs that contain secretory epithelial glands. Highly expressed in pancreas, skin, kidney and testis. Weakly expressed in prostate, ovary, intestine and colon. Also expressed in placenta and lung and fetal lung and fetal kidney.
• KEGG Pathway:
  Mucin type O-glycan biosynthesis (hsa00512)
  Other types of O-glycan biosynthesis (hsa00514)
  Metabolic pathways (hsa01100)
• Reactome Pathway:
  Defective GALNT3 causes HFTC (R-HSA-5083625)
  O-linked glycosylation of mucins (R-HSA-913709)
  FGFR3c ligand binding and activation (R-HSA-190372)

Molecular Interaction Atlas (MIA) of This DOT

43 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autosomal recessive hypophosphatemic rickets	DIS8E3KA	Definitive	Biomarker	[1]
Coronary atherosclerosis	DISKNDYU	Definitive	Genetic Variation	[2]
Lung adenocarcinoma	DISD51WR	Definitive	Altered Expression	[3]
Lung carcinoma	DISTR26C	Definitive	Altered Expression	[3]
Melanoma	DIS1RRCY	Definitive	Altered Expression	[4]
Tumoral calcinosis, hyperphosphatemic, familial, 1	DISL1J2S	Definitive	Autosomal recessive	[5]
Adenocarcinoma	DIS3IHTY	Strong	Altered Expression	[6]
Benign prostatic hyperplasia	DISI3CW2	Strong	Altered Expression	[7]
CHARGE syndrome	DISKD3CW	Strong	Genetic Variation	[8]
Chondrocalcinosis	DISP4AHX	Strong	Biomarker	[9]
Chronic kidney disease	DISW82R7	Strong	Biomarker	[10]
Chronic renal failure	DISGG7K6	Strong	Biomarker	[10]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[11]
End-stage renal disease	DISXA7GG	Strong	Biomarker	[10]
Endometriosis	DISX1AG8	Strong	Altered Expression	[12]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[13]
Familial tumoral calcinosis	DISYJZKG	Strong	Genetic Variation	[14]
Hoyeraal-Hreidarsson syndrome	DISAUR8F	Strong	Genetic Variation	[8]
Hyperostosis	DIS60EOE	Strong	Genetic Variation	[15]
Hypotrichosis 1	DIS0XPER	Strong	Genetic Variation	[8]
Lung neoplasm	DISVARNB	Strong	Biomarker	[16]
Matthew-Wood syndrome	DISA7HR7	Strong	Biomarker	[17]
Metabolic disorder	DIS71G5H	Strong	Genetic Variation	[18]
Neoplasm	DISZKGEW	Strong	Altered Expression	[4]
Obsolete tumoral calcinosis, hyperphosphatemic, familial, 1	DISP6X5E	Strong	Autosomal recessive	[19]
Pancreatic cancer	DISJC981	Strong	Biomarker	[20]
Prostate carcinoma	DISMJPLE	Strong	Altered Expression	[7]
Prostate neoplasm	DISHDKGQ	Strong	Biomarker	[21]
Renal cell carcinoma	DISQZ2X8	Strong	Altered Expression	[22]
Squamous cell carcinoma	DISQVIFL	Strong	Biomarker	[23]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[24]
Calcinosis	DISQP4OR	moderate	Genetic Variation	[25]
Hypotrichosis simplex	DIS8WHDJ	moderate	Genetic Variation	[26]
Ovarian neoplasm	DISEAFTY	moderate	Biomarker	[24]
Type-1 diabetes	DIS7HLUB	moderate	Genetic Variation	[27]
Type-1/2 diabetes	DISIUHAP	moderate	Genetic Variation	[27]
Carcinoma	DISH9F1N	Limited	Altered Expression	[28]
Coronary heart disease	DIS5OIP1	Limited	Genetic Variation	[2]
Gallbladder carcinoma	DISD6ACL	Limited	Altered Expression	[28]
Hyperphosphatemia	DISHW3R3	Limited	Altered Expression	[1]
Osteoporosis	DISF2JE0	Limited	Altered Expression	[29]
Prostate cancer	DISF190Y	Limited	Biomarker	[21]
Stroke	DISX6UHX	Limited	Biomarker	[30]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fluorouracil	DMUM7HZ	Approved	Polypeptide N-acetylgalactosaminyltransferase 3 (GALNT3) affects the response to substance of Fluorouracil.	[44]
Topotecan	DMP6G8T	Approved	Polypeptide N-acetylgalactosaminyltransferase 3 (GALNT3) affects the response to substance of Topotecan.	[44]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Polypeptide N-acetylgalactosaminyltransferase 3 (GALNT3).	[31]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Polypeptide N-acetylgalactosaminyltransferase 3 (GALNT3).	[34]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Polypeptide N-acetylgalactosaminyltransferase 3 (GALNT3).	[40]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Polypeptide N-acetylgalactosaminyltransferase 3 (GALNT3).	[32]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Polypeptide N-acetylgalactosaminyltransferase 3 (GALNT3).	[33]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Polypeptide N-acetylgalactosaminyltransferase 3 (GALNT3).	[35]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Polypeptide N-acetylgalactosaminyltransferase 3 (GALNT3).	[36]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Polypeptide N-acetylgalactosaminyltransferase 3 (GALNT3).	[37]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Polypeptide N-acetylgalactosaminyltransferase 3 (GALNT3).	[38]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Polypeptide N-acetylgalactosaminyltransferase 3 (GALNT3).	[38]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Polypeptide N-acetylgalactosaminyltransferase 3 (GALNT3).	[39]
Belinostat	DM6OC53	Phase 2	Belinostat increases the expression of Polypeptide N-acetylgalactosaminyltransferase 3 (GALNT3).	[38]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Polypeptide N-acetylgalactosaminyltransferase 3 (GALNT3).	[41]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Polypeptide N-acetylgalactosaminyltransferase 3 (GALNT3).	[42]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of Polypeptide N-acetylgalactosaminyltransferase 3 (GALNT3).	[43]

References

• [1] A Mutation in the Dmp1 Gene Alters Phosphate Responsiveness in Mice.Endocrinology. 2017 Mar 1;158(3):470-476. doi: 10.1210/en.2016-1642.
• [2] Variant in GALNT3 Gene Linked with Reduced Coronary Artery Disease Risk in Chinese Population.DNA Cell Biol. 2017 Jul;36(7):529-534. doi: 10.1089/dna.2017.3688. Epub 2017 Apr 28.
• [3] Low expression of polypeptide GalNAc N-acetylgalactosaminyl transferase-3 in lung adenocarcinoma: impact on poor prognosis and early recurrence.Br J Cancer. 2004 Jan 26;90(2):436-42. doi: 10.1038/sj.bjc.6601531.
• [4] Genome-wide analysis of endogenously expressed ZEB2 binding sites reveals inverse correlations between ZEB2 and GalNAc-transferase GALNT3 in human tumors.Cell Oncol (Dordr). 2018 Aug;41(4):379-393. doi: 10.1007/s13402-018-0375-7. Epub 2018 Mar 7.
• [5] 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.
• [6] Expression of uridine diphosphate N-acetyl-alpha-D-galactosamine: polypeptide N-acetylgalactosaminyl transferase 3 in adenocarcinoma of the pancreas.Pathobiology. 2004;71(1):12-8. doi: 10.1159/000072957.
• [7] Use of multiple biomarkers for a molecular diagnosis of prostate cancer.Int J Cancer. 2005 May 10;114(6):950-6. doi: 10.1002/ijc.20760.
• [8] Novel GALNT3 mutations causing hyperostosis-hyperphosphatemia syndrome result in low intact fibroblast growth factor 23 concentrations.J Clin Endocrinol Metab. 2007 May;92(5):1943-7. doi: 10.1210/jc.2006-1825. Epub 2007 Feb 20.
• [9] A mouse with an N-Ethyl-N-nitrosourea (ENU) Induced Trp589Arg Galnt3 mutation represents a model for hyperphosphataemic familial tumoural calcinosis.PLoS One. 2012;7(8):e43205. doi: 10.1371/journal.pone.0043205. Epub 2012 Aug 13.
• [10] Familial tumoral calcinosis and the role of O-glycosylation in the maintenance of phosphate homeostasis.Biochim Biophys Acta. 2009 Sep;1792(9):847-52. doi: 10.1016/j.bbadis.2008.10.008. Epub 2008 Oct 25.
• [11] Oncogenic BRAFV600E drives expression of MGL ligands in the colorectal cancer cell line HT29 through N-acetylgalactosamine-transferase 3.Biol Chem. 2018 Jun 27;399(7):649-659. doi: 10.1515/hsz-2018-0120.
• [12] Correlation of polypeptide N-acetylgalactosamine transferases-3 and -6 to different stages of endometriosis.Arch Gynecol Obstet. 2017 Jun;295(6):1413-1419. doi: 10.1007/s00404-017-4344-6. Epub 2017 Apr 5.
• [13] The polypeptide GALNT6 Displays Redundant Functions upon Suppression of its Closest Homolog GALNT3 in Mediating Aberrant O-Glycosylation, Associated with Ovarian Cancer Progression.Int J Mol Sci. 2019 May 8;20(9):2264. doi: 10.3390/ijms20092264.
• [14] Human Preosteoblastic Cell Culture from a Patient with Severe Tumoral Calcinosis-Hyperphosphatemia Due to a New GALNT3 Gene Mutation: Study of In Vitro Mineralization.Calcif Tissue Int. 2015 May;96(5):438-52. doi: 10.1007/s00223-015-9974-8. Epub 2015 Apr 23.
• [15] Long-term clinical outcome and phenotypic variability in hyperphosphatemic familial tumoral calcinosis and hyperphosphatemic hyperostosis syndrome caused by a novel GALNT3 mutation; case report and review of the literature.BMC Genet. 2014 Sep 24;15:98. doi: 10.1186/s12863-014-0098-3.
• [16] N-acetylgalactosaminyl transferase-3 is a potential new marker for non-small cell lung cancers.Br J Cancer. 2002 Sep 23;87(7):751-5. doi: 10.1038/sj.bjc.6600536.
• [17] Loss of N-acetylgalactosaminyltransferase 3 in poorly differentiated pancreatic cancer: augmented aggressiveness and aberrant ErbB family glycosylation.Br J Cancer. 2016 Jun 14;114(12):1376-86. doi: 10.1038/bjc.2016.116. Epub 2016 May 17.
• [18] Polypeptide GalNAc-transferase T3 and familial tumoral calcinosis. Secretion of fibroblast growth factor 23 requires O-glycosylation.J Biol Chem. 2006 Jul 7;281(27):18370-7. doi: 10.1074/jbc.M602469200. Epub 2006 Apr 25.
• [19] Mutations in GALNT3, encoding a protein involved in O-linked glycosylation, cause familial tumoral calcinosis. Nat Genet. 2004 Jun;36(6):579-81. doi: 10.1038/ng1358. Epub 2004 May 9.
• [20] Overexpression of GalNAc-transferase GalNAc-T3 promotes pancreatic cancer cell growth.Oncogene. 2011 Dec 8;30(49):4843-54. doi: 10.1038/onc.2011.194. Epub 2011 May 30.
• [21] Identification of genes potentially involved in the acquisition of androgen-independent and metastatic tumor growth in an autochthonous genetically engineered mouse prostate cancer model.Prostate. 2007 Jan 1;67(1):83-106. doi: 10.1002/pros.20505.
• [22] Polypeptide N-acetylgalactosaminyl transferase 3 independently predicts high-grade tumours and poor prognosis in patients with renal cell carcinomas.Br J Cancer. 2013 Jul 23;109(2):472-81. doi: 10.1038/bjc.2013.331. Epub 2013 Jun 25.
• [23] The expression pattern of UDP-N-acetyl-alpha-D-galactosamine-polypeptide N-acetyl-galactosaminyl transferase-3 in squamous cell carcinoma of the esophagus.Pathobiology. 2005;72(3):139-45. doi: 10.1159/000084117.
• [24] Role of the polypeptide N-acetylgalactosaminyltransferase 3 in ovarian cancer progression: possible implications in abnormal mucin O-glycosylation.Oncotarget. 2014 Jan 30;5(2):544-60. doi: 10.18632/oncotarget.1652.
• [25] Tumoral calcinosis due to GALNT3 C.516-2A >T mutation in a black African family.Genet Couns. 2008;19(2):183-92.
• [26] A new locus for hereditary hypotrichosis simplex maps to chromosome 13q12.12 approximately 12.3 in a Chinese family.J Cutan Pathol. 2010 Jul;37(7):758-63. doi: 10.1111/j.1600-0560.2009.01415.x. Epub 2009 Sep 14.
• [27] IDDM7 links to insulin-dependent diabetes mellitus in Danish multiplex families but linkage is not explained by novel polymorphisms in the candidate gene GALNT3. The Danish Study Group of Diabetes in Childhood and The Danish IDDM Epidemiology and Genetics Group.Hum Mutat. 2000 Mar;15(3):295-6. doi: 10.1002/(SICI)1098-1004(200003)15:3<295::AID-HUMU16>3.0.CO;2-5.
• [28] Expression of UDP-N-acetyl-alpha-D-galactosamine-polypeptide N-acetylgalactosaminyltransferase isozyme 3 in the subserosal layer correlates with postsurgical survival of pathological tumor stage 2 carcinoma of the gallbladder.Clin Cancer Res. 2004 Mar 15;10(6):2090-9. doi: 10.1158/1078-0432.ccr-1024-03.
• [29] Research on correlation between GALNT3 gene and osteoporosis.Eur Rev Med Pharmacol Sci. 2018 Jul;22(1 Suppl):69-75. doi: 10.26355/eurrev_201807_15366.
• [30] Improving Community Stroke Preparedness in the HHS (Hip-Hop Stroke) Randomized Clinical Trial.Stroke. 2018 Apr;49(4):972-979. doi: 10.1161/STROKEAHA.117.019861.
• [31] 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.
• [32] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [33] 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.
• [34] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [35] 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.
• [36] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [37] 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.
• [38] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [39] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [40] 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.
• [41] Bisphenol-A and estradiol exert novel gene regulation in human MCF-7 derived breast cancer cells. Mol Cell Endocrinol. 2004 Jun 30;221(1-2):47-55. doi: 10.1016/j.mce.2004.04.010.
• [42] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [43] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.
• [44] 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.