Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTCY80HS)

• DOT Name: Beta-1,4 N-acetylgalactosaminyltransferase 1 (B4GALNT1)
• Synonyms: EC 2.4.1.92; (N-acetylneuraminyl)-galactosylglucosylceramide; GM2/GD2 synthase; GalNAc-T
• Gene Name: B4GALNT1
• Related Disease:
  Complex hereditary spastic paraplegia
  Parkinson disease
  Advanced cancer
  Breast neoplasm
  Epithelial ovarian cancer
  Hepatocellular carcinoma
  Hereditary spastic paraplegia
  Hereditary spastic paraplegia 26
  Hypogonadism, male
  Intellectual disability
  Intestinal neoplasm
  Malignant neoplasm
  Metastatic malignant neoplasm
  Nervous system disease
  Vascular purpura
  Neoplasm
  Small lymphocytic lymphoma
  Clear cell renal carcinoma
  Coronary heart disease
  Melanoma
  Neuroblastoma
• UniProt ID: B4GN1_HUMAN
• EC Number: 2.4.1.92
• Pfam ID: PF00535
• Sequence:
  MWLGRRALCALVLLLACASLGLLYASTRDAPGLRLPLAPWAPPQSPRRPELPDLAPEPRY
  AHIPVRIKEQVVGLLAWNNCSCESSGGGLPLPFQKQVRAIDLTKAFDPAELRAASATREQ
  EFQAFLSRSQSPADQLLIAPANSPLQYPLQGVEVQPLRSILVPGLSLQAASGQEVYQVNL
  TASLGTWDVAGEVTGVTLTGEGQADLTLVSPGLDQLNRQLQLVTYSSRSYQTNTADTVRF
  STEGHEAAFTIRIRHPPNPRLYPPGSLPQGAQYNISALVTIATKTFLRYDRLRALITSIR
  RFYPTVTVVIADDSDKPERVSGPYVEHYLMPFGKGWFAGRNLAVSQVTTKYVLWVDDDFV
  FTARTRLERLVDVLERTPLDLVGGAVREISGFATTYRQLLSVEPGAPGLGNCLRQRRGFH
  HELVGFPGCVVTDGVVNFFLARTDKVREVGFDPRLSRVAHLEFFLDGLGSLRVGSCSDVV
  VDHASKLKLPWTSRDAGAETYARYRYPGSLDESQMAKHRLLFFKHRLQCMTSQ
• Function: Involved in the biosynthesis of gangliosides GM2, GD2, GT2 and GA2 from GM3, GD3, GT3 and GA3, respectively.
• KEGG Pathway:
  Sphingolipid metabolism (hsa00600)
  Glycosphingolipid biosynthesis - ganglio series (hsa00604)
  Metabolic pathways (hsa01100)
• Reactome Pathway: Glycosphingolipid biosynthesis (R-HSA-9840309)
• BioCyc Pathway: MetaCyc:HS06011-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
Complex hereditary spastic paraplegia	DIS9KXQY	Definitive	Autosomal recessive	[1]
Parkinson disease	DISQVHKL	Definitive	Genetic Variation	[2]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[3]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[4]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[5]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[3]
Hereditary spastic paraplegia	DISGZQV1	Strong	Genetic Variation	[6]
Hereditary spastic paraplegia 26	DIS38XRT	Strong	Autosomal recessive	[7]
Hypogonadism, male	DISV1F5R	Strong	Biomarker	[6]
Intellectual disability	DISMBNXP	Strong	Genetic Variation	[8]
Intestinal neoplasm	DISK0GUH	Strong	Altered Expression	[4]
Malignant neoplasm	DISS6SNG	Strong	Altered Expression	[9]
Metastatic malignant neoplasm	DIS86UK6	Strong	Altered Expression	[3]
Nervous system disease	DISJ7GGT	Strong	Genetic Variation	[6]
Vascular purpura	DIS6ZZMF	Strong	Genetic Variation	[10]
Neoplasm	DISZKGEW	moderate	Altered Expression	[11]
Small lymphocytic lymphoma	DIS30POX	moderate	Biomarker	[12]
Clear cell renal carcinoma	DISBXRFJ	Limited	Biomarker	[13]
Coronary heart disease	DIS5OIP1	Limited	Biomarker	[14]
Melanoma	DIS1RRCY	Limited	Altered Expression	[15]
Neuroblastoma	DISVZBI4	Limited	Biomarker	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Beta-1,4 N-acetylgalactosaminyltransferase 1 (B4GALNT1).	[17]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Beta-1,4 N-acetylgalactosaminyltransferase 1 (B4GALNT1).	[18]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Beta-1,4 N-acetylgalactosaminyltransferase 1 (B4GALNT1).	[18]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Beta-1,4 N-acetylgalactosaminyltransferase 1 (B4GALNT1).	[19]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Beta-1,4 N-acetylgalactosaminyltransferase 1 (B4GALNT1).	[20]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Beta-1,4 N-acetylgalactosaminyltransferase 1 (B4GALNT1).	[21]
Troglitazone	DM3VFPD	Approved	Troglitazone increases the expression of Beta-1,4 N-acetylgalactosaminyltransferase 1 (B4GALNT1).	[22]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of Beta-1,4 N-acetylgalactosaminyltransferase 1 (B4GALNT1).	[24]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Beta-1,4 N-acetylgalactosaminyltransferase 1 (B4GALNT1).	[23]

References

• [1] 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.
• [2] Gangliosides, -Synuclein, and Parkinson's Disease.Prog Mol Biol Transl Sci. 2018;156:435-454. doi: 10.1016/bs.pmbts.2017.12.009. Epub 2018 Feb 24.
• [3] Overexpression of beta 1,4N-acetylgalactosaminyl- transferase mRNA as a molecular marker for various types of cancers.Oncology. 2002;62(2):149-56. doi: 10.1159/000048261.
• [4] Evaluation of SAT-1, SAT-2 and GalNAcT-1 mRNA in colon cancer by real-time PCR.Mol Cell Biochem. 2007 Apr;298(1-2):59-68. doi: 10.1007/s11010-006-9350-0. Epub 2006 Nov 21.
• [5] Altered expression of different GalNActransferases is associated with disease progression and poor prognosis in women with high-grade serous ovarian cancer.Int J Oncol. 2017 Dec;51(6):1887-1897. doi: 10.3892/ijo.2017.4147. Epub 2017 Oct 9.
• [6] Loss of Enzyme Activity in Mutated B4GALNT1 Gene Products in Patients with Hereditary Spastic Paraplegia Results in Relatively Mild Neurological Disorders: Similarity with Phenotypes of B4galnt1 Knockout Mice.Neuroscience. 2019 Jan 15;397:94-106. doi: 10.1016/j.neuroscience.2018.11.034. Epub 2018 Dec 4.
• [7] Alteration of ganglioside biosynthesis responsible for complex hereditary spastic paraplegia. Am J Hum Genet. 2013 Jul 11;93(1):118-23. doi: 10.1016/j.ajhg.2013.05.006. Epub 2013 Jun 6.
• [8] Congenital Disorders of Ganglioside Biosynthesis.Prog Mol Biol Transl Sci. 2018;156:63-82. doi: 10.1016/bs.pmbts.2018.01.001. Epub 2018 Mar 22.
• [9] GALNT9 gene expression is a prognostic marker in neuroblastoma patients.Clin Chem. 2013 Jan;59(1):225-33. doi: 10.1373/clinchem.2012.192328. Epub 2012 Nov 7.
• [10] Diseases of ganglioside biosynthesis: An expanding group of congenital disorders of glycosylation.Mol Genet Metab. 2018 Aug;124(4):230-237. doi: 10.1016/j.ymgme.2018.06.014. Epub 2018 Jun 28.
• [11] CD70 as a target for chimeric antigen receptor T cells in head and neck squamous cell carcinoma.Oral Oncol. 2018 Mar;78:145-150. doi: 10.1016/j.oraloncology.2018.01.024. Epub 2018 Feb 20.
• [12] GALNT11 as a new molecular marker in chronic lymphocytic leukemia.Gene. 2014 Jan 1;533(1):270-9. doi: 10.1016/j.gene.2013.09.052. Epub 2013 Sep 27.
• [13] Exploring the mechanism of clear cell renal cell carcinoma metastasis and key genes based on multi-tool joint analysis.Gene. 2019 Dec 15;720:144103. doi: 10.1016/j.gene.2019.144103. Epub 2019 Sep 3.
• [14] Down regulation of GALNT3 contributes to endothelial cell injury via activation of p38 MAPK signaling pathway.Atherosclerosis. 2016 Feb;245:94-100. doi: 10.1016/j.atherosclerosis.2015.12.019. Epub 2015 Dec 17.
• [15] UVB-irradiated keratinocytes induce melanoma-associated ganglioside GD3 synthase gene in melanocytes via secretion of tumor necrosis factor and interleukin 6.Biochem Biophys Res Commun. 2014 Mar 7;445(2):504-10. doi: 10.1016/j.bbrc.2014.02.038. Epub 2014 Feb 15.
• [16] Prospective investigation of applicability and the prognostic significance of bone marrow involvement in patients with neuroblastoma detected by quantitative reverse transcription PCR.Pediatr Blood Cancer. 2018 Nov;65(11):e27354. doi: 10.1002/pbc.27354. Epub 2018 Jul 14.
• [17] Effects of lithium and valproic acid on gene expression and phenotypic markers in an NT2 neurosphere model of neural development. PLoS One. 2013;8(3):e58822.
• [18] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [19] 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.
• [20] 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.
• [21] Chronic occupational exposure to arsenic induces carcinogenic gene signaling networks and neoplastic transformation in human lung epithelial cells. Toxicol Appl Pharmacol. 2012 Jun 1;261(2):204-16.
• [22] Transcriptomic analysis of untreated and drug-treated differentiated HepaRG cells over a 2-week period. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):27-35.
• [23] 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.
• [24] Sulforaphane-induced apoptosis in human leukemia HL-60 cells through extrinsic and intrinsic signal pathways and altering associated genes expression assayed by cDNA microarray. Environ Toxicol. 2017 Jan;32(1):311-328.