Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT8WM21E)

• DOT Name: CMP-N-acetylneuraminate-beta-galactosamide-alpha-2,3-sialyltransferase 2 (ST3GAL2)
• Synonyms: Alpha 2,3-ST 2; Beta-galactoside alpha-2,3-sialyltransferase 2; EC 2.4.3.4; Gal-NAc6S; Gal-beta-1,3-GalNAc-alpha-2,3-sialyltransferase; Monosialoganglioside sialyltransferase; EC 2.4.3.2; ST3Gal II; ST3GalII; ST3GalA.2; Sialyltransferase 4B; SIAT4-B
• Gene Name: ST3GAL2
• Related Disease:
  Clear cell renal carcinoma
  Late-onset Parkinson disease
  Mucopolysaccharidosis type 4A
  Obesity
  Parkinson disease
  Renal cell carcinoma
  Castration-resistant prostate carcinoma
  Oral cancer
  Oral cavity carcinoma
• UniProt ID: SIA4B_HUMAN
• EC Number: 2.4.3.2; 2.4.3.4
• Pfam ID: PF00777
• Sequence:
  MKCSLRVWFLSVAFLLVFIMSLLFTYSHHSMATLPYLDSGALDGTHRVKLVPGYAGLQRL
  SKERLSGKSCACRRCMGDAGASDWFDSHFDGNISPVWTRENMDLPPDVQRWWMMLQPQFK
  SHNTNEVLEKLFQIVPGENPYRFRDPHQCRRCAVVGNSGNLRGSGYGQDVDGHNFIMRMN
  QAPTVGFEQDVGSRTTHHFMYPESAKNLPANVSFVLVPFKVLDLLWIASALSTGQIRFTY
  APVKSFLRVDKEKVQIYNPAFFKYIHDRWTEHHGRYPSTGMLVLFFALHVCDEVNVYGFG
  ADSRGNWHHYWENNRYAGEFRKTGVHDADFEAHIIDMLAKASKIEVYRGN
• Function: A beta-galactoside alpha2-3 sialyltransferase primarily involved in terminal sialylation of ganglio and globo series glycolipids. Catalyzes the transfer of sialic acid (N-acetyl-neuraminic acid; Neu5Ac) from the nucleotide sugar donor CMP-Neu5Ac onto acceptor Galbeta-(1->3)-GalNAc-terminated glycoconjugates through an alpha2-3 linkage. Sialylates GM1/GM1a, GA1/asialo-GM1 and GD1b gangliosides to form GD1a, GM1b and GT1b, respectively. Together with ST3GAL3, primarily responsible for biosynthesis of brain GD1a and GT1b that function as ligands for myelin-associated glycoprotein MAG on axons, regulating MAG expression and axonal myelin stability and regeneration. Via GT1b regulates TLR2 signaling in spinal cord microglia in response to nerve injury. Responsible for the sialylation of the pluripotent stem cell- and cancer stem cell-associated antigen SSEA3, forming SSEA4. Sialylates with low efficiency asialofetuin, presumably onto O-glycosidically linked Galbeta-(1->3)-GalNAc-O-Ser.
• Tissue Specificity: Highly expressed in skeletal muscle and heart and to a much lesser extent in brain, placenta, liver and pancreas. Scarcely detectable in lung and kidney.
• KEGG Pathway:
  Mucin type O-glycan biosynthesis (hsa00512)
  Glycosaminoglycan biosynthesis - keratan sulfate (hsa00533)
  Glycosphingolipid biosynthesis - globo and isoglobo series (hsa00603)
  Glycosphingolipid biosynthesis - ganglio series (hsa00604)
  Metabolic pathways (hsa01100)
• Reactome Pathway:
  Sialic acid metabolism (R-HSA-4085001)
  Maturation of protein 3a (R-HSA-9683673)
  Maturation of spike protein (R-HSA-9694548)
  Maturation of protein 3a (R-HSA-9694719)
  Termination of O-glycan biosynthesis (R-HSA-977068)
  Keratan sulfate biosynthesis (R-HSA-2022854)
• BioCyc Pathway: MetaCyc:HS08206-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Clear cell renal carcinoma	DISBXRFJ	Strong	Altered Expression	[1]
Late-onset Parkinson disease	DIS9IOUI	Strong	Altered Expression	[2]
Mucopolysaccharidosis type 4A	DISTYFQS	Strong	Biomarker	[3]
Obesity	DIS47Y1K	Strong	Biomarker	[4]
Parkinson disease	DISQVHKL	Strong	Altered Expression	[2]
Renal cell carcinoma	DISQZ2X8	Strong	Altered Expression	[1]
Castration-resistant prostate carcinoma	DISVGAE6	moderate	Altered Expression	[5]
Oral cancer	DISLD42D	moderate	Altered Expression	[6]
Oral cavity carcinoma	DISZXMVL	moderate	Altered Expression	[6]

9 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 CMP-N-acetylneuraminate-beta-galactosamide-alpha-2,3-sialyltransferase 2 (ST3GAL2).	[7]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of CMP-N-acetylneuraminate-beta-galactosamide-alpha-2,3-sialyltransferase 2 (ST3GAL2).	[8]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of CMP-N-acetylneuraminate-beta-galactosamide-alpha-2,3-sialyltransferase 2 (ST3GAL2).	[9]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of CMP-N-acetylneuraminate-beta-galactosamide-alpha-2,3-sialyltransferase 2 (ST3GAL2).	[10]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of CMP-N-acetylneuraminate-beta-galactosamide-alpha-2,3-sialyltransferase 2 (ST3GAL2).	[11]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of CMP-N-acetylneuraminate-beta-galactosamide-alpha-2,3-sialyltransferase 2 (ST3GAL2).	[13]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of CMP-N-acetylneuraminate-beta-galactosamide-alpha-2,3-sialyltransferase 2 (ST3GAL2).	[14]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of CMP-N-acetylneuraminate-beta-galactosamide-alpha-2,3-sialyltransferase 2 (ST3GAL2).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of CMP-N-acetylneuraminate-beta-galactosamide-alpha-2,3-sialyltransferase 2 (ST3GAL2).	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of CMP-N-acetylneuraminate-beta-galactosamide-alpha-2,3-sialyltransferase 2 (ST3GAL2).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of CMP-N-acetylneuraminate-beta-galactosamide-alpha-2,3-sialyltransferase 2 (ST3GAL2).	[15]

References

• [1] Human alpha2,3-sialyltransferase (ST3Gal II) is a stage-specific embryonic antigen-4 synthase.J Biol Chem. 2003 Jul 18;278(29):26474-9. doi: 10.1074/jbc.M213223200. Epub 2003 Apr 25.
• [2] siRNA-mediated knockdown of B3GALT4 decreases GM1 ganglioside expression and enhances vulnerability for neurodegeneration.Mol Cell Neurosci. 2019 Mar;95:25-30. doi: 10.1016/j.mcn.2019.01.001. Epub 2019 Jan 3.
• [3] Mucopolysaccharidosis type IVA. N-acetylgalactosamine-6-sulfate sulfatase exonic point mutations in classical Morquio and mild cases.J Clin Invest. 1992 Sep;90(3):1049-53. doi: 10.1172/JCI115919.
• [4] Mice lacking sialyltransferase ST3Gal-II develop late-onset obesity and insulin resistance.Glycobiology. 2017 Jan;27(2):129-139. doi: 10.1093/glycob/cww098. Epub 2016 Sep 28.
• [5] Expression of gangliosides, GD1a, and sialyl paragloboside is regulated by NF-B-dependent transcriptional control of 2,3-sialyltransferase I, II, and VI in human castration-resistant prostate cancer cells.Int J Cancer. 2011 Oct 15;129(8):1838-47. doi: 10.1002/ijc.25860. Epub 2011 Apr 13.
• [6] "Aberrant sialylation plays a significant role in oral squamous cell carcinoma progression".J Oral Pathol Med. 2020 Mar;49(3):253-259. doi: 10.1111/jop.12976. Epub 2020 Jan 7.
• [7] 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.
• [8] 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.
• [9] 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.
• [10] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [11] Comparative effects of raloxifene, tamoxifen and estradiol on human osteoblasts in vitro: estrogen receptor dependent or independent pathways of raloxifene. J Steroid Biochem Mol Biol. 2009 Feb;113(3-5):281-9.
• [12] 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.
• [13] 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.
• [14] Cannabidiol enhances cytotoxicity of anti-cancer drugs in human head and neck squamous cell carcinoma. Sci Rep. 2020 Nov 26;10(1):20622. doi: 10.1038/s41598-020-77674-y.
• [15] 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.
• [16] 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.
• [17] Characterization of the Molecular Alterations Induced by the Prolonged Exposure of Normal Colon Mucosa and Colon Cancer Cells to Low-Dose Bisphenol A. Int J Mol Sci. 2022 Oct 1;23(19):11620. doi: 10.3390/ijms231911620.