Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTJCJQI7)

• DOT Name: Alpha-N-acetyl-neuraminyl-2,3-beta-galactosyl-1,3-N-acetyl-galactosaminide alpha-2,6-sialyltransferase (ST6GALNAC4)
• Synonyms: EC 2.4.3.7; NeuAc-alpha-2,3-Gal-beta-1,3-GalNAc-alpha-2,6-sialyltransferase; ST6GalNAc IV; ST6GalNAcIV; Sialyltransferase 3C; SIAT3-C; Sialyltransferase 7D; SIAT7-D
• Gene Name: ST6GALNAC4
• Related Disease:
  Neoplasm
  Thyroid gland follicular carcinoma
• UniProt ID: SIA7D_HUMAN
• EC Number: 2.4.3.7
• Pfam ID: PF00777
• Sequence:
  MKAPGRLVLIILCSVVFSAVYILLCCWAGLPLCLATCLDHHFPTGSRPTVPGPLHFSGYS
  SVPDGKPLVREPCRSCAVVSSSGQMLGSGLGAEIDSAECVFRMNQAPTVGFEADVGQRST
  LRVVSHTSVPLLLRNYSHYFQKARDTLYMVWGQGRHMDRVLGGRTYRTLLQLTRMYPGLQ
  VYTFTERMMAYCDQIFQDETGKNRRQSGSFLSTGWFTMILALELCEEIVVYGMVSDSYCR
  EKSHPSVPYHYFEKGRLDECQMYLAHEQAPRSAHRFITEKAVFSRWAKKRPIVFAHPSWR
  TE
• Function: Transfers the sialyl group (N-acetyl-alpha-neuraminyl or NeuAc) from CMP-NeuAc to the GalNAc residue on the NeuAc-alpha-2,3-Gal-beta-1,3-GalNAc sequence of glycoproteins and glycolipids forming an alpha-2,6-linkage. Produces branched type disialyl structures by transfer of a sialyl group onto a GalNAc residue inside the backbone core chains. Prefers O-glycans to glycoproteins or glycolipids.
• Tissue Specificity: Ubiquitous.
• KEGG Pathway:
  Mucin type O-glycan biosynthesis (hsa00512)
  Glycosphingolipid biosynthesis - ganglio series (hsa00604)
  Metabolic pathways (hsa01100)
• Reactome Pathway:
  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)
  Sialic acid metabolism (R-HSA-4085001)
• BioCyc Pathway: MetaCyc:HS06223-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neoplasm	DISZKGEW	Strong	Altered Expression	[1]
Thyroid gland follicular carcinoma	DISFK2QT	moderate	Biomarker	[2]

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 Alpha-N-acetyl-neuraminyl-2,3-beta-galactosyl-1,3-N-acetyl-galactosaminide alpha-2,6-sialyltransferase (ST6GALNAC4).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Alpha-N-acetyl-neuraminyl-2,3-beta-galactosyl-1,3-N-acetyl-galactosaminide alpha-2,6-sialyltransferase (ST6GALNAC4).	[4]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Alpha-N-acetyl-neuraminyl-2,3-beta-galactosyl-1,3-N-acetyl-galactosaminide alpha-2,6-sialyltransferase (ST6GALNAC4).	[5]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Alpha-N-acetyl-neuraminyl-2,3-beta-galactosyl-1,3-N-acetyl-galactosaminide alpha-2,6-sialyltransferase (ST6GALNAC4).	[6]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Alpha-N-acetyl-neuraminyl-2,3-beta-galactosyl-1,3-N-acetyl-galactosaminide alpha-2,6-sialyltransferase (ST6GALNAC4).	[8]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Alpha-N-acetyl-neuraminyl-2,3-beta-galactosyl-1,3-N-acetyl-galactosaminide alpha-2,6-sialyltransferase (ST6GALNAC4).	[10]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Alpha-N-acetyl-neuraminyl-2,3-beta-galactosyl-1,3-N-acetyl-galactosaminide alpha-2,6-sialyltransferase (ST6GALNAC4).	[11]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride decreases the expression of Alpha-N-acetyl-neuraminyl-2,3-beta-galactosyl-1,3-N-acetyl-galactosaminide alpha-2,6-sialyltransferase (ST6GALNAC4).	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Alpha-N-acetyl-neuraminyl-2,3-beta-galactosyl-1,3-N-acetyl-galactosaminide alpha-2,6-sialyltransferase (ST6GALNAC4).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Alpha-N-acetyl-neuraminyl-2,3-beta-galactosyl-1,3-N-acetyl-galactosaminide alpha-2,6-sialyltransferase (ST6GALNAC4).	[9]

References

• [1] Prognostic significance of ST6GalNAc-1 expression in patients with non-metastatic clear cell renal cell carcinoma.Oncotarget. 2016 Aug 12;9(3):3112-3120. doi: 10.18632/oncotarget.11258. eCollection 2018 Jan 9.
• [2] miR-4299 mediates the invasive properties and tumorigenicity of human follicular thyroid carcinoma by targeting ST6GALNAC4.IUBMB Life. 2016 Feb;68(2):136-44. doi: 10.1002/iub.1467. Epub 2015 Dec 30.
• [3] 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.
• [4] 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.
• [5] Classification of heavy-metal toxicity by human DNA microarray analysis. Environ Sci Technol. 2007 May 15;41(10):3769-74.
• [6] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [7] 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.
• [8] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [9] 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.
• [10] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.
• [11] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.