Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTG9MXV9)

• DOT Name: Alpha-N-acetylneuraminate alpha-2,8-sialyltransferase ST8SIA3 (ST8SIA3)
• Synonyms: EC 2.4.3.-; Alpha-2,8-sialyltransferase 8C; Alpha-2,8-sialyltransferase III; Ganglioside GD3 synthase ST8SIA3; EC 2.4.3.8; ST8 alpha-N-acetyl-neuraminide alpha-2,8-sialyltransferase 3; Sia-a2,3-Gal-b1,4-Glc-NAc-R:a2,8-sialyltransferase; hST8Sia III; Sialyltransferase 8C; SIAT8-C; Sialyltransferase St8Sia III; ST8SiaIII
• Gene Name: ST8SIA3
• Related Disease:
  Neoplasm
  Acute myelogenous leukaemia
  Advanced cancer
• UniProt ID: SIA8C_HUMAN
• PDB ID: 5BO6; 5BO7; 5BO8; 5BO9; 5CXY
• EC Number: 2.4.3.-; 2.4.3.8
• Pfam ID: PF00777
• Sequence:
  MRNCKMARVASVLGLVMLSVALLILSLISYVSLKKENIFTTPKYASPGAPRMYMFHAGFR
  SQFALKFLDPSFVPITNSLTQELQEKPSKWKFNRTAFLHQRQEILQHVDVIKNFSLTKNS
  VRIGQLMHYDYSSHKYVFSISNNFRSLLPDVSPIMNKHYNICAVVGNSGILTGSQCGQEI
  DKSDFVFRCNFAPTEAFQRDVGRKTNLTTFNPSILEKYYNNLLTIQDRNNFFLSLKKLDG
  AILWIPAFFFHTSATVTRTLVDFFVEHRGQLKVQLAWPGNIMQHVNRYWKNKHLSPKRLS
  TGILMYTLASAICEEIHLYGFWPFGFDPNTREDLPYHYYDKKGTKFTTKWQESHQLPAEF
  QLLYRMHGEGLTKLTLSHCA
• Function: Catalyzes the transfer of sialic acid from a CMP-linked sialic acid donor onto a terminal alpha-2,3-, alpha-2,6-, or alpha-2,8-linked sialic acid of an acceptor, such as N-linked oligosaccharides of glycoproteins and glycolipids through alpha-2,8-linkages. Forms oligosialic and polysialic acid on various sialylated N-acetyllactosamine oligosaccharides of glycoproteins, including FETUB N-glycans, a2-HS-glycoprotein (AHSG) and alpha 2,3-sialylated glycosphingolipids, such as alpha 2,3-sialylparagloboside and ganglioside GM3 and to a lesser extent NCAM1 N-glycans. However, it is much more specific to N-linked oligosaccharides of glycoproteins than glycosphingolipids. 2,3-sialylparagloboside serves as the best acceptor substrate among the glycolipids. alpha-Neu5Ac-(2->8)-alpha-Neu5Ac-(2->3)-beta-D-Gal-(1->4)-6S-D-GlcNAc and monosialyl and disialyl N-acetyllactosamines are the best acceptor substrates among glycoproteins. May plays critical role in the striatum by mediating the formation of disialylated and trisialylated terminal glycotopes on N- and O-glycans of specific striatal proteins, regulating their distribution in lipid rafts, affecting their interaction with other binding partners, and subsequently modulating striatal functions.
• Tissue Specificity: Expressed in fetal and adult brain and fetal liver.
• Reactome Pathway:
  N-Glycan antennae elongation (R-HSA-975577)
  Sialic acid metabolism (R-HSA-4085001)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neoplasm	DISZKGEW	Definitive	Altered Expression	[1]
Acute myelogenous leukaemia	DISCSPTN	Limited	Genetic Variation	[2]
Advanced cancer	DISAT1Z9	Limited	Altered Expression	[3]

6 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-acetylneuraminate alpha-2,8-sialyltransferase ST8SIA3 (ST8SIA3).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Alpha-N-acetylneuraminate alpha-2,8-sialyltransferase ST8SIA3 (ST8SIA3).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Alpha-N-acetylneuraminate alpha-2,8-sialyltransferase ST8SIA3 (ST8SIA3).	[6]
Panobinostat	DM58WKG	Approved	Panobinostat affects the expression of Alpha-N-acetylneuraminate alpha-2,8-sialyltransferase ST8SIA3 (ST8SIA3).	[7]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 affects the expression of Alpha-N-acetylneuraminate alpha-2,8-sialyltransferase ST8SIA3 (ST8SIA3).	[7]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Alpha-N-acetylneuraminate alpha-2,8-sialyltransferase ST8SIA3 (ST8SIA3).	[9]

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 Alpha-N-acetylneuraminate alpha-2,8-sialyltransferase ST8SIA3 (ST8SIA3).	[8]

References

• [1] Glycolipids Recognized by A2B5 Antibody Promote Proliferation, Migration, and Clonogenicity in Glioblastoma Cells.Cancers (Basel). 2019 Aug 28;11(9):1267. doi: 10.3390/cancers11091267.
• [2] 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.
• [3] Glyco-genes change expression in cancer through aberrant methylation.Biochim Biophys Acta. 2016 Aug;1860(8):1776-85. doi: 10.1016/j.bbagen.2016.01.002. Epub 2016 Jan 12.
• [4] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [5] Transcriptional regulation of the human Sia-alpha2,3-Gal-beta1,4-GlcNAc-R:alpha2,8-sialyltransferase (hST8Sia III) by retinoic acid in human glioblastoma tumor cell line. Biochim Biophys Acta. 2006 Oct;1759(10):451-7. doi: 10.1016/j.bbaexp.2006.09.003. Epub 2006 Sep 19.
• [6] 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.
• [7] The Bromodomain Inhibitor JQ1 and the Histone Deacetylase Inhibitor Panobinostat Synergistically Reduce N-Myc Expression and Induce Anticancer Effects. Clin Cancer Res. 2016 May 15;22(10):2534-44. doi: 10.1158/1078-0432.CCR-15-1666. Epub 2016 Jan 5.
• [8] 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.
• [9] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.