Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTLAQ14Q)

• DOT Name: Alpha-N-acetylgalactosaminide alpha-2,6-sialyltransferase 3 (ST6GALNAC3)
• Synonyms: EC 2.4.3.7; GalNAc alpha-2,6-sialyltransferase III; ST6GalNAc III; ST6GalNAcIII; STY; Sialyltransferase 7C; SIAT7-C
• Gene Name: ST6GALNAC3
• Related Disease:
  Non-insulin dependent diabetes
  Prostate cancer
  Prostate carcinoma
• UniProt ID: SIA7C_HUMAN
• EC Number: 2.4.3.7
• Pfam ID: PF00777
• Sequence:
  MACILKRKSVIAVSFIAAFLFLLVVRLVNEVNFPLLLNCFGQPGTKWIPFSYTYRRPLRT
  HYGYINVKTQEPLQLDCDLCAIVSNSGQMVGQKVGNEIDRSSCIWRMNNAPTKGYEEDVG
  RMTMIRVVSHTSVPLLLKNPDYFFKEANTTIYVIWGPFRNMRKDGNGIVYNMLKKTVGIY
  PNAQIYVTTEKRMSYCDGVFKKETGKDRVQSGSYLSTGWFTFLLAMDACYGIHVYGMIND
  TYCKTEGYRKVPYHYYEQGRDECDEYFLHEHAPYGGHRFITEKKVFAKWAKKHRIIFTHP
  NWTLS
• 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. ST6GalNAcIII prefers glycolipids to glycoproteins, predominantly catalyzing the biosynthesis of ganglioside GD1alpha from GM1b. GD1alpha is a critical molecule in the communication and interaction between neuronal cells and their supportive cells, particularly in brain tissues, and functions as an adhesion molecule in the process of metastasis. Sialylation of glycoproteins or glycosphingolipids is very important in tumor development, neuronal development, nerve repair, immunological processes and regulation of hormone sensitivity.
• Tissue Specificity: Expressed in brain and kidney . Observed in the epithelium of the proximal tubules, marginal expression was also found in the distal tubules and collecting tubules .
• 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)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Non-insulin dependent diabetes	DISK1O5Z	Strong	Genetic Variation	[1]
Prostate cancer	DISF190Y	Strong	Biomarker	[2]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[2]

7 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-acetylgalactosaminide alpha-2,6-sialyltransferase 3 (ST6GALNAC3).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Alpha-N-acetylgalactosaminide alpha-2,6-sialyltransferase 3 (ST6GALNAC3).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Alpha-N-acetylgalactosaminide alpha-2,6-sialyltransferase 3 (ST6GALNAC3).	[5]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Alpha-N-acetylgalactosaminide alpha-2,6-sialyltransferase 3 (ST6GALNAC3).	[6]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Alpha-N-acetylgalactosaminide alpha-2,6-sialyltransferase 3 (ST6GALNAC3).	[7]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of Alpha-N-acetylgalactosaminide alpha-2,6-sialyltransferase 3 (ST6GALNAC3).	[8]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Alpha-N-acetylgalactosaminide alpha-2,6-sialyltransferase 3 (ST6GALNAC3).	[10]

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-acetylgalactosaminide alpha-2,6-sialyltransferase 3 (ST6GALNAC3).	[9]

References

• [1] Genetic Variants in HSD17B3, SMAD3, and IPO11 Impact Circulating Lipids in Response to Fenofibrate in Individuals With Type 2 Diabetes.Clin Pharmacol Ther. 2018 Apr;103(4):712-721. doi: 10.1002/cpt.798. Epub 2017 Nov 3.
• [2] Biomarker potential of ST6GALNAC3 and ZNF660 promoter hypermethylation in prostate cancer tissue and liquid biopsies.Mol Oncol. 2018 Apr;12(4):545-560. doi: 10.1002/1878-0261.12183. Epub 2018 Mar 13.
• [3] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [4] 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.
• [5] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [6] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [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] Cytosine arabinoside induces ectoderm and inhibits mesoderm expression in human embryonic stem cells during multilineage differentiation. Br J Pharmacol. 2011 Apr;162(8):1743-56.
• [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] 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.