Details of Drug Off-Target (DOT)

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

• DOT Name: CMP-N-acetylneuraminate-beta-1,4-galactoside alpha-2,3-sialyltransferase (ST3GAL3)
• Synonyms: EC 2.4.3.6; Beta-galactoside alpha-2,3-sialyltransferase 3; Alpha 2,3-ST 3; Gal beta-1,3(4) GlcNAc alpha-2,3 sialyltransferase; N-acetyllactosaminide alpha-2,3-sialyltransferase; ST3Gal III; ST3GalIII; ST3N; Sialyltransferase 6
• Gene Name: ST3GAL3
• Related Disease:
  Advanced cancer
  Amyotrophic lateral sclerosis
  Bipolar disorder
  Breast cancer
  Breast carcinoma
  Developmental and epileptic encephalopathy, 15
  Gastric cancer
  Hepatocellular carcinoma
  Influenza
  Intellectual disability
  Intellectual disability, autosomal recessive 12
  Neoplasm
  Non-insulin dependent diabetes
  Pancreatic adenocarcinoma
  Prostate cancer
  Prostate carcinoma
  Stomach cancer
  Complex neurodevelopmental disorder
  Oral cancer
  Oral cavity carcinoma
  Autosomal recessive non-syndromic intellectual disability
  West syndrome
  Attention deficit hyperactivity disorder
  Cervical cancer
  Cervical carcinoma
  Congenital disorder of glycosylation
  Epilepsy
  Neurodevelopmental disorder
  Schizophrenia
• UniProt ID: SIAT6_HUMAN
• EC Number: 2.4.3.6
• Pfam ID: PF00777
• Sequence:
  MGLLVFVRNLLLALCLFLVLGFLYYSAWKLHLLQWEEDSNSVVLSFDSAGQTLGSEYDRL
  GFLLNLDSKLPAELATKYANFSEGACKPGYASALMTAIFPRFSKPAPMFLDDSFRKWARI
  REFVPPFGIKGQDNLIKAILSVTKEYRLTPALDSLRCRRCIIVGNGGVLANKSLGSRIDD
  YDIVVRLNSAPVKGFEKDVGSKTTLRITYPEGAMQRPEQYERDSLFVLAGFKWQDFKWLK
  YIVYKERVSASDGFWKSVATRVPKEPPEIRILNPYFIQEAAFTLIGLPFNNGLMGRGNIP
  TLGSVAVTMALHGCDEVAVAGFGYDMSTPNAPLHYYETVRMAAIKESWTHNIQREKEFLR
  KLVKARVITDLSSGI
• Function: Catalyzes the formation of the NeuAc-alpha-2,3-Gal-beta-1,4-GlcNAc-, NeuAc-alpha-2,3-Gal-beta-1,3-GlcNAc- and NeuAc-alpha-2,3-Gal-beta-1,3-GalNAc- sequences found in terminal carbohydrate groups of glycoproteins and glycolipids. The highest activity is toward Gal-beta-1,3-GlcNAc and the lowest toward Gal-beta-1,3-GalNAc.
• Tissue Specificity: Highly expressed in adult skeletal muscle and in all fetal tissues examined and to a much lesser extent in placenta, lung and liver.
• KEGG Pathway:
  Various types of N-glycan biosynthesis (hsa00513)
  Other types of O-glycan biosynthesis (hsa00514)
  Mannose type O-glycan biosynthesis (hsa00515)
  Glycosaminoglycan biosynthesis - keratan sulfate (hsa00533)
  Glycosphingolipid biosynthesis - lacto and neolacto series (hsa00601)
  Metabolic pathways (hsa01100)
• Reactome Pathway:
  Keratan sulfate biosynthesis (R-HSA-2022854)
  Defective ST3GAL3 causes MCT12 and EIEE15 (R-HSA-3656243)
  Sialic acid metabolism (R-HSA-4085001)
  Lewis blood group biosynthesis (R-HSA-9037629)
  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)
  Pre-NOTCH Processing in Golgi (R-HSA-1912420)
• BioCyc Pathway: MetaCyc:HS04994-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

29 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Amyotrophic lateral sclerosis	DISF7HVM	Strong	Genetic Variation	[2]
Bipolar disorder	DISAM7J2	Strong	Biomarker	[3]
Breast cancer	DIS7DPX1	Strong	Biomarker	[4]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[4]
Developmental and epileptic encephalopathy, 15	DIS6KG8I	Strong	Autosomal recessive	[5]
Gastric cancer	DISXGOUK	Strong	Biomarker	[6]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[7]
Influenza	DIS3PNU3	Strong	Biomarker	[8]
Intellectual disability	DISMBNXP	Strong	Biomarker	[9]
Intellectual disability, autosomal recessive 12	DISRUKGY	Strong	Autosomal recessive	[5]
Neoplasm	DISZKGEW	Strong	Altered Expression	[6]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Genetic Variation	[10]
Pancreatic adenocarcinoma	DISKHX7S	Strong	Biomarker	[11]
Prostate cancer	DISF190Y	Strong	Biomarker	[12]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[12]
Stomach cancer	DISKIJSX	Strong	Biomarker	[6]
Complex neurodevelopmental disorder	DISB9AFI	Moderate	Autosomal recessive	[13]
Oral cancer	DISLD42D	moderate	Altered Expression	[14]
Oral cavity carcinoma	DISZXMVL	moderate	Altered Expression	[14]
Autosomal recessive non-syndromic intellectual disability	DISJWRZZ	Supportive	Autosomal recessive	[5]
West syndrome	DISLIAU9	Supportive	Autosomal dominant	[15]
Attention deficit hyperactivity disorder	DISL8MX9	Limited	Genetic Variation	[16]
Cervical cancer	DISFSHPF	Limited	Altered Expression	[17]
Cervical carcinoma	DIST4S00	Limited	Altered Expression	[17]
Congenital disorder of glycosylation	DIS400QP	Limited	Genetic Variation	[9]
Epilepsy	DISBB28L	Limited	Genetic Variation	[9]
Neurodevelopmental disorder	DIS372XH	Limited	Genetic Variation	[9]
Schizophrenia	DISSRV2N	Limited	Genetic Variation	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of CMP-N-acetylneuraminate-beta-1,4-galactoside alpha-2,3-sialyltransferase (ST3GAL3).	[19]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of CMP-N-acetylneuraminate-beta-1,4-galactoside alpha-2,3-sialyltransferase (ST3GAL3).	[24]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of CMP-N-acetylneuraminate-beta-1,4-galactoside alpha-2,3-sialyltransferase (ST3GAL3).	[26]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of CMP-N-acetylneuraminate-beta-1,4-galactoside alpha-2,3-sialyltransferase (ST3GAL3).	[20]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of CMP-N-acetylneuraminate-beta-1,4-galactoside alpha-2,3-sialyltransferase (ST3GAL3).	[21]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of CMP-N-acetylneuraminate-beta-1,4-galactoside alpha-2,3-sialyltransferase (ST3GAL3).	[22]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of CMP-N-acetylneuraminate-beta-1,4-galactoside alpha-2,3-sialyltransferase (ST3GAL3).	[23]
Hydroquinone	DM6AVR4	Approved	Hydroquinone decreases the expression of CMP-N-acetylneuraminate-beta-1,4-galactoside alpha-2,3-sialyltransferase (ST3GAL3).	[25]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of CMP-N-acetylneuraminate-beta-1,4-galactoside alpha-2,3-sialyltransferase (ST3GAL3).	[27]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of CMP-N-acetylneuraminate-beta-1,4-galactoside alpha-2,3-sialyltransferase (ST3GAL3).	[28]
	DM9CEI5		decreases the activity of CMP-N-acetylneuraminate-beta-1,4-galactoside alpha-2,3-sialyltransferase (ST3GAL3).	[29]

References

• [1] Alpha2,3-sialyltransferase III knockdown sensitized ovarian cancer cells to cisplatin-induced apoptosis.Biochem Biophys Res Commun. 2017 Jan 22;482(4):758-763. doi: 10.1016/j.bbrc.2016.11.107. Epub 2016 Nov 19.
• [2] Age of onset of amyotrophic lateral sclerosis is modulated by a locus on 1p34.1.Neurobiol Aging. 2013 Jan;34(1):357.e7-19. doi: 10.1016/j.neurobiolaging.2012.07.017. Epub 2012 Sep 5.
• [3] A large-scale integrative analysis of GWAS and common meQTLs across whole life course identifies genes, pathways and tissue/cell types for three major psychiatric disorders.Neurosci Biobehav Rev. 2018 Dec;95:347-352. doi: 10.1016/j.neubiorev.2018.10.005. Epub 2018 Oct 16.
• [4] ST3Gal III modulates breast cancer cell adhesion and invasion by altering the expression of invasion-related molecules.Oncol Rep. 2016 Dec;36(6):3317-3324. doi: 10.3892/or.2016.5180. Epub 2016 Oct 18.
• [5] ST3GAL3 mutations impair the development of higher cognitive functions. Am J Hum Genet. 2011 Sep 9;89(3):407-14. doi: 10.1016/j.ajhg.2011.08.008.
• [6] Clinical relevance of sialyltransferases ST6GAL-I and ST3GAL-III in gastric cancer.Oncology. 2003;65(2):139-45. doi: 10.1159/000072339.
• [7] Differences in CD75s- and iso-CD75s-ganglioside content and altered mRNA expression of sialyltransferases ST6GAL1 and ST3GAL6 in human hepatocellular carcinomas and nontumoral liver tissues.Glycobiology. 2011 May;21(5):584-94. doi: 10.1093/glycob/cwq200. Epub 2010 Dec 7.
• [8] The expression pattern and histological distribution of sialyltransferases ST3Gal III in yellow chicken.Vet Res Commun. 2013 Dec;37(4):285-91. doi: 10.1007/s11259-013-9573-y. Epub 2013 Aug 14.
• [9] A novel nonsense and inactivating variant of ST3GAL3 in two infant siblings suffering severe epilepsy and expressing circulating CA19.9.Glycobiology. 2020 Jan 28;30(2):95-104. doi: 10.1093/glycob/cwz079.
• [10] Genome-wide association study of coronary artery calcified atherosclerotic plaque in African Americans with type 2 diabetes.BMC Genet. 2017 Dec 8;18(1):105. doi: 10.1186/s12863-017-0572-9.
• [11] alpha2,3-sialyltransferase ST3Gal III modulates pancreatic cancer cell motility and adhesion in vitro and enhances its metastatic potential in vivo.PLoS One. 2010 Sep 1;5(9):e12524. doi: 10.1371/journal.pone.0012524.
• [12] Gene structure and transcriptional regulation of human Gal beta1,4(3) GlcNAc alpha2,3-sialyltransferase VI (hST3Gal VI) gene in prostate cancer cell line.Biochem Biophys Res Commun. 2001 Oct 12;287(5):1148-56. doi: 10.1006/bbrc.2001.5709.
• [13] 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.
• [14] "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.
• [15] West syndrome caused by ST3Gal-III deficiency. Epilepsia. 2013 Feb;54(2):e24-7. doi: 10.1111/epi.12050. Epub 2012 Dec 17.
• [16] A Genetic Investigation of Sex Bias in the Prevalence of Attention-Deficit/Hyperactivity Disorder.Biol Psychiatry. 2018 Jun 15;83(12):1044-1053. doi: 10.1016/j.biopsych.2017.11.026. Epub 2017 Dec 2.
• [17] Altered mRNA expression of sialyltransferase in squamous cell carcinomas of the cervix.Gynecol Oncol. 2001 Oct;83(1):121-7. doi: 10.1006/gyno.2001.6358.
• [18] Pleiotropic Meta-Analysis of Cognition, Education, and Schizophrenia Differentiates Roles of Early Neurodevelopmental and Adult Synaptic Pathways.Am J Hum Genet. 2019 Aug 1;105(2):334-350. doi: 10.1016/j.ajhg.2019.06.012.
• [19] 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.
• [20] Galactomutarotase and other galactose-related genes are rapidly induced by retinoic acid in human myeloid cells. Biochemistry. 2007 Dec 25;46(51):15198-207. doi: 10.1021/bi701891t. Epub 2007 Dec 4.
• [21] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [22] 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.
• [23] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [24] 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.
• [25] Phenolic metabolites of benzene induced caspase-dependent cytotoxicities to K562 cells accompanied with decrease in cell surface sialic acids. Environ Toxicol. 2014 Dec;29(12):1437-51. doi: 10.1002/tox.21874. Epub 2013 Jun 17.
• [26] 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.
• [27] 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.
• [28] Cellular reactions to long-term volatile organic compound (VOC) exposures. Sci Rep. 2016 Dec 1;6:37842. doi: 10.1038/srep37842.
• [29] A novel sialyltransferase inhibitor suppresses FAK/paxillin signaling and cancer angiogenesis and metastasis pathways. Cancer Res. 2011 Jan 15;71(2):473-83. doi: 10.1158/0008-5472.CAN-10-1303. Epub 2011 Jan 11.