Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTFCO8QX)

• DOT Name: CMP-N-acetylneuraminate-beta-galactosamide-alpha-2,3-sialyltransferase 1 (ST3GAL1)
• Synonyms: Alpha 2,3-ST 1; Beta-galactoside alpha-2,3-sialyltransferase 1; EC 2.4.3.4; Gal-NAc6S; Gal-beta-1,3-GalNAc-alpha-2,3-sialyltransferase; Monosialoganglioside sialyltransferase; EC 2.4.3.2; SIATFL; ST3Gal I; ST3GalI; ST3GalA.1; ST3O; Sialyltransferase 4A; SIAT4-A
• Gene Name: ST3GAL1
• Related Disease:
  Advanced cancer
  Bipolar disorder
  Bladder cancer
  Breast cancer
  Castration-resistant prostate carcinoma
  Enterovirus infection
  Epithelial ovarian cancer
  Estrogen-receptor positive breast cancer
  Graves disease
  Mucopolysaccharidosis type 4A
  Neoplasm
  Ovarian cancer
  Ovarian neoplasm
  Ovarian serous adenocarcinoma
  Prostate cancer
  Prostate carcinoma
  Psychotic disorder
  Schizophrenia
  Systemic sclerosis
  Urinary bladder cancer
  Urinary bladder neoplasm
  Breast carcinoma
  Cutaneous squamous cell carcinoma
• UniProt ID: SIA4A_HUMAN
• EC Number: 2.4.3.2; 2.4.3.4
• Pfam ID: PF00777
• Sequence:
  MVTLRKRTLKVLTFLVLFIFLTSFFLNYSHTMVATTWFPKQMVLELSENLKRLIKHRPCT
  CTHCIGQRKLSAWFDERFNQTMQPLLTAQNALLEDDTYRWWLRLQREKKPNNLNDTIKEL
  FRVVPGNVDPMLEKRSVGCRRCAVVGNSGNLRESSYGPEIDSHDFVLRMNKAPTAGFEAD
  VGTKTTHHLVYPESFRELGDNVSMILVPFKTIDLEWVVSAITTGTISHTYIPVPAKIRVK
  QDKILIYHPAFIKYVFDNWLQGHGRYPSTGILSVIFSMHVCDEVDLYGFGADSKGNWHHY
  WENNPSAGAFRKTGVHDADFESNVTATLASINKIRIFKGR
• Function: A beta-galactoside alpha2-3 sialyltransferase involved in terminal sialylation of glycoproteins and 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. Adds sialic acid to the core 1 O-glycan, Galbeta-(1->3)-GalNAc-O-Ser/Thr, which is a major structure of mucin-type O-glycans. As part of a homeostatic mechanism that regulates CD8-positive T cell numbers, sialylates core 1 O-glycans of T cell glycoproteins, SPN/CD43 and PTPRC/CD45. Prevents premature apoptosis of thymic CD8-positive T cells prior to peripheral emigration, whereas in the secondary lymphoid organs controls the survival of CD8-positive memory T cells generated following a successful immune response. Transfers sialic acid to asialofetuin, presumably onto Galbeta-(1->3)-GalNAc-O-Ser. Sialylates GM1a, GA1 and GD1b gangliosides to form GD1a, GM1b and GT1b, respectively.
• Tissue Specificity: Expressed in several tissues. Highest expression in lung, liver, skeletal muscle, kidney, pancreas, spleen and placenta.
• 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:HS00250-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

23 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[1]
Bipolar disorder	DISAM7J2	Strong	Biomarker	[2]
Bladder cancer	DISUHNM0	Strong	Genetic Variation	[1]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[3]
Castration-resistant prostate carcinoma	DISVGAE6	Strong	Biomarker	[4]
Enterovirus infection	DISH2UDP	Strong	Biomarker	[5]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[6]
Estrogen-receptor positive breast cancer	DIS1H502	Strong	Biomarker	[7]
Graves disease	DISU4KOQ	Strong	Altered Expression	[8]
Mucopolysaccharidosis type 4A	DISTYFQS	Strong	Biomarker	[9]
Neoplasm	DISZKGEW	Strong	Altered Expression	[3]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[6]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[6]
Ovarian serous adenocarcinoma	DISSU72Z	Strong	Altered Expression	[10]
Prostate cancer	DISF190Y	Strong	Biomarker	[4]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[4]
Psychotic disorder	DIS4UQOT	Strong	Biomarker	[11]
Schizophrenia	DISSRV2N	Strong	Biomarker	[11]
Systemic sclerosis	DISF44L6	Strong	Altered Expression	[12]
Urinary bladder cancer	DISDV4T7	Strong	Genetic Variation	[1]
Urinary bladder neoplasm	DIS7HACE	Strong	Genetic Variation	[1]
Breast carcinoma	DIS2UE88	moderate	Altered Expression	[3]
Cutaneous squamous cell carcinoma	DIS3LXUG	Limited	Genetic Variation	[13]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Temozolomide	DMKECZD	Approved	CMP-N-acetylneuraminate-beta-galactosamide-alpha-2,3-sialyltransferase 1 (ST3GAL1) affects the response to substance of Temozolomide.	[29]
DTI-015	DMXZRW0	Approved	CMP-N-acetylneuraminate-beta-galactosamide-alpha-2,3-sialyltransferase 1 (ST3GAL1) affects the response to substance of DTI-015.	[29]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of CMP-N-acetylneuraminate-beta-galactosamide-alpha-2,3-sialyltransferase 1 (ST3GAL1).	[14]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of CMP-N-acetylneuraminate-beta-galactosamide-alpha-2,3-sialyltransferase 1 (ST3GAL1).	[15]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of CMP-N-acetylneuraminate-beta-galactosamide-alpha-2,3-sialyltransferase 1 (ST3GAL1).	[16]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of CMP-N-acetylneuraminate-beta-galactosamide-alpha-2,3-sialyltransferase 1 (ST3GAL1).	[17]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of CMP-N-acetylneuraminate-beta-galactosamide-alpha-2,3-sialyltransferase 1 (ST3GAL1).	[18]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of CMP-N-acetylneuraminate-beta-galactosamide-alpha-2,3-sialyltransferase 1 (ST3GAL1).	[19]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of CMP-N-acetylneuraminate-beta-galactosamide-alpha-2,3-sialyltransferase 1 (ST3GAL1).	[21]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of CMP-N-acetylneuraminate-beta-galactosamide-alpha-2,3-sialyltransferase 1 (ST3GAL1).	[22]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of CMP-N-acetylneuraminate-beta-galactosamide-alpha-2,3-sialyltransferase 1 (ST3GAL1).	[23]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of CMP-N-acetylneuraminate-beta-galactosamide-alpha-2,3-sialyltransferase 1 (ST3GAL1).	[24]
Fenretinide	DMRD5SP	Phase 3	Fenretinide increases the expression of CMP-N-acetylneuraminate-beta-galactosamide-alpha-2,3-sialyltransferase 1 (ST3GAL1).	[25]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of CMP-N-acetylneuraminate-beta-galactosamide-alpha-2,3-sialyltransferase 1 (ST3GAL1).	[27]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of CMP-N-acetylneuraminate-beta-galactosamide-alpha-2,3-sialyltransferase 1 (ST3GAL1).	[28]

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 1 (ST3GAL1).	[20]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of CMP-N-acetylneuraminate-beta-galactosamide-alpha-2,3-sialyltransferase 1 (ST3GAL1).	[26]

References

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• [2] Family-based SNP association study on 8q24 in bipolar disorder.Am J Med Genet B Neuropsychiatr Genet. 2008 Jul 5;147B(5):612-8. doi: 10.1002/ajmg.b.30651.
• [3] Sialylation of vasorin by ST3Gal1 facilitates TGF-1-mediated tumor angiogenesis and progression.Int J Cancer. 2019 Apr 15;144(8):1996-2007. doi: 10.1002/ijc.31891. Epub 2019 Jan 3.
• [4] O-Glycosylation-mediated signaling circuit drives metastatic castration-resistant prostate cancer.FASEB J. 2018 Jun 15:fj201800687. doi: 10.1096/fj.201800687. Online ahead of print.
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• [8] Thyroid sialyltransferase mRNA level and activity are increased in Graves' disease.Thyroid. 2005 Jul;15(7):645-52. doi: 10.1089/thy.2005.15.645.
• [9] 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.
• [10] Altered mRNA expressions of sialyltransferases in ovarian cancers.Gynecol Oncol. 2005 Dec;99(3):631-9. doi: 10.1016/j.ygyno.2005.07.016. Epub 2005 Aug 19.
• [11] Family-based association study of lithium-related and other candidate genes in bipolar disorder.Arch Gen Psychiatry. 2008 Jan;65(1):53-61. doi: 10.1001/archgenpsychiatry.2007.15.
• [12] Multiplex reverse transcription polymerase chain reaction assessment of sialyltransferase expression in peripheral blood mononuclear cells in systemic sclerosis.J Rheumatol. 2004 Jan;31(1):88-95.
• [13] A Genome-Wide Association Study of Cutaneous Squamous Cell Carcinoma among European Descendants.Cancer Epidemiol Biomarkers Prev. 2016 Apr;25(4):714-20. doi: 10.1158/1055-9965.EPI-15-1070. Epub 2016 Feb 12.
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• [17] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [18] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [19] Long-term estrogen exposure promotes carcinogen bioactivation, induces persistent changes in gene expression, and enhances the tumorigenicity of MCF-7 human breast cancer cells. Toxicol Appl Pharmacol. 2009 Nov 1;240(3):355-66.
• [20] 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.
• [21] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [22] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [23] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [24] 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.
• [25] The transforming growth factor-beta family members bone morphogenetic protein-2 and macrophage inhibitory cytokine-1 as mediators of the antiangiogenic activity of N-(4-hydroxyphenyl)retinamide. Clin Cancer Res. 2005 Jun 15;11(12):4610-9.
• [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] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [28] Epigenetic influences of low-dose bisphenol A in primary human breast epithelial cells. Toxicol Appl Pharmacol. 2010 Oct 15;248(2):111-21.
• [29] Tumor necrosis factor-alpha-induced protein 3 as a putative regulator of nuclear factor-kappaB-mediated resistance to O6-alkylating agents in human glioblastomas. J Clin Oncol. 2006 Jan 10;24(2):274-87. doi: 10.1200/JCO.2005.02.9405. Epub 2005 Dec 19.