Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT27CCUF)

• DOT Name: Lactosylceramide alpha-2,3-sialyltransferase (ST3GAL5)
• Synonyms: EC 2.4.3.9; CMP-NeuAc:lactosylceramide alpha-2,3-sialyltransferase; GM3 synthase; Ganglioside GM3 synthase; ST3Gal V; ST3GalV; Sialyltransferase 9
• Gene Name: ST3GAL5
• Related Disease: GM3 synthase deficiency
• UniProt ID: SIAT9_HUMAN
• EC Number: 2.4.3.9
• Pfam ID: PF00777
• Sequence:
  MRTKAAGCAERRPLQPRTEAAAAPAGRAMPSEYTYVKLRSDCSRPSLQWYTRAQSKMRRP
  SLLLKDILKCTLLVFGVWILYILKLNYTTEECDMKKMHYVDPDHVKRAQKYAQQVLQKEC
  RPKFAKTSMALLFEHRYSVDLLPFVQKAPKDSEAESKYDPPFGFRKFSSKVQTLLELLPE
  HDLPEHLKAKTCRRCVVIGSGGILHGLELGHTLNQFDVVIRLNSAPVEGYSEHVGNKTTI
  RMTYPEGAPLSDLEYYSNDLFVAVLFKSVDFNWLQAMVKKETLPFWVRLFFWKQVAEKIP
  LQPKHFRILNPVIIKETAFDILQYSEPQSRFWGRDKNVPTIGVIAVVLATHLCDEVSLAG
  FGYDLNQPRTPLHYFDSQCMAAMNFQTMHNVTTETKFLLKLVKEGVVKDLSGGIDREF
• Function: Transfers the sialyl group (N-acetyl-alpha-neuraminyl or NeuAc) from CMP-NeuAc to the non-reducing terminal galactose (Gal) of glycosphingolipids forming gangliosides (important molecules involved in the regulation of multiple cellular processes, including cell proliferation and differentiation, apoptosis, embryogenesis, development, and oncogenesis). Mainly involved in the biosynthesis of ganglioside GM3 but can also use different glycolipids as substrate acceptors such as D-galactosylceramide (GalCer), asialo-GM2 (GA2) and asialo-GM1 (GA1), although less preferentially than beta-D-Gal-(1->4)-beta-D-Glc-(1<->1)-Cer (LacCer).
• Tissue Specificity: Ubiquitous. High expression in brain, skeletal muscle, placenta, and testis. mRNA widely distributed in human brain, but slightly elevated expression was observed in the cerebral cortex, temporal lobe, and putamen.
• KEGG Pathway:
  Glycosphingolipid biosynthesis - ganglio series (hsa00604)
  Metabolic pathways (hsa01100)
• Reactome Pathway: Sialic acid metabolism (R-HSA-4085001)
• BioCyc Pathway: MetaCyc:HS03904-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
GM3 synthase deficiency	DISAWA41	Definitive	Autosomal recessive	[1]

16 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 Lactosylceramide alpha-2,3-sialyltransferase (ST3GAL5).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Lactosylceramide alpha-2,3-sialyltransferase (ST3GAL5).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Lactosylceramide alpha-2,3-sialyltransferase (ST3GAL5).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Lactosylceramide alpha-2,3-sialyltransferase (ST3GAL5).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Lactosylceramide alpha-2,3-sialyltransferase (ST3GAL5).	[6]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Lactosylceramide alpha-2,3-sialyltransferase (ST3GAL5).	[8]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Lactosylceramide alpha-2,3-sialyltransferase (ST3GAL5).	[9]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of Lactosylceramide alpha-2,3-sialyltransferase (ST3GAL5).	[9]
Bleomycin	DMNER5S	Approved	Bleomycin decreases the expression of Lactosylceramide alpha-2,3-sialyltransferase (ST3GAL5).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Lactosylceramide alpha-2,3-sialyltransferase (ST3GAL5).	[10]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Lactosylceramide alpha-2,3-sialyltransferase (ST3GAL5).	[11]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Lactosylceramide alpha-2,3-sialyltransferase (ST3GAL5).	[12]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Lactosylceramide alpha-2,3-sialyltransferase (ST3GAL5).	[9]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Lactosylceramide alpha-2,3-sialyltransferase (ST3GAL5).	[13]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Lactosylceramide alpha-2,3-sialyltransferase (ST3GAL5).	[14]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A increases the expression of Lactosylceramide alpha-2,3-sialyltransferase (ST3GAL5).	[15]

1 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 Lactosylceramide alpha-2,3-sialyltransferase (ST3GAL5).	[7]

References

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• [2] The neuroprotective action of the mood stabilizing drugs lithium chloride and sodium valproate is mediated through the up-regulation of the homeodomain protein Six1. Toxicol Appl Pharmacol. 2009 Feb 15;235(1):124-34.
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• [5] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [6] 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.
• [7] 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.
• [8] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [9] Development and validation of the TGx-HDACi transcriptomic biomarker to detect histone deacetylase inhibitors in human TK6 cells. Arch Toxicol. 2021 May;95(5):1631-1645. doi: 10.1007/s00204-021-03014-2. Epub 2021 Mar 26.
• [10] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [11] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [12] 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.
• [13] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [14] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [15] Linking site-specific loss of histone acetylation to repression of gene expression by the mycotoxin ochratoxin A. Arch Toxicol. 2018 Feb;92(2):995-1014.