Details of Drug Off-Target (DOT)

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

• DOT Name: Putative Dol-P-Glc:Glc(2)Man(9)GlcNAc(2)-PP-Dol alpha-1,2-glucosyltransferase (ALG10B)
• Synonyms: EC 2.4.1.256; Alpha-1,2-glucosyltransferase ALG10-A; Alpha-2-glucosyltransferase ALG10-B; Asparagine-linked glycosylation protein 10 homolog B; Potassium channel regulator 1
• Gene Name: ALG10B
• Related Disease:
  Ventricular fibrillation
  Long QT syndrome
  Arrhythmia
  Long QT syndrome 2
• UniProt ID: AG10B_HUMAN
• EC Number: 2.4.1.256
• Pfam ID: PF04922
• Sequence:
  MAQLEGYCFSAALSCTFLVSCLLFSAFSRALREPYMDEIFHLPQAQRYCEGHFSLSQWDP
  MITTLPGLYLVSVGVVKPAIWIFAWSEHVVCSIGMLRFVNLLFSVGNFYLLYLLFHKVQP
  RNKAASSIQRVLSTLTLAVFPTLYFFNFLYYTEAGSMFFTLFAYLMCLYGNHKTSAFLGF
  CGFMFRQTNIIWAVFCAGNVIAQKLTEAWKTELQKKEDRLPPIKGPFAEFRKILQFLLAY
  SMSFKNLSMLFCLTWPYILLGFLFCAFVVVNGGIVIGDRSSHEACLHFPQLFYFFSFTLF
  FSFPHLLSPSKIKTFLSLVWKHGILFLVVTLVSVFLVWKFTYAHKYLLADNRHYTFYVWK
  RVFQRYAILKYLLVPAYIFAGWSIADSLKSKPIFWNLMFFICLFIVIVPQKLLEFRYFIL
  PYVIYRLNITLPPTSRLVCELSCYAIVNFITFYIFLNKTFQWPNSQDIQRFMW
• Function: Putative alpha-1,2-glucosyltransferase, which adds the third glucose residue to the lipid-linked oligosaccharide precursor for N-linked glycosylation. Transfers glucose from dolichyl phosphate glucose (Dol-P-Glc) onto the lipid-linked oligosaccharide Glc(2)Man(9)GlcNAc(2)-PP-Dol. When coupled to KCNH2 may reduce KCNH2 sensitivity to classic proarrhythmic drug blockade, possibly by mediating glycosylation of KCNH2. Has a role in maintenance of cochlear outer hair cell function.
• Tissue Specificity: Highly expressed in heart, placenta, liver, kidney and pancreas. Weakly expressed in lung, skeletal muscle and brain.
• KEGG Pathway:
  N-Glycan biosynthesis (hsa00510)
  Metabolic pathways (hsa01100)
• Reactome Pathway: Biosynthesis of the N-glycan precursor (dolichol lipid-linked oligosaccharide, LLO) and transfer to a nascent protein (R-HSA-446193)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Ventricular fibrillation	DIS7IN76	Strong	Genetic Variation	[1]
Long QT syndrome	DISMKWS3	moderate	Genetic Variation	[1]
Arrhythmia	DISFF2NI	Limited	Altered Expression	[2]
Long QT syndrome 2	DISQQFTJ	Limited	Unknown	[3]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Flucloxacillin	DMNUWST	Approved	Putative Dol-P-Glc:Glc(2)Man(9)GlcNAc(2)-PP-Dol alpha-1,2-glucosyltransferase (ALG10B) increases the Liver injury ADR of Flucloxacillin.	[8]

1 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 Putative Dol-P-Glc:Glc(2)Man(9)GlcNAc(2)-PP-Dol alpha-1,2-glucosyltransferase (ALG10B).	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Putative Dol-P-Glc:Glc(2)Man(9)GlcNAc(2)-PP-Dol alpha-1,2-glucosyltransferase (ALG10B).	[5]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Putative Dol-P-Glc:Glc(2)Man(9)GlcNAc(2)-PP-Dol alpha-1,2-glucosyltransferase (ALG10B).	[6]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Putative Dol-P-Glc:Glc(2)Man(9)GlcNAc(2)-PP-Dol alpha-1,2-glucosyltransferase (ALG10B).	[6]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Putative Dol-P-Glc:Glc(2)Man(9)GlcNAc(2)-PP-Dol alpha-1,2-glucosyltransferase (ALG10B).	[7]

References

• [1] A KCR1 variant implicated in susceptibility to the long QT syndrome.J Mol Cell Cardiol. 2011 Jan;50(1):50-7. doi: 10.1016/j.yjmcc.2010.10.007. Epub 2010 Oct 13.
• [2] HERG is protected from pharmacological block by alpha-1,2-glucosyltransferase function.J Biol Chem. 2007 Feb 23;282(8):5506-13. doi: 10.1074/jbc.M605976200. Epub 2006 Dec 21.
• [3] Beh?et's disease. An update based on the 1985 International Conference in London. Arch Dermatol. 1986 May;122(5):556-8. doi: 10.1001/archderm.122.5.556.
• [4] 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.
• [5] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [6] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [7] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.
• [8] HLA-B*5701 genotype is a major determinant of drug-induced liver injury due to flucloxacillin. Nat Genet. 2009 Jul;41(7):816-9. doi: 10.1038/ng.379. Epub 2009 May 31.