Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTZRVUH4)

• DOT Name: Dolichyl pyrophosphate Man9GlcNAc2 alpha-1,3-glucosyltransferase (ALG6)
• Synonyms: EC 2.4.1.267; Asparagine-linked glycosylation protein 6 homolog; Dol-P-Glc:Man(9)GlcNAc(2)-PP-Dol alpha-1,3-glucosyltransferase; Dolichyl-P-Glc:Man9GlcNAc2-PP-dolichyl glucosyltransferase
• Gene Name: ALG6
• Related Disease:
  ALG6-congenital disorder of glycosylation 1C
  PMM2-congenital disorder of glycosylation
  Epilepsy
  Cystic kidney disease
• UniProt ID: ALG6_HUMAN
• EC Number: 2.4.1.267
• Pfam ID: PF03155
• Sequence:
  MEKWYLMTVVVLIGLTVRWTVSLNSYSGAGKPPMFGDYEAQRHWQEITFNLPVKQWYFNS
  SDNNLQYWGLDYPPLTAYHSLLCAYVAKFINPDWIALHTSRGYESQAHKLFMRTTVLIAD
  LLIYIPAVVLYCCCLKEISTKKKIANALCILLYPGLILIDYGHFQYNSVSLGFALWGVLG
  ISCDCDLLGSLAFCLAINYKQMELYHALPFFCFLLGKCFKKGLKGKGFVLLVKLACIVVA
  SFVLCWLPFFTEREQTLQVLRRLFPVDRGLFEDKVANIWCSFNVFLKIKDILPRHIQLIM
  SFCSTFLSLLPACIKLILQPSSKGFKFTLVSCALSFFLFSFQVHEKSILLVSLPVCLVLS
  EIPFMSTWFLLVSTFSMLPLLLKDELLMPSVVTTMAFFIACVTSFSIFEKTSEEELQLKS
  FSISVRKYLPCFTFLSRIIQYLFLISVITMVLLTLMTVTLDPPQKLPDLFSVLVCFVSCL
  NFLFFLVYFNIIIMWDSKSGRNQKKIS
• Function: Adds the first 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 Man(9)GlcNAc(2)-PP-Dol.
• KEGG Pathway:
  N-Glycan biosynthesis (hsa00510)
  Metabolic pathways (hsa01100)
• Reactome Pathway:
  Defective ALG6 causes CDG-1c (R-HSA-4724289)
  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
ALG6-congenital disorder of glycosylation 1C	DISS4LUL	Definitive	Autosomal recessive	[1]
PMM2-congenital disorder of glycosylation	DISZRBCA	Definitive	Biomarker	[2]
Epilepsy	DISBB28L	Strong	Genetic Variation	[3]
Cystic kidney disease	DISRT1LM	Limited	Autosomal dominant	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Dolichyl pyrophosphate Man9GlcNAc2 alpha-1,3-glucosyltransferase (ALG6).	[4]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Dolichyl pyrophosphate Man9GlcNAc2 alpha-1,3-glucosyltransferase (ALG6).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Dolichyl pyrophosphate Man9GlcNAc2 alpha-1,3-glucosyltransferase (ALG6).	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Dolichyl pyrophosphate Man9GlcNAc2 alpha-1,3-glucosyltransferase (ALG6).	[7]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Dolichyl pyrophosphate Man9GlcNAc2 alpha-1,3-glucosyltransferase (ALG6).	[8]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Dolichyl pyrophosphate Man9GlcNAc2 alpha-1,3-glucosyltransferase (ALG6).	[9]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of Dolichyl pyrophosphate Man9GlcNAc2 alpha-1,3-glucosyltransferase (ALG6).	[10]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Dolichyl pyrophosphate Man9GlcNAc2 alpha-1,3-glucosyltransferase (ALG6).	[11]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Dolichyl pyrophosphate Man9GlcNAc2 alpha-1,3-glucosyltransferase (ALG6).	[12]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Dolichyl pyrophosphate Man9GlcNAc2 alpha-1,3-glucosyltransferase (ALG6).	[13]

References

• [1] 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.
• [2] N-Glycosylation Defects in Humans Lower Low-Density Lipoprotein Cholesterol Through Increased Low-Density Lipoprotein Receptor Expression.Circulation. 2019 Jul 23;140(4):280-292. doi: 10.1161/CIRCULATIONAHA.118.036484. Epub 2019 May 23.
• [3] ALG6-CDG: a recognizable phenotype with epilepsy, proximal muscle weakness, ataxia and behavioral and limb anomalies.J Inherit Metab Dis. 2016 Sep;39(5):713-723. doi: 10.1007/s10545-016-9945-x. Epub 2016 Jun 10.
• [4] 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.
• [5] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [8] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [9] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [10] Cannabidiol enhances cytotoxicity of anti-cancer drugs in human head and neck squamous cell carcinoma. Sci Rep. 2020 Nov 26;10(1):20622. doi: 10.1038/s41598-020-77674-y.
• [11] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [12] 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.
• [13] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.