Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTMFG2YY)

• DOT Name: Probable dolichyl pyrophosphate Glc1Man9GlcNAc2 alpha-1,3-glucosyltransferase (ALG8)
• Synonyms: EC 2.4.1.265; Asparagine-linked glycosylation protein 8 homolog; Dol-P-Glc:Glc(1)Man(9)GlcNAc(2)-PP-dolichyl alpha-1,3-glucosyltransferase; Dolichyl-P-Glc:Glc1Man9GlcNAc2-PP-dolichyl glucosyltransferase
• Gene Name: ALG8
• Related Disease:
  ALG8-congenital disorder of glycosylation
  Congenital disorder of glycosylation
  Depression
  Developmental and epileptic encephalopathy, 36
  Intestinal disorder
  Non-immune hydrops fetalis
  Polycystic liver disease 3 with or without kidney cysts
  Autosomal dominant polycystic liver disease
• UniProt ID: ALG8_HUMAN
• EC Number: 2.4.1.265
• Pfam ID: PF03155
• Sequence:
  MAALTIATGTGNWFSALALGVTLLKCLLIPTYHSTDFEVHRNWLAITHSLPISQWYYEAT
  SEWTLDYPPFFAWFEYILSHVAKYFDQEMLNVHNLNYSSSRTLLFQRFSVIFMDVLFVYA
  VRECCKCIDGKKVGKELTEKPKFILSVLLLWNFGLLIVDHIHFQYNGFLFGLMLLSIARL
  FQKRHMEGAFLFAVLLHFKHIYLYVAPAYGVYLLRSYCFTANKPDGSIRWKSFSFVRVIS
  LGLVVFLVSALSLGPFLALNQLPQVFSRLFPFKRGLCHAYWAPNFWALYNALDKVLSVIG
  LKLKFLDPNNIPKASMTSGLVQQFQHTVLPSVTPLATLICTLIAILPSIFCLWFKPQGPR
  GFLRCLTLCALSSFMFGWHVHEKAILLAILPMSLLSVGKAGDASIFLILTTTGHYSLFPL
  LFTAPELPIKILLMLLFTIYSISSLKTLFRKEKPLFNWMETFYLLGLGPLEVCCEFVFPF
  TSWKVKYPFIPLLLTSVYCAVGITYAWFKLYVSVLIDSAIGKTKKQ
• Function: Adds the second 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(1)Man(9)GlcNAc(2)-PP-Dol before it is transferred to the nascent peptide. Required for PKD1/Polycystin-1 maturation and localization to the plasma membrane of the primary cilia.
• KEGG Pathway:
  N-Glycan biosynthesis (hsa00510)
  Metabolic pathways (hsa01100)
• Reactome Pathway:
  Defective ALG8 causes CDG-1h (R-HSA-4724325)
  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

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
ALG8-congenital disorder of glycosylation	DISIK17Y	Definitive	Autosomal recessive	[1]
Congenital disorder of glycosylation	DIS400QP	Strong	Genetic Variation	[2]
Depression	DIS3XJ69	Strong	Biomarker	[3]
Developmental and epileptic encephalopathy, 36	DISG4MY5	Strong	Biomarker	[4]
Intestinal disorder	DISGPMUQ	Strong	Genetic Variation	[5]
Non-immune hydrops fetalis	DISPUY8C	Strong	Genetic Variation	[2]
Polycystic liver disease 3 with or without kidney cysts	DISF3P78	Strong	Autosomal dominant	[6]
Autosomal dominant polycystic liver disease	DISJS005	Limited	Biomarker	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Paclitaxel	DMLB81S	Approved	Probable dolichyl pyrophosphate Glc1Man9GlcNAc2 alpha-1,3-glucosyltransferase (ALG8) affects the response to substance of Paclitaxel.	[20]

12 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 Probable dolichyl pyrophosphate Glc1Man9GlcNAc2 alpha-1,3-glucosyltransferase (ALG8).	[8]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Probable dolichyl pyrophosphate Glc1Man9GlcNAc2 alpha-1,3-glucosyltransferase (ALG8).	[9]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Probable dolichyl pyrophosphate Glc1Man9GlcNAc2 alpha-1,3-glucosyltransferase (ALG8).	[10]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Probable dolichyl pyrophosphate Glc1Man9GlcNAc2 alpha-1,3-glucosyltransferase (ALG8).	[11]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Probable dolichyl pyrophosphate Glc1Man9GlcNAc2 alpha-1,3-glucosyltransferase (ALG8).	[12]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Probable dolichyl pyrophosphate Glc1Man9GlcNAc2 alpha-1,3-glucosyltransferase (ALG8).	[13]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Probable dolichyl pyrophosphate Glc1Man9GlcNAc2 alpha-1,3-glucosyltransferase (ALG8).	[14]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Probable dolichyl pyrophosphate Glc1Man9GlcNAc2 alpha-1,3-glucosyltransferase (ALG8).	[15]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Probable dolichyl pyrophosphate Glc1Man9GlcNAc2 alpha-1,3-glucosyltransferase (ALG8).	[16]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Probable dolichyl pyrophosphate Glc1Man9GlcNAc2 alpha-1,3-glucosyltransferase (ALG8).	[17]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Probable dolichyl pyrophosphate Glc1Man9GlcNAc2 alpha-1,3-glucosyltransferase (ALG8).	[18]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Probable dolichyl pyrophosphate Glc1Man9GlcNAc2 alpha-1,3-glucosyltransferase (ALG8).	[19]

References

• [1] Flexible and scalable diagnostic filtering of genomic variants using G2P with Ensembl VEP. Nat Commun. 2019 May 30;10(1):2373. doi: 10.1038/s41467-019-10016-3.
• [2] Nonimmune hydrops fetalis and congenital disorders of glycosylation: A systematic literature review.J Inherit Metab Dis. 2020 Mar;43(2):223-233. doi: 10.1002/jimd.12162. Epub 2019 Nov 8.
• [3] miRNA-mediated relationships between Cis-SNP genotypes and transcript intensities in lymphocyte cell lines.PLoS One. 2012;7(2):e31429. doi: 10.1371/journal.pone.0031429. Epub 2012 Feb 14.
• [4] Wide clinical spectrum in ALG8-CDG: clues from molecular findings suggest an explanation for a milder phenotype in the first-described patient.Pediatr Res. 2019 Feb;85(3):384-389. doi: 10.1038/s41390-018-0231-5. Epub 2018 Nov 12.
• [5] ALG8-CDG: novel patients and review of the literature. Orphanet J Rare Dis. 2015 Jun 12;10:73. doi: 10.1186/s13023-015-0289-7.
• [6] PKD2 founder mutation is the most common mutation of polycystic kidney disease in Taiwan. NPJ Genom Med. 2022 Jul 1;7(1):40. doi: 10.1038/s41525-022-00309-w.
• [7] Genetics of polycystic liver diseases.Curr Opin Gastroenterol. 2019 Mar;35(2):65-72. doi: 10.1097/MOG.0000000000000514.
• [8] 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.
• [9] 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.
• [10] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [11] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [12] 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.
• [13] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [14] 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.
• [15] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [16] 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.
• [17] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [18] 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.
• [19] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [20] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.