Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTOH9PMY)

• DOT Name: Putative bifunctional UDP-N-acetylglucosamine transferase and deubiquitinase ALG13 (ALG13)
• Synonyms: EC 2.4.1.141; EC 3.4.19.12; Asparagine-linked glycosylation 13 homolog; Glycosyltransferase 28 domain-containing protein 1; UDP-N-acetylglucosamine transferase subunit ALG13 homolog
• Gene Name: ALG13
• Related Disease:
  Infantile spasm
  West syndrome
  Choreatic disease
  Congenital disorder of glycosylation
  Developmental and epileptic encephalopathy, 36
  Epilepsy
  Hypophosphatemia
  Intellectual disability, X-linked 1
  Neurodevelopmental disorder
  Non-small-cell lung cancer
  Intellectual disability
  Non-syndromic X-linked intellectual disability
• UniProt ID: ALG13_HUMAN
• EC Number: 2.4.1.141; 3.4.19.12
• Pfam ID: PF04101 ; PF02338
• Sequence:
  MKCVFVTVGTTSFDDLIACVSAPDSLQKIESLGYNRLILQIGRGTVVPEPFSTESFTLDV
  YRYKDSLKEDIQKADLVISHAGAGSCLETLEKGKPLVVVINEKLMNNHQLELAKQLHKEG
  HLFYCTCRVLTCPGQAKSIASAPGKCQDSAALTSTAFSGLDFGLLSGYLHKQALVTATHP
  TCTLLFPSCHAFFPLPLTPTLYKMHKGWKNYCSQKSLNEASMDEYLGSLGLFRKLTAKDA
  SCLFRAISEQLFCSQVHHLEIRKACVSYMRENQQTFESYVEGSFEKYLERLGDPKESAGQ
  LEIRALSLIYNRDFILYRFPGKPPTYVTDNGYEDKILLCYSSSGHYDSVYSKQFQSSAAV
  CQAVLYEILYKDVFVVDEEELKTAIKLFRSGSKKNRNNAVTGSEDAHTDYKSSNQNRMEE
  WGACYNAENIPEGYNKGTEETKSPENPSKMPFPYKVLKALDPEIYRNVEFDVWLDSRKEL
  QKSDYMEYAGRQYYLGDKCQVCLESEGRYYNAHIQEVGNENNSVTVFIEELAEKHVVPLA
  NLKPVTQVMSVPAWNAMPSRKGRGYQKMPGGYVPEIVISEMDIKQQKKMFKKIRGKEVYM
  TMAYGKGDPLLPPRLQHSMHYGHDPPMHYSQTAGNVMSNEHFHPQHPSPRQGRGYGMPRN
  SSRFINRHNMPGPKVDFYPGPGKRCCQSYDNFSYRSRSFRRSHRQMSCVNKESQYGFTPG
  NGQMPRGLEETITFYEVEEGDETAYPTLPNHGGPSTMVPATSGYCVGRRGHSSGKQTLNL
  EEGNGQSENGRYHEEYLYRAEPDYETSGVYSTTASTANLSLQDRKSCSMSPQDTVTSYNY
  PQKMMGNIAAVAASCANNVPAPVLSNGAAANQAISTTSVSSQNAIQPLFVSPPTHGRPVI
  ASPSYPCHSAIPHAGASLPPPPPPPPPPPPPPPPPPPPPPPPPPPALDVGETSNLQPPPP
  LPPPPYSCDPSGSDLPQDTKVLQYYFNLGLQCYYHSYWHSMVYVPQMQQQLHVENYPVYT
  EPPLVDQTVPQCYSEVRREDGIQAEASANDTFPNADSSSVPHGAVYYPVMSDPYGQPPLP
  GFDSCLPVVPDYSCVPPWHPVGTAYGGSSQIHGAINPGPIGCIAPSPPASHYVPQGM
• Function: [Isoform 1]: Possible multifunctional enzyme with both glycosyltransferase and deubiquitinase activities.; [Isoform 2]: May be involved in protein N-glycosylation, second step of the dolichol-linked oligosaccharide pathway.
• KEGG Pathway:
  N-Glycan biosynthesis (hsa00510)
  Various types of N-glycan biosynthesis (hsa00513)
  Metabolic pathways (hsa01100)
• Reactome Pathway:
  Defective ALG14 causes ALG14-CMS (R-HSA-5633231)
  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

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Infantile spasm	DISZSKDG	Definitive	X-linked	[1]
West syndrome	DISLIAU9	Definitive	Genetic Variation	[2]
Choreatic disease	DISH8K3M	Strong	CausalMutation	[3]
Congenital disorder of glycosylation	DIS400QP	Strong	Genetic Variation	[4]
Developmental and epileptic encephalopathy, 36	DISG4MY5	Strong	X-linked	[5]
Epilepsy	DISBB28L	Strong	Biomarker	[6]
Hypophosphatemia	DIS9DZYF	Strong	CausalMutation	[3]
Intellectual disability, X-linked 1	DISET38E	Strong	GermlineCausalMutation	[4]
Neurodevelopmental disorder	DIS372XH	Strong	Biomarker	[7]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[8]
Intellectual disability	DISMBNXP	moderate	Biomarker	[9]
Non-syndromic X-linked intellectual disability	DIS71AI3	Supportive	X-linked	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Putative bifunctional UDP-N-acetylglucosamine transferase and deubiquitinase ALG13 (ALG13).	[10]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Putative bifunctional UDP-N-acetylglucosamine transferase and deubiquitinase ALG13 (ALG13).	[11]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Putative bifunctional UDP-N-acetylglucosamine transferase and deubiquitinase ALG13 (ALG13).	[12]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Putative bifunctional UDP-N-acetylglucosamine transferase and deubiquitinase ALG13 (ALG13).	[13]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Putative bifunctional UDP-N-acetylglucosamine transferase and deubiquitinase ALG13 (ALG13).	[14]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Putative bifunctional UDP-N-acetylglucosamine transferase and deubiquitinase ALG13 (ALG13).	[15]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Putative bifunctional UDP-N-acetylglucosamine transferase and deubiquitinase ALG13 (ALG13).	[16]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of Putative bifunctional UDP-N-acetylglucosamine transferase and deubiquitinase ALG13 (ALG13).	[19]

2 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Putative bifunctional UDP-N-acetylglucosamine transferase and deubiquitinase ALG13 (ALG13).	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Putative bifunctional UDP-N-acetylglucosamine transferase and deubiquitinase ALG13 (ALG13).	[18]

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] Whole-exome sequencing improves the diagnosis yield in sporadic infantile spasm syndrome.Clin Genet. 2016 Feb;89(2):198-204. doi: 10.1111/cge.12636. Epub 2015 Jul 30.
• [3] De novo mutations in epileptic encephalopathies. Nature. 2013 Sep 12;501(7466):217-21. doi: 10.1038/nature12439. Epub 2013 Aug 11.
• [4] X chromosome exome sequencing reveals a novel ALG13 mutation in a nonsyndromic intellectual disability family with multiple affected male siblings. Am J Med Genet A. 2014 Jan;164A(1):164-9. doi: 10.1002/ajmg.a.36233.
• [5] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [6] ALG13 Deficiency Associated with Increased Seizure Susceptibility and Severity.Neuroscience. 2019 Jun 15;409:204-221. doi: 10.1016/j.neuroscience.2019.03.009. Epub 2019 Mar 12.
• [7] De novo variants in neurodevelopmental disorders with epilepsy.Nat Genet. 2018 Jul;50(7):1048-1053. doi: 10.1038/s41588-018-0143-7. Epub 2018 Jun 25.
• [8] Distinct expression and prognostic value of OTU domain-containing proteins in non-small-cell lung cancer.Oncol Lett. 2019 Nov;18(5):5417-5427. doi: 10.3892/ol.2019.10883. Epub 2019 Sep 19.
• [9] Advantages and pitfalls of an extended gene panel for investigating complex neurometabolic phenotypes.Brain. 2016 Nov 1;139(11):2844-2854. doi: 10.1093/brain/aww221.
• [10] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [11] 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.
• [12] 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.
• [13] Arsenic suppresses gene expression in promyelocytic leukemia cells partly through Sp1 oxidation. Blood. 2005 Jul 1;106(1):304-10.
• [14] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [15] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [16] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [17] 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.
• [18] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [19] Ochratoxin a lowers mRNA levels of genes encoding for key proteins of liver cell metabolism. Cancer Genomics Proteomics. 2008 Nov-Dec;5(6):319-32.