Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTUH7H9F)

• DOT Name: Xylosyl- and glucuronyltransferase LARGE1 (LARGE1)
• Synonyms: EC 2.4.-.-; Acetylglucosaminyltransferase-like 1A; Glycosyltransferase-like protein; LARGE xylosyl- and glucuronyltransferase 1
• Gene Name: LARGE1
• Related Disease:
  Diabetic kidney disease
  Muscular dystrophy-dystroglycanopathy type B6
  Non-insulin dependent diabetes
  Becker muscular dystrophy
  Central core myopathy
  Congenital fiber-type disproportion myopathy
  Congenital muscular dystrophy
  Congenital myopathy
  Duchenne muscular dystrophy
  Intellectual disability
  Limb-girdle muscular dystrophy due to POMK deficiency
  Liver cancer
  Major depressive disorder
  Multiminicore myopathy
  Muscle-eye-brain disease
  Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A6
  Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B2
  Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B3
  Myeloid leukaemia
  Nemaline myopathy
  Neoplasm
  Meningioma
  Rhabdomyosarcoma
  Congenital muscular dystrophy with intellectual disability
  Muscular dystrophy-dystroglycanopathy, type A
  Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 4
• UniProt ID: LARG1_HUMAN
• PDB ID: 7UI6; 7UI7; 7ZVJ
• EC Number: 2.4.-.-; 2.4.1.-; 2.4.2.-
• Pfam ID: PF13896 ; PF01501
• Sequence:
  MLGICRGRRKFLAASLSLLCIPAITWIYLFSGSFEDGKPVSLSPLESQAHSPRYTASSQR
  ERESLEVRMREVEEENRALRRQLSLAQGRAPSHRRGNHSKTYSMEEGTGDSENLRAGIVA
  GNSSECGQQPVVEKCETIHVAIVCAGYNASRDVVTLVKSVLFHRRNPLHFHLIADSIAEQ
  ILATLFQTWMVPAVRVDFYNADELKSEVSWIPNKHYSGIYGLMKLVLTKTLPANLERVIV
  LDTDITFATDIAELWAVFHKFKGQQVLGLVENQSDWYLGNLWKNHRPWPALGRGYNTGVI
  LLLLDKLRKMKWEQMWRLTAERELMGMLSTSLADQDIFNAVIKQNPFLVYQLPCFWNVQL
  SDHTRSEQCYRDVSDLKVIHWNSPKKLRVKNKHVEFFRNLYLTFLEYDGNLLRRELFGCP
  SEADVNSENLQKQLSELDEDDLCYEFRRERFTVHRTHLYFLHYEYEPAADSTDVTLVAQL
  SMDRLQMLEAICKHWEGPISLALYLSDAEAQQFLRYAQGSEVLMSRHNVGYHIVYKEGQF
  YPVNLLRNVAMKHISTPYMFLSDIDFLPMYGLYEYLRKSVIQLDLANTKKAMIVPAFETL
  RYRLSFPKSKAELLSMLDMGTLFTFRYHVWTKGHAPTNFAKWRTATTPYRVEWEADFEPY
  VVVRRDCPEYDRRFVGFGWNKVAHIMELDVQEYEFIVLPNAYMIHMPHAPSFDITKFRSN
  KQYRICLKTLKEEFQQDMSRRYGFAALKYLTAENNS
• Function: Bifunctional glycosyltransferase with both alpha-1,3-xylosyltransferase and beta-1,3-glucuronyltransferase activities involved in the maturation of alpha-dystroglycan (DAG1) by glycosylation leading to DAG1 binding to laminin G-like domain-containing extracellular proteins with high affinity. Elongates the glucuronyl-beta-1,4-xylose-beta disaccharide primer structure initiated by B4GAT1 by adding repeating units [-3-Xylose-alpha-1,3-GlcA-beta-1-] to produce a heteropolysaccharide. Requires the phosphorylation of core M3 (O-mannosyl trisaccharide) by POMK to elongate the glucuronyl-beta-1,4-xylose-beta disaccharide primer. Plays a key role in skeletal muscle function and regeneration.
• Tissue Specificity: Ubiquitous. Highest expression in heart, brain and skeletal muscle.
• KEGG Pathway:
  Mannose type O-glycan biosynthesis (hsa00515)
  Metabolic pathways (hsa01100)
• Reactome Pathway:
  O-linked glycosylation (R-HSA-5173105)
  Defective LARGE causes MDDGA6 and MDDGB6 (R-HSA-5083627)
• BioCyc Pathway: MetaCyc:ENSG00000133424-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

26 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Diabetic kidney disease	DISJMWEY	Definitive	Genetic Variation	[1]
Muscular dystrophy-dystroglycanopathy type B6	DISITWWS	Definitive	Autosomal recessive	[2]
Non-insulin dependent diabetes	DISK1O5Z	Definitive	Genetic Variation	[3]
Becker muscular dystrophy	DIS5IYHL	Strong	Altered Expression	[4]
Central core myopathy	DIS18AZZ	Strong	Biomarker	[5]
Congenital fiber-type disproportion myopathy	DISU9T2M	Strong	Biomarker	[5]
Congenital muscular dystrophy	DISKY7OY	Strong	Genetic Variation	[6]
Congenital myopathy	DISLSK9G	Strong	Biomarker	[5]
Duchenne muscular dystrophy	DISRQ3NV	Strong	Altered Expression	[4]
Intellectual disability	DISMBNXP	Strong	Biomarker	[6]
Limb-girdle muscular dystrophy due to POMK deficiency	DISM63SY	Strong	Biomarker	[5]
Liver cancer	DISDE4BI	Strong	Biomarker	[7]
Major depressive disorder	DIS4CL3X	Strong	Genetic Variation	[8]
Multiminicore myopathy	DISE6VYN	Strong	Biomarker	[5]
Muscle-eye-brain disease	DISJUOQB	Strong	Biomarker	[6]
Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A6	DIS459QE	Strong	Autosomal recessive	[9]
Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B2	DIS2BGID	Strong	Biomarker	[5]
Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B3	DISSP7OL	Strong	Biomarker	[5]
Myeloid leukaemia	DISMN944	Strong	Biomarker	[10]
Nemaline myopathy	DIS5IYLY	Strong	Biomarker	[5]
Neoplasm	DISZKGEW	Strong	Biomarker	[11]
Meningioma	DISPT4TG	moderate	Biomarker	[12]
Rhabdomyosarcoma	DISNR7MS	moderate	Altered Expression	[13]
Congenital muscular dystrophy with intellectual disability	DISWHF75	Supportive	Autosomal recessive	[14]
Muscular dystrophy-dystroglycanopathy, type A	DISZTBC4	Supportive	Autosomal recessive	[15]
Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 4	DISGM0K5	Limited	Genetic Variation	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Methamphetamine	DMPM4SK	Approved	Xylosyl- and glucuronyltransferase LARGE1 (LARGE1) affects the response to substance of Methamphetamine.	[26]

8 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 Xylosyl- and glucuronyltransferase LARGE1 (LARGE1).	[17]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Xylosyl- and glucuronyltransferase LARGE1 (LARGE1).	[18]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Xylosyl- and glucuronyltransferase LARGE1 (LARGE1).	[19]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Xylosyl- and glucuronyltransferase LARGE1 (LARGE1).	[20]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Xylosyl- and glucuronyltransferase LARGE1 (LARGE1).	[21]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Xylosyl- and glucuronyltransferase LARGE1 (LARGE1).	[22]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Xylosyl- and glucuronyltransferase LARGE1 (LARGE1).	[23]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Xylosyl- and glucuronyltransferase LARGE1 (LARGE1).	[24]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Xylosyl- and glucuronyltransferase LARGE1 (LARGE1).	[25]

References

• [1] A genome-wide association study for diabetic nephropathy genes in African Americans.Kidney Int. 2011 Mar;79(5):563-72. doi: 10.1038/ki.2010.467. Epub 2010 Dec 8.
• [2] Mutations in the human LARGE gene cause MDC1D, a novel form of congenital muscular dystrophy with severe mental retardation and abnormal glycosylation of alpha-dystroglycan. Hum Mol Genet. 2003 Nov 1;12(21):2853-61. doi: 10.1093/hmg/ddg307. Epub 2003 Sep 9.
• [3] Identification of novel high-impact recessively inherited type 2 diabetes risk variants in the Greenlandic population.Diabetologia. 2018 Sep;61(9):2005-2015. doi: 10.1007/s00125-018-4659-2. Epub 2018 Jun 20.
• [4] LARGE expression in different types of muscular dystrophies other than dystroglycanopathy.BMC Neurol. 2018 Dec 15;18(1):207. doi: 10.1186/s12883-018-1207-0.
• [5] Ocular abnormalities in Large(myd) and Large(vls) mice, spontaneous models for muscle, eye, and brain diseases.Mol Cell Neurosci. 2005 Oct;30(2):160-72. doi: 10.1016/j.mcn.2005.07.009.
• [6] Congenital muscular dystrophy type 1D (MDC1D) due to a large intragenic insertion/deletion, involving intron 10 of the LARGE gene.Eur J Hum Genet. 2011 Apr;19(4):452-7. doi: 10.1038/ejhg.2010.212. Epub 2011 Jan 19.
• [7] Multiple genes exhibit phenobarbital-induced constitutive active/androstane receptor-mediated DNA methylation changes during liver tumorigenesis and in liver tumors.Toxicol Sci. 2009 Apr;108(2):273-89. doi: 10.1093/toxsci/kfp031. Epub 2009 Feb 20.
• [8] Identification of 15 genetic loci associated with risk of major depression in individuals of European descent.Nat Genet. 2016 Sep;48(9):1031-6. doi: 10.1038/ng.3623. Epub 2016 Aug 1.
• [9] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [10] Optical computed tomography for spatially isotropic four-dimensional imaging of live single cells.Sci Adv. 2017 Dec 6;3(12):e1602580. doi: 10.1126/sciadv.1602580. eCollection 2017 Dec.
• [11] Macrophage depletion using clodronate liposomes decreases tumorigenesis and alters gut microbiota in the AOM/DSS mouse model of colon cancer.Am J Physiol Gastrointest Liver Physiol. 2018 Jan 1;314(1):G22-G31. doi: 10.1152/ajpgi.00229.2017. Epub 2017 Oct 12.
• [12] The human LARGE gene from 22q12.3-q13.1 is a new, distinct member of the glycosyltransferase gene family.Proc Natl Acad Sci U S A. 1999 Jan 19;96(2):598-603. doi: 10.1073/pnas.96.2.598.
• [13] Exogenous expression of the glycosyltransferase LARGE1 restores -dystroglycan matriglycan and laminin binding in rhabdomyosarcoma.Skelet Muscle. 2019 May 4;9(1):11. doi: 10.1186/s13395-019-0195-0.
• [14] Dystroglycanopathies: coming into focus. Curr Opin Genet Dev. 2011 Jun;21(3):278-85. doi: 10.1016/j.gde.2011.02.001. Epub 2011 Mar 11.
• [15] Intragenic rearrangements in LARGE and POMGNT1 genes in severe dystroglycanopathies. Neuromuscul Disord. 2011 Nov;21(11):782-90. doi: 10.1016/j.nmd.2011.06.001. Epub 2011 Jul 2.
• [16] The role of defective glycosylation in congenital muscular dystrophy.Glycoconj J. 2004;20(5):291-300. doi: 10.1023/B:GLYC.0000033626.65127.e4.
• [17] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [18] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [19] 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.
• [20] 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.
• [21] 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.
• [22] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [23] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [24] 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.
• [25] 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.
• [26] Genome-wide association for methamphetamine dependence: convergent results from 2 samples. Arch Gen Psychiatry. 2008 Mar;65(3):345-55. doi: 10.1001/archpsyc.65.3.345.