Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT5BZS3J)

• DOT Name: Xylosyl- and glucuronyltransferase LARGE2 (LARGE2)
• Synonyms: EC 2.4.-.-; Glycosyltransferase-like 1B; LARGE xylosyl- and glucuronyltransferase 2
• Gene Name: LARGE2
• Related Disease:
  Clear cell renal carcinoma
  Muscular dystrophy
  Myocardial infarction
  Prostate cancer
  Prostate carcinoma
  Transitional cell carcinoma
  Urothelial carcinoma
• UniProt ID: LARG2_HUMAN
• EC Number: 2.4.-.-; 2.4.1.-; 2.4.2.-
• Pfam ID: PF13896 ; PF01501
• Sequence:
  MLPRGRPRALGAAALLLLLLLLGFLLFGGDLGCERREPGGRAGAPGCFPGPLMPRVPPDG
  RLRRAAALDGDPGAGPGDHNRSDCGPQPPPPPKCELLHVAIVCAGHNSSRDVITLVKSML
  FYRKNPLHLHLVTDAVARNILETLFHTWMVPAVRVSFYHADQLKPQVSWIPNKHYSGLYG
  LMKLVLPSALPAELARVIVLDTDVTFASDISELWALFAHFSDTQAIGLVENQSDWYLGNL
  WKNHRPWPALGRGFNTGVILLRLDRLRQAGWEQMWRLTARRELLSLPATSLADQDIFNAV
  IKEHPGLVQRLPCVWNVQLSDHTLAERCYSEASDLKVIHWNSPKKLRVKNKHVEFFRNFY
  LTFLEYDGNLLRRELFVCPSQPPPGAEQLQQALAQLDEEDPCFEFRQQQLTVHRVHVTFL
  PHEPPPPRPHDVTLVAQLSMDRLQMLEALCRHWPGPMSLALYLTDAEAQQFLHFVEASPV
  LAARQDVAYHVVYREGPLYPVNQLRNVALAQALTPYVFLSDIDFLPAYSLYDYLRASIEQ
  LGLGSRRKAALVVPAFETLRYRFSFPHSKVELLALLDAGTLYTFRYHEWPRGHAPTDYAR
  WREAQAPYRVQWAANYEPYVVVPRDCPRYDPRFVGFGWNKVAHIVELDAQEYELLVLPEA
  FTIHLPHAPSLDISRFRSSPTYRDCLQALKDEFHQDLSRHHGAAALKYLPALQQPQSPAR
  G
• 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 and in a phosphorylated-O-mannosyl trisaccharide dependent manner. Elongates the glucuronyl-beta-1,4-xylose-beta disaccharide primer structure by adding repeating units [-3-Xylose-alpha-1,3-GlcA-beta-1-] to produce a heteropolysaccharide. Supports the maturation of DAG1 more effectively than LARGE1. In addition, can modify both heparan sulfate (HS)- and chondroitin/dermatan sulfate (CS/DS)-proteoglycans (PGs), namely GPC4, with a glycosaminoglycan (GAG)-like polysaccharide composed of xylose and glucuronic acid to confer laminin binding.
• Tissue Specificity: Widely expressed. Expressed at high level in placenta, pancreas and kidney compared to LARGE. Not expressed in brain.
• KEGG Pathway:
  Mannose type O-glycan biosynthesis (hsa00515)
  Metabolic pathways (hsa01100)
• Reactome Pathway: O-linked glycosylation (R-HSA-5173105)
• BioCyc Pathway: MetaCyc:ENSG00000165905-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Clear cell renal carcinoma	DISBXRFJ	Strong	Altered Expression	[1]
Muscular dystrophy	DISJD6P7	Strong	Biomarker	[2]
Myocardial infarction	DIS655KI	Strong	Genetic Variation	[3]
Prostate cancer	DISF190Y	Strong	Altered Expression	[4]
Prostate carcinoma	DISMJPLE	Strong	Altered Expression	[4]
Transitional cell carcinoma	DISWVVDR	Strong	Biomarker	[5]
Urothelial carcinoma	DISRTNTN	Strong	Biomarker	[5]

3 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 Xylosyl- and glucuronyltransferase LARGE2 (LARGE2).	[6]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of Xylosyl- and glucuronyltransferase LARGE2 (LARGE2).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Xylosyl- and glucuronyltransferase LARGE2 (LARGE2).	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic increases the methylation of Xylosyl- and glucuronyltransferase LARGE2 (LARGE2).	[7]
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Xylosyl- and glucuronyltransferase LARGE2 (LARGE2).	[9]

References

• [1] Downregulation of dystroglycan glycosyltransferases LARGE2 and ISPD associate with increased mortality in clear cell renal cell carcinoma.Mol Cancer. 2015 Jul 30;14:141. doi: 10.1186/s12943-015-0416-z.
• [2] Localization and functional analysis of the LARGE family of glycosyltransferases: significance for muscular dystrophy.Hum Mol Genet. 2005 Mar 1;14(5):657-65. doi: 10.1093/hmg/ddi062. Epub 2005 Jan 20.
• [3] Association of a polymorphism of BTN2A1 with myocardial infarction in East Asian populations.Atherosclerosis. 2011 Mar;215(1):145-52. doi: 10.1016/j.atherosclerosis.2010.12.005. Epub 2010 Dec 15.
• [4] The glycosyltransferase LARGE2 is repressed by Snail and ZEB1 in prostate cancer.Cancer Biol Ther. 2015;16(1):125-36. doi: 10.4161/15384047.2014.987078.
• [5] Ureteroscopic Management of Large ? cm Upper Tract Urothelial Carcinoma: A Comprehensive 23-Year Experience.Urology. 2018 Nov;121:66-73. doi: 10.1016/j.urology.2018.05.042. Epub 2018 Jun 30.
• [6] Antiepileptic drugs are endocrine disruptors for the human fetal testis ex vivo. Toxicol Sci. 2023 Sep 28;195(2):169-183. doi: 10.1093/toxsci/kfad076.
• [7] Effect of prenatal arsenic exposure on DNA methylation and leukocyte subpopulations in cord blood. Epigenetics. 2014 May;9(5):774-82. doi: 10.4161/epi.28153. Epub 2014 Feb 13.
• [8] Endometrial receptivity is affected in women with high circulating progesterone levels at the end of the follicular phase: a functional genomics analysis. Hum Reprod. 2011 Jul;26(7):1813-25.
• [9] 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.
• [10] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.