Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTQTO7VU)

• DOT Name: Ribitol-5-phosphate xylosyltransferase 1 (RXYLT1)
• Synonyms: EC 2.4.2.61; Transmembrane protein 5; UDP-D-xylose:ribitol-5-phosphate beta1,4-xylosyltransferase
• Gene Name: RXYLT1
• Related Disease:
  Muscle-eye-brain disease
  Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type a, 10
  Congenital disorder of glycosylation
  Muscular dystrophy
  Neural tube defect
  Cobblestone lissencephaly
  Muscular dystrophy-dystroglycanopathy, type A
• UniProt ID: RXLT1_HUMAN
• EC Number: 2.4.2.61
• Sequence:
  MRLTRKRLCSFLIALYCLFSLYAAYHVFFGRRRQAPAGSPRGLRKGAAPARERRGREQST
  LESEEWNPWEGDEKNEQQHRFKTSLQILDKSTKGKTDLSVQIWGKAAIGLYLWEHIFEGL
  LDPSDVTAQWREGKSIVGRTQYSFITGPAVIPGYFSVDVNNVVLILNGREKAKIFYATQW
  LLYAQNLVQIQKLQHLAVVLLGNEHCDNEWINPFLKRNGGFVELLFIIYDSPWINDVDVF
  QWPLGVATYRNFPVVEASWSMLHDERPYLCNFLGTIYENSSRQALMNILKKDGNDKLCWV
  SAREHWQPQETNESLKNYQDALLQSDLTLCPVGVNTECYRIYEACSYGSIPVVEDVMTAG
  NCGNTSVHHGAPLQLLKSMGAPFIFIKNWKELPAVLEKEKTIILQEKIERRKMLLQWYQH
  FKTELKMKFTNILESSFLMNNKS
• Function: Acts as a UDP-D-xylose:ribitol-5-phosphate beta1,4-xylosyltransferase, which catalyzes the transfer of UDP-D-xylose to ribitol 5-phosphate (Rbo5P) to form the Xylbeta1-4Rbo5P linkage on O-mannosyl glycan (Probable). Participates in the biosynthesis of the phosphorylated O-mannosyl trisaccharide (N-acetylgalactosamine-beta-3-N-acetylglucosamine-beta-4-(phosphate-6-)mannose), a carbohydrate structure present in alpha-dystroglycan (DAG1), which is required for binding laminin G-like domain-containing extracellular proteins with high affinity (Probable).
• KEGG Pathway:
  Mannose type O-glycan biosynthesis (hsa00515)
  Metabolic pathways (hsa01100)
• BioCyc Pathway: MetaCyc:ENSG00000118600-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
Muscle-eye-brain disease	DISJUOQB	Definitive	Autosomal recessive	[1]
Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type a, 10	DIS6L2RX	Definitive	Autosomal recessive	[2]
Congenital disorder of glycosylation	DIS400QP	Strong	Biomarker	[3]
Muscular dystrophy	DISJD6P7	Strong	Biomarker	[4]
Neural tube defect	DIS5J95E	Strong	Genetic Variation	[2]
Cobblestone lissencephaly	DIS56826	moderate	Genetic Variation	[2]
Muscular dystrophy-dystroglycanopathy, type A	DISZTBC4	Supportive	Autosomal recessive	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Ribitol-5-phosphate xylosyltransferase 1 (RXYLT1).	[5]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Ribitol-5-phosphate xylosyltransferase 1 (RXYLT1).	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Ribitol-5-phosphate xylosyltransferase 1 (RXYLT1).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Ribitol-5-phosphate xylosyltransferase 1 (RXYLT1).	[7]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Ribitol-5-phosphate xylosyltransferase 1 (RXYLT1).	[8]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Ribitol-5-phosphate xylosyltransferase 1 (RXYLT1).	[10]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Ribitol-5-phosphate xylosyltransferase 1 (RXYLT1).	[11]
Deguelin	DMXT7WG	Investigative	Deguelin increases the expression of Ribitol-5-phosphate xylosyltransferase 1 (RXYLT1).	[12]

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] Identification of mutations in TMEM5 and ISPD as a cause of severe cobblestone lissencephaly. Am J Hum Genet. 2012 Dec 7;91(6):1135-43. doi: 10.1016/j.ajhg.2012.10.009.
• [3] What is new in CDG?.J Inherit Metab Dis. 2017 Jul;40(4):569-586. doi: 10.1007/s10545-017-0050-6. Epub 2017 May 8.
• [4] The Muscular Dystrophy Gene TMEM5 Encodes a Ribitol 1,4-Xylosyltransferase Required for the Functional Glycosylation of Dystroglycan.J Biol Chem. 2016 Nov 18;291(47):24618-24627. doi: 10.1074/jbc.M116.751917. Epub 2016 Oct 12.
• [5] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [6] 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.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] 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.
• [9] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [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] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [12] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.