Details of Drug Off-Target (DOT)

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

• DOT Name: Xylosyltransferase 1
• Synonyms: EC 2.4.2.26; Peptide O-xylosyltransferase 1; Xylosyltransferase I; XT-I; XylT-I
• Gene Name: XYLT1
• Related Disease:
  Desbuquois dysplasia 2
  Desbuquois dysplasia
  XYLT1-congenital disorder of glycosylation
• UniProt ID: XYLT1_HUMAN
• PDB ID: 6EJ7; 6EJ8; 6EJ9; 6EJA; 6EJB; 6EJC; 6EJD; 6EJE; 6FOA
• EC Number: 2.4.2.26
• Pfam ID: PF02485 ; PF12529
• Sequence:
  MVAAPCARRLARRSHSALLAALTVLLLQTLVVWNFSSLDSGAGERRGGAAVGGGEQPPPA
  PAPRRERRDLPAEPAAARGGGGGGGGGGGGRGPQARARGGGPGEPRGQQPASRGALPARA
  LDPHPSPLITLETQDGYFSHRPKEKVRTDSNNENSVPKDFENVDNSNFAPRTQKQKHQPE
  LAKKPPSRQKELLKRKLEQQEKGKGHTFPGKGPGEVLPPGDRAAANSSHGKDVSRPPHAR
  KTGGSSPETKYDQPPKCDISGKEAISALSRAKSKHCRQEIGETYCRHKLGLLMPEKVTRF
  CPLEGKANKNVQWDEDSVEYMPANPVRIAFVLVVHGRASRQLQRMFKAIYHKDHFYYIHV
  DKRSNYLHRQVLQVSRQYSNVRVTPWRMATIWGGASLLSTYLQSMRDLLEMTDWPWDFFI
  NLSAADYPIRTNDQLVAFLSRYRDMNFLKSHGRDNARFIRKQGLDRLFLECDAHMWRLGD
  RRIPEGIAVDGGSDWFLLNRRFVEYVTFSTDDLVTKMKQFYSYTLLPAESFFHTVLENSP
  HCDTMVDNNLRITNWNRKLGCKCQYKHIVDWCGCSPNDFKPQDFHRFQQTARPTFFARKF
  EAVVNQEIIGQLDYYLYGNYPAGTPGLRSYWENVYDEPDGIHSLSDVTLTLYHSFARLGL
  RRAETSLHTDGENSCRYYPMGHPASVHLYFLADRFQGFLIKHHATNLAVSKLETLETWVM
  PKKVFKIASPPSDFGRLQFSEVGTDWDAKERLFRNFGGLLGPMDEPVGMQKWGKGPNVTV
  TVIWVDPVNVIAATYDILIESTAEFTHYKPPLNLPLRPGVWTVKILHHWVPVAETKFLVA
  PLTFSNRQPIKPEEALKLHNGPLRNAYMEQSFQSLNPVLSLPINPAQVEQARRNAASTGT
  ALEGWLDSLVGGMWTAMDICATGPTACPVMQTCSQTAWSSFSPDPKSELGAVKPDGRLR
• Function: Catalyzes the first step in the biosynthesis of chondroitin sulfate and dermatan sulfate proteoglycans, such as DCN. Transfers D-xylose from UDP-D-xylose to specific serine residues of the core protein. Required for normal embryonic and postnatal skeleton development, especially of the long bones. Required for normal maturation of chondrocytes during bone development, and normal onset of ossification.
• Tissue Specificity: Widely expressed. Expressed at higher level in placenta, kidney and pancreas. Weakly expressed in skeletal muscle.
• KEGG Pathway:
  Glycosaminoglycan biosynthesis - chondroitin sulfate / dermatan sulfate (hsa00532)
  Glycosaminoglycan biosynthesis - heparan sulfate / heparin (hsa00534)
  Metabolic pathways (hsa01100)
• Reactome Pathway: A tetrasaccharide linker sequence is required for GAG synthesis (R-HSA-1971475)
• BioCyc Pathway: MetaCyc:HS02509-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Desbuquois dysplasia 2	DIS26XB7	Strong	Autosomal recessive	[1]
Desbuquois dysplasia	DISCBF04	Supportive	Autosomal recessive	[2]
XYLT1-congenital disorder of glycosylation	DISV90RW	Supportive	Autosomal recessive	[3]

11 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 Xylosyltransferase 1.	[4]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Xylosyltransferase 1.	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Xylosyltransferase 1.	[6]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Xylosyltransferase 1.	[7]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Xylosyltransferase 1.	[9]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Xylosyltransferase 1.	[10]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Xylosyltransferase 1.	[11]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Xylosyltransferase 1.	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Xylosyltransferase 1.	[14]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Xylosyltransferase 1.	[15]
Microcystin-LR	DMTMLRN	Investigative	Microcystin-LR decreases the expression of Xylosyltransferase 1.	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Xylosyltransferase 1.	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Xylosyltransferase 1.	[12]

References

• [1] GGC Repeat Expansion and Exon 1 Methylation of XYLT1 Is a Common Pathogenic Variant in Baratela-Scott Syndrome. Am J Hum Genet. 2019 Jan 3;104(1):35-44. doi: 10.1016/j.ajhg.2018.11.005. Epub 2018 Dec 13.
• [2] XYLT1 mutations in Desbuquois dysplasia type 2. Am J Hum Genet. 2014 Mar 6;94(3):405-14. doi: 10.1016/j.ajhg.2014.01.020. Epub 2014 Feb 27.
• [3] The missing "link": an autosomal recessive short stature syndrome caused by a hypofunctional XYLT1 mutation. Hum Genet. 2014 Jan;133(1):29-39. doi: 10.1007/s00439-013-1351-y. Epub 2013 Aug 27.
• [4] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [5] 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.
• [6] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [7] Epidermal growth factor receptor signalling in human breast cancer cells operates parallel to estrogen receptor alpha signalling and results in tamoxifen insensitive proliferation. BMC Cancer. 2014 Apr 23;14:283.
• [8] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [9] 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.
• [10] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [11] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [12] 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.
• [13] 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.
• [14] Environmental pollutant induced cellular injury is reflected in exosomes from placental explants. Placenta. 2020 Jan 1;89:42-49. doi: 10.1016/j.placenta.2019.10.008. Epub 2019 Oct 17.
• [15] 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.
• [16] Gene expression network regulated by DNA methylation and microRNA during microcystin-leucine arginine induced malignant transformation in human hepatocyte L02 cells. Toxicol Lett. 2018 Jun 1;289:42-53. doi: 10.1016/j.toxlet.2018.03.003. Epub 2018 Mar 5.