Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT8U672K)

• DOT Name: Exostosin-like 2 (EXTL2)
• Synonyms: EC 2.4.1.223; Alpha-1,4-N-acetylhexosaminyltransferase EXTL2; Alpha-GalNAcT EXTL2; EXT-related protein 2; Glucuronyl-galactosyl-proteoglycan 4-alpha-N-acetylglucosaminyltransferase
• Gene Name: EXTL2
• Related Disease:
  Chronic kidney disease
  Mucopolysaccharidosis
  Mucopolysaccharidosis type 3A
  Mucopolysaccharidosis type 3C
  Neoplasm
  Osteopetrosis
• UniProt ID: EXTL2_HUMAN
• EC Number: 2.4.1.223
• Pfam ID: PF09258
• Sequence:
  MRCCHICKLPGRVMGIRVLRLSLVVILVLLLVAGALTALLPSVKEDKMLMLRREIKSQGK
  STMDSFTLIMQTYNRTDLLLKLLNHYQAVPNLHKVIVVWNNIGEKAPDELWNSLGPHPIP
  VIFKQQTANRMRNRLQVFPELETNAVLMVDDDTLISTPDLVFAFSVWQQFPDQIVGFVPR
  KHVSTSSGIYSYGSFEMQAPGSGNGDQYSMVLIGASFFNSKYLELFQRQPAAVHALIDDT
  QNCDDIAMNFIIAKHIGKTSGIFVKPVNMDNLEKETNSGYSGMWHRAEHALQRSYCINKL
  VNIYDSMPLRYSNIMISQFGFPYANYKRKI
• Function: Glycosyltransferase required for the biosynthesis of heparan-sulfate and responsible for the alternating addition of beta-1-4-linked glucuronic acid (GlcA) and alpha-1-4-linked N-acetylglucosamine (GlcNAc) units to nascent heparan sulfate chains.
• Tissue Specificity: Ubiquitous.
• KEGG Pathway:
  Glycosaminoglycan biosynthesis - heparan sulfate / heparin (hsa00534)
  Metabolic pathways (hsa01100)
• Reactome Pathway: XBP1(S) activates chaperone genes (R-HSA-381038)
• BioCyc Pathway: MetaCyc:HS08719-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Chronic kidney disease	DISW82R7	Strong	Biomarker	[1]
Mucopolysaccharidosis	DISB083T	Limited	Biomarker	[2]
Mucopolysaccharidosis type 3A	DIS2TLNF	Limited	Altered Expression	[2]
Mucopolysaccharidosis type 3C	DISH5D5W	Limited	Biomarker	[3]
Neoplasm	DISZKGEW	Limited	Altered Expression	[4]
Osteopetrosis	DIS7GHNM	Limited	Biomarker	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Mitoxantrone	DMM39BF	Approved	Exostosin-like 2 (EXTL2) affects the response to substance of Mitoxantrone.	[15]

1 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 Exostosin-like 2 (EXTL2).	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Exostosin-like 2 (EXTL2).	[6]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Exostosin-like 2 (EXTL2).	[7]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Exostosin-like 2 (EXTL2).	[8]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Exostosin-like 2 (EXTL2).	[9]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Exostosin-like 2 (EXTL2).	[10]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Exostosin-like 2 (EXTL2).	[11]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Exostosin-like 2 (EXTL2).	[12]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Exostosin-like 2 (EXTL2).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Exostosin-like 2 (EXTL2).	[14]

References

• [1] EXTL2 controls liver regeneration and aortic calcification through xylose kinase-dependent regulation of glycosaminoglycan biosynthesis.Matrix Biol. 2014 Apr;35:18-24. doi: 10.1016/j.matbio.2013.10.010. Epub 2013 Oct 24.
• [2] Gene silencing of EXTL2 and EXTL3 as a substrate deprivation therapy for heparan sulphate storing mucopolysaccharidoses.Eur J Hum Genet. 2010 Feb;18(2):194-9. doi: 10.1038/ejhg.2009.143. Epub 2009 Aug 19.
• [3] EXTL2 and EXTL3 inhibition with siRNAs as a promising substrate reduction therapy for Sanfilippo C syndrome.Sci Rep. 2015 Sep 8;5:13654. doi: 10.1038/srep13654.
• [4] Structure, chromosomal location, and expression profile of EXTR1 and EXTR2, new members of the multiple exostoses gene family.Biochem Biophys Res Commun. 1998 Feb 4;243(1):61-6. doi: 10.1006/bbrc.1997.8062.
• [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] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [8] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [9] 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.
• [10] 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.
• [11] 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.
• [12] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [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] Isobaric tags for relative and absolute quantitation-based proteomics analysis of the effect of ginger oil on bisphenol A-induced breast cancer cell proliferation. Oncol Lett. 2021 Feb;21(2):101. doi: 10.3892/ol.2020.12362. Epub 2020 Dec 8.
• [15] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.