Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT2BRUBN)

• DOT Name: Exostosin-like 3 (EXTL3)
• Synonyms: EC 2.4.1.223; EXT-related protein 1; Glucuronyl-galactosyl-proteoglycan 4-alpha-N-acetylglucosaminyltransferase; Hereditary multiple exostoses gene isolog; Multiple exostosis-like protein 3; Putative tumor suppressor protein EXTL3
• Gene Name: EXTL3
• Related Disease:
  Head and neck cancer
  Head and neck carcinoma
  Lung cancer
  Brain cancer
  Breast cancer
  Breast carcinoma
  Cocaine addiction
  Endometriosis
  Exostosis
  Glioblastoma multiforme
  Immunoskeletal dysplasia with neurodevelopmental abnormalities
  Osteochondrodysplasia
  Pyle disease
  Sarcoma
  Severe combined immunodeficiency
  Sexually transmitted infection
  Skeletal dysplasia
  Soft tissue sarcoma
  Tuberculosis
  Uveitis
  Acute myelogenous leukaemia
  Colorectal neoplasm
  Lung carcinoma
  Mucopolysaccharidosis
  Mucopolysaccharidosis type 3A
  Mucopolysaccharidosis type 3C
  Non-small-cell lung cancer
  Osteopetrosis
  Secondary syphilis
  Syphilis
• UniProt ID: EXTL3_HUMAN
• PDB ID: 7AU2; 7AUA; 8OG1; 8OG4
• EC Number: 2.4.1.223
• Pfam ID: PF03016 ; PF09258
• Sequence:
  MTGYTMLRNGGAGNGGQTCMLRWSNRIRLTWLSFTLFVILVFFPLIAHYYLTTLDEADEA
  GKRIFGPRVGNELCEVKHVLDLCRIRESVSEELLQLEAKRQELNSEIAKLNLKIEACKKS
  IENAKQDLLQLKNVISQTEHSYKELMAQNQPKLSLPIRLLPEKDDAGLPPPKATRGCRLH
  NCFDYSRCPLTSGFPVYVYDSDQFVFGSYLDPLVKQAFQATARANVYVTENADIACLYVI
  LVGEMQEPVVLRPAELEKQLYSLPHWRTDGHNHVIINLSRKSDTQNLLYNVSTGRAMVAQ
  STFYTVQYRPGFDLVVSPLVHAMSEPNFMEIPPQVPVKRKYLFTFQGEKIESLRSSLQEA
  RSFEEEMEGDPPADYDDRIIATLKAVQDSKLDQVLVEFTCKNQPKPSLPTEWALCGERED
  RLELLKLSTFALIITPGDPRLVISSGCATRLFEALEVGAVPVVLGEQVQLPYQDMLQWNE
  AALVVPKPRVTEVHFLLRSLSDSDLLAMRRQGRFLWETYFSTADSIFNTVLAMIRTRIQI
  PAAPIREEAAAEIPHRSGKAAGTDPNMADNGDLDLGPVETEPPYASPRYLRNFTLTVTDF
  YRSWNCAPGPFHLFPHTPFDPVLPSEAKFLGSGTGFRPIGGGAGGSGKEFQAALGGNVPR
  EQFTVVMLTYEREEVLMNSLERLNGLPYLNKVVVVWNSPKLPSEDLLWPDIGVPIMVVRT
  EKNSLNNRFLPWNEIETEAILSIDDDAHLRHDEIMFGFRVWREARDRIVGFPGRYHAWDI
  PHQSWLYNSNYSCELSMVLTGAAFFHKYYAYLYSYVMPQAIRDMVDEYINCEDIAMNFLV
  SHITRKPPIKVTSRWTFRCPGCPQALSHDDSHFHERHKCINFFVKVYGYMPLLYTQFRVD
  SVLFKTRLPHDKTKCFKFI
• Function: Glycosyltransferase which regulates the biosynthesis of heparan sulfate (HS). Initiates HS synthesis by transferring the first N-acetyl-alpha-D-glucosamine (alpha-GlcNAc) residue (GlcNAcT-I activity) to the tetrasaccharide linker (GlcA-Gal-Gal-Xyl-)Ser core linker. May also transfer alpha-GlcNAc residues during HS elongation (GlcNAcT-II activity). Lacks glucuronyl transferase II (GlcAT-II) activity. Important for both skeletal development and hematopoiesis, through the formation of HS proteoglycans (HSPGs). Through the synthesis of HS, regulates postnatal pancreatic islet maturation and insulin secretion; Receptor for REG3A, REG3B and REG3G, induces the activation of downstream signaling pathways such as PI3K-AKT or RAS-RAF-MEK-ERK signaling pathway. Required for the function of REG3A in regulating keratinocyte proliferation and differentiation. Required for the inhibition of skin inflammation mediated by REGA through the activation of PI3K-AKT-STAT3 pathway. Required for the function of REGA and REG3G in glucose tolerance in pancreas. Expressed in microglia, is activated by nociceptor-derived REG3G in response to endotoxins, leading to the inhibition of kynurenine pathway to prevent endotoxic death.
• Tissue Specificity: Ubiquitous. Expressed in keratinocytes. Expressed in pancreas .
• KEGG Pathway:
  Glycosaminoglycan biosynthesis - heparan sulfate / heparin (hsa00534)
  Metabolic pathways (hsa01100)
• Reactome Pathway: XBP1(S) activates chaperone genes (R-HSA-381038)
• BioCyc Pathway: MetaCyc:HS00333-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

30 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Head and neck cancer	DISBPSQZ	Definitive	Biomarker	[1]
Head and neck carcinoma	DISOU1DS	Definitive	Biomarker	[1]
Lung cancer	DISCM4YA	Definitive	Biomarker	[1]
Brain cancer	DISBKFB7	Strong	Biomarker	[2]
Breast cancer	DIS7DPX1	Strong	Biomarker	[3]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[3]
Cocaine addiction	DISHTRXG	Strong	Biomarker	[4]
Endometriosis	DISX1AG8	Strong	Biomarker	[5]
Exostosis	DIS3VKEI	Strong	Biomarker	[6]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[2]
Immunoskeletal dysplasia with neurodevelopmental abnormalities	DISHQP40	Strong	Autosomal recessive	[7]
Osteochondrodysplasia	DIS9SPWW	Strong	Genetic Variation	[7]
Pyle disease	DISJ2YQ3	Strong	Genetic Variation	[8]
Sarcoma	DISZDG3U	Strong	Altered Expression	[9]
Severe combined immunodeficiency	DIS6MF4Q	Strong	Biomarker	[7]
Sexually transmitted infection	DISIVIAL	Strong	Biomarker	[10]
Skeletal dysplasia	DIS5Z8U6	Strong	Genetic Variation	[7]
Soft tissue sarcoma	DISSN8XB	Strong	Altered Expression	[9]
Tuberculosis	DIS2YIMD	Strong	Biomarker	[11]
Uveitis	DISV0RYS	Strong	Biomarker	[12]
Acute myelogenous leukaemia	DISCSPTN	moderate	Genetic Variation	[13]
Colorectal neoplasm	DISR1UCN	moderate	Altered Expression	[14]
Lung carcinoma	DISTR26C	Limited	Biomarker	[2]
Mucopolysaccharidosis	DISB083T	Limited	Biomarker	[15]
Mucopolysaccharidosis type 3A	DIS2TLNF	Limited	Altered Expression	[15]
Mucopolysaccharidosis type 3C	DISH5D5W	Limited	Biomarker	[16]
Non-small-cell lung cancer	DIS5Y6R9	Limited	Biomarker	[17]
Osteopetrosis	DIS7GHNM	Limited	Biomarker	[18]
Secondary syphilis	DISXOVHB	Limited	Biomarker	[19]
Syphilis	DISJ73BS	Limited	Biomarker	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Exostosin-like 3 (EXTL3).	[21]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Exostosin-like 3 (EXTL3).	[22]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Exostosin-like 3 (EXTL3).	[23]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Exostosin-like 3 (EXTL3).	[24]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Exostosin-like 3 (EXTL3).	[26]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Exostosin-like 3 (EXTL3).	[25]

References

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• [2] INGN 201: Ad-p53, Ad5CMV-p53, Adenoviral p53, INGN 101, p53 gene therapy--Introgen, RPR/INGN 201.BioDrugs. 2003;17(3):216-22. doi: 10.2165/00063030-200317030-00010.
• [3] Tumor suppression and therapy sensitization of localized and metastatic breast cancer by adenovirus p53.Hum Gene Ther. 2001 May 1;12(7):763-72. doi: 10.1089/104303401750148685.
• [4] A cholecystokinin B receptor antagonist and cocaine interaction, phase I study.CNS Neurosci Ther. 2019 Jan;25(1):136-146. doi: 10.1111/cns.12994. Epub 2018 Jun 20.
• [5] EXTL3-interacting endometriosis-specific serum factors induce colony formation of endometrial stromal cells.Sci Rep. 2019 Aug 29;9(1):12562. doi: 10.1038/s41598-019-48840-8.
• [6] EXTL3 promoter methylation down-regulates EXTL3 and heparan sulphate expression in mucinous colorectal cancers.J Pathol. 2008 Sep;216(1):32-42. doi: 10.1002/path.2377.
• [7] Mutations in EXTL3 Cause Neuro-immuno-skeletal Dysplasia Syndrome. Am J Hum Genet. 2017 Feb 2;100(2):281-296. doi: 10.1016/j.ajhg.2017.01.013. Epub 2017 Jan 26.
• [8] Identification of biallelic EXTL3 mutations in a novel type of spondylo-epi-metaphyseal dysplasia.J Hum Genet. 2017 Aug;62(8):797-801. doi: 10.1038/jhg.2017.38. Epub 2017 Mar 23.
• [9] Chondroitin sulfate synthase 1 expression is associated with malignant potential of soft tissue sarcomas with myxoid substance.Hum Pathol. 2016 Apr;50:15-23. doi: 10.1016/j.humpath.2015.11.005. Epub 2015 Nov 22.
• [10] The PICASSO Cohort: baseline characteristics of a cohort of men who have sex with men and male-to-female transgender women at high risk for syphilis infection in Lima, Peru.BMC Infect Dis. 2017 Apr 11;17(1):255. doi: 10.1186/s12879-017-2332-x.
• [11] Migration and health: A retrospective study about the prevalence of HBV, HIV, HCV, tuberculosis and syphilis infections amongst newly arrived migrants screened at the Infectious Diseases Unit of Modena, Italy.J Infect Public Health. 2019 Mar-Apr;12(2):200-204. doi: 10.1016/j.jiph.2018.10.004. Epub 2018 Oct 28.
• [12] Neurosyphilis cerebrospinal fluid findings in patients with ocular syphilis.Ocul Immunol Inflamm. 2021 Jan 2;29(1):95-101. doi: 10.1080/09273948.2019.1672193. Epub 2019 Oct 24.
• [13] Genome-wide haplotype association study identify the FGFR2 gene as a risk gene for acute myeloid leukemia.Oncotarget. 2017 Jan 31;8(5):7891-7899. doi: 10.18632/oncotarget.13631.
• [14] Dysregulation of Reg gene expression occurs early in gastrointestinal tumorigenesis and regulates anti-apoptotic genes.Cancer Biol Ther. 2006 Dec;5(12):1714-20. doi: 10.4161/cbt.5.12.3469. Epub 2006 Dec 30.
• [15] 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.
• [16] 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.
• [17] Adenovirus-mediated wild-type p53 gene expression radiosensitizes non-small cell lung cancer cells but not normal lung fibroblasts.Int J Radiat Biol. 2001 Feb;77(2):185-94. doi: 10.1080/09553000010008540.
• [18] 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.
• [19] Sensitive detection of Treponema pallidum DNA from the whole blood of patients with syphilis by the nested PCR assay.Emerg Microbes Infect. 2018 May 9;7(1):83. doi: 10.1038/s41426-018-0085-2.
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• [21] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [22] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [23] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [24] Changes in gene expressions elicited by physiological concentrations of genistein on human endometrial cancer cells. Mol Carcinog. 2006 Oct;45(10):752-63.
• [25] 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.
• [26] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.