Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTMSNY9N)

• DOT Name: Exostosin-like 1 (EXTL1)
• Synonyms: EC 2.4.1.224; Exostosin-L; Glucuronosyl-N-acetylglucosaminyl-proteoglycan 4-alpha-N-acetylglucosaminyltransferase; Multiple exostosis-like protein
• Gene Name: EXTL1
• Related Disease:
  Neoplasm
  Advanced cancer
• UniProt ID: EXTL1_HUMAN
• EC Number: 2.4.1.224
• Pfam ID: PF03016 ; PF09258
• Sequence:
  MQSWRRRKSLWLALSASWLLLVLLGGFSLLRLALPPRPRPGASQGWPRWLDAELLQSFSQ
  PGELPEDAVSPPQAPHGGSCNWESCFDTSKCRGDGLKVFVYPAVGTISETHRRILASIEG
  SRFYTFSPAGACLLLLLSLDAQTGECSSMPLQWNRGRNHLVLRLHPAPCPRTFQLGQAMV
  AEASPTVDSFRPGFDVALPFLPEAHPLRGGAPGQLRQHSPQPGVALLALEEERGGWRTAD
  TGSSACPWDGRCEQDPGPGQTQRQETLPNATFCLISGHRPEAASRFLQALQAGCIPVLLS
  PRWELPFSEVIDWTKAAIVADERLPLQVLAALQEMSPARVLALRQQTQFLWDAYFSSVEK
  VIHTTLEVIQDRIFGTSAHPSLLWNSPPGALLALSTFSTSPQDFPFYYLQQGSRPEGRFS
  ALIWVGPPGQPPLKLIQAVAGSQHCAQILVLWSNERPLPSRWPETAVPLTVIDGHRKVSD
  RFYPYSTIRTDAILSLDARSSLSTSEVDFAFLVWQSFPERMVGFLTSSHFWDEAHGGWGY
  TAERTNEFSMVLTTAAFYHRYYHTLFTHSLPKALRTLADEAPTCVDVLMNFIVAAVTKLP
  PIKVPYGKQRQEAAPLAPGGPGPRPKPPAPAPDCINQIAAAFGHMPLLSSRLRLDPVLFK
  DPVSVQRKKYRSLEKP
• Function: Glycosyltransferase required for the biosynthesis of heparan-sulfate (HS). Transfers N-acetyl-alpha-D-glucosamine to the nascent HS chain (GlcNAcT-II activity). Appears to lack GlcNAcT I and GlcAT-II activities.
• KEGG Pathway:
  Glycosaminoglycan biosynthesis - heparan sulfate / heparin (hsa00534)
  Metabolic pathways (hsa01100)
• Reactome Pathway: XBP1(S) activates chaperone genes (R-HSA-381038)
• BioCyc Pathway: MetaCyc:HS08259-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neoplasm	DISZKGEW	moderate	Genetic Variation	[1]
Advanced cancer	DISAT1Z9	Limited	Posttranslational Modification	[2]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Temozolomide	DMKECZD	Approved	Exostosin-like 1 (EXTL1) affects the response to substance of Temozolomide.	[12]
DTI-015	DMXZRW0	Approved	Exostosin-like 1 (EXTL1) affects the response to substance of DTI-015.	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Exostosin-like 1 (EXTL1).	[3]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Exostosin-like 1 (EXTL1).	[6]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Exostosin-like 1 (EXTL1).	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Exostosin-like 1 (EXTL1).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Exostosin-like 1 (EXTL1).	[5]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Exostosin-like 1 (EXTL1).	[7]
Ethanol	DMDRQZU	Approved	Ethanol increases the expression of Exostosin-like 1 (EXTL1).	[8]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Exostosin-like 1 (EXTL1).	[9]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Exostosin-like 1 (EXTL1).	[10]

References

• [1] Molecular analysis of the putative tumour-suppressor gene EXTL1 in neuroblastoma patients and cell lines.Eur J Cancer. 2004 May;40(8):1255-61. doi: 10.1016/j.ejca.2004.01.013.
• [2] The DNA methylation profile of liver tumors in C3H mice and identification of differentially methylated regions involved in the regulation of tumorigenic genes.BMC Cancer. 2018 Mar 22;18(1):317. doi: 10.1186/s12885-018-4221-0.
• [3] 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.
• [4] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [5] 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.
• [6] 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.
• [7] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [8] Gene expression signatures after ethanol exposure in differentiating embryoid bodies. Toxicol In Vitro. 2018 Feb;46:66-76.
• [9] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [10] 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.
• [11] 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.
• [12] Tumor necrosis factor-alpha-induced protein 3 as a putative regulator of nuclear factor-kappaB-mediated resistance to O6-alkylating agents in human glioblastomas. J Clin Oncol. 2006 Jan 10;24(2):274-87. doi: 10.1200/JCO.2005.02.9405. Epub 2005 Dec 19.