Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT03MYQ2)

• DOT Name: Palmitoleoyl-protein carboxylesterase NOTUM (NOTUM)
• Synonyms: EC 3.1.1.98; hNOTUM
• Gene Name: NOTUM
• Related Disease:
  Bilateral renal agenesis
  Renal agenesis
  Renal hypodysplasia/aplasia 1
  Colorectal carcinoma
  Hepatocellular carcinoma
• UniProt ID: NOTUM_HUMAN
• PDB ID: 4UYU ; 4UYW ; 4UYZ ; 4UZ1 ; 4UZ5 ; 4UZ6 ; 4UZ7 ; 4UZ9 ; 4UZA ; 4UZL ; 4UZQ ; 4WBH ; 6R8P ; 6R8Q ; 6R8R ; 6T2H ; 6T2K ; 6TR5 ; 6TR6 ; 6TR7 ; 6TUZ ; 6TV4 ; 6YSK ; 6YUW ; 6YUY ; 6YV0 ; 6YV2 ; 6YV4 ; 6YXI ; 6ZUV ; 6ZVL ; 6ZYF ; 7ARG ; 7B2V ; 7B2Y ; 7B2Z ; 7B37 ; 7B3F ; 7B3G ; 7B3H ; 7B3I ; 7B3P ; 7B3X ; 7B45 ; 7B4X ; 7B50 ; 7B7W ; 7B7X ; 7B7Y ; 7B84 ; 7B86 ; 7B87 ; 7B89 ; 7B8A ; 7B8C ; 7B8D ; 7B8F ; 7B8G ; 7B8J ; 7B8K ; 7B8L ; 7B8M ; 7B8N ; 7B8O ; 7B8U ; 7B8X ; 7B8Y ; 7B8Z ; 7B98 ; 7B99 ; 7B9D ; 7B9I ; 7B9N ; 7B9U ; 7BA1 ; 7BAC ; 7BAP ; 7BC8 ; 7BC9 ; 7BCC ; 7BCD ; 7BCF ; 7BCH ; 7BCI ; 7BCK ; 7BCL ; 7BD2 ; 7BD3 ; 7BD4 ; 7BD5 ; 7BD6 ; 7BD8 ; 7BD9 ; 7BDA ; 7BDB ; 7BDC ; 7BDD ; 7BDF ; 7BDG ; 7BDH ; 7BLI ; 7BLS ; 7BLT ; 7BLU ; 7BLW ; 7BM1 ; 7BM3 ; 7BM7 ; 7BMB ; 7BMD ; 7BN5 ; 7BN8 ; 7BNB ; 7BNC ; 7BND ; 7BNE ; 7BNF ; 7BNJ ; 7BNL ; 7BO1 ; 7BO2 ; 7BO5 ; 7PJR ; 7PK3 ; 7PKV ; 7QVZ ; 8BSP ; 8BSQ ; 8BSR ; 8BSZ ; 8BT0 ; 8BT2 ; 8BT5 ; 8BT7 ; 8BT8 ; 8BTA ; 8BTC ; 8BTE ; 8BTH ; 8BTI
• EC Number: 3.1.1.98
• Pfam ID: PF03283
• Sequence:
  MGRGVRVLLLLSLLHCAGGSEGRKTWRRRGQQPPPPPRTEAAPAAGQPVESFPLDFTAVE
  GNMDSFMAQVKSLAQSLYPCSAQQLNEDLRLHLLLNTSVTCNDGSPAGYYLKESRGSRRW
  LLFLEGGWYCFNRENCDSRYDTMRRLMSSRDWPRTRTGTGILSSQPEENPYWWNANMVFI
  PYCSSDVWSGASSKSEKNEYAFMGALIIQEVVRELLGRGLSGAKVLLLAGSSAGGTGVLL
  NVDRVAEQLEKLGYPAIQVRGLADSGWFLDNKQYRHTDCVDTITCAPTEAIRRGIRYWNG
  VVPERCRRQFQEGEEWNCFFGYKVYPTLRCPVFVVQWLFDEAQLTVDNVHLTGQPVQEGL
  RLYIQNLGRELRHTLKDVPASFAPACLSHEIIIRSHWTDVQVKGTSLPRALHCWDRSLHD
  SHKASKTPLKGCPVHLVDSCPWPHCNPSCPTVRDQFTGQEMNVAQFLMHMGFDMQTVAQP
  QGLEPSELLGMLSNGS
• Function: Carboxylesterase that acts as a key negative regulator of the Wnt signaling pathway by specifically mediating depalmitoleoylation of WNT proteins. Serine palmitoleoylation of WNT proteins is required for efficient binding to frizzled receptors.
• Tissue Specificity: Rarely expressed in adult normal tissues.
• KEGG Pathway: Wnt sig.ling pathway (hsa04310)
• Reactome Pathway:
  Release of Hh-Np from the secreting cell (R-HSA-5362798)
  Post-translational protein phosphorylation (R-HSA-8957275)
  Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) (R-HSA-381426)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Bilateral renal agenesis	DISOR5IA	Definitive	Biomarker	[1]
Renal agenesis	DIS0M9AF	Definitive	Biomarker	[1]
Renal hypodysplasia/aplasia 1	DISOH8XN	Definitive	Biomarker	[1]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[2]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[3]

2 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 Palmitoleoyl-protein carboxylesterase NOTUM (NOTUM).	[4]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Palmitoleoyl-protein carboxylesterase NOTUM (NOTUM).	[8]

7 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 Palmitoleoyl-protein carboxylesterase NOTUM (NOTUM).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Palmitoleoyl-protein carboxylesterase NOTUM (NOTUM).	[6]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Palmitoleoyl-protein carboxylesterase NOTUM (NOTUM).	[7]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Palmitoleoyl-protein carboxylesterase NOTUM (NOTUM).	[9]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Palmitoleoyl-protein carboxylesterase NOTUM (NOTUM).	[10]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Palmitoleoyl-protein carboxylesterase NOTUM (NOTUM).	[11]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Palmitoleoyl-protein carboxylesterase NOTUM (NOTUM).	[12]

References

• [1] Dentin Dysplasia in Notum Knockout Mice.Vet Pathol. 2016 Jul;53(4):853-62. doi: 10.1177/0300985815626778. Epub 2016 Feb 29.
• [2] NOTUM Is Involved in the Progression of Colorectal Cancer.Cancer Genomics Proteomics. 2018 Nov-Dec;15(6):485-497. doi: 10.21873/cgp.20107.
• [3] Human homolog of NOTUM, overexpressed in hepatocellular carcinoma, is regulated transcriptionally by beta-catenin/TCF.Cancer Sci. 2008 Jun;99(6):1139-46. doi: 10.1111/j.1349-7006.2008.00814.x. Epub 2008 Apr 21.
• [4] 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.
• [5] 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.
• [6] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [7] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [8] 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.
• [9] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [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] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.
• [12] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.