Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTOW778B)

• DOT Name: Presenilin-2 (PSEN2)
• Synonyms: PS-2; EC 3.4.23.-; AD3LP; AD5; E5-1; STM-2
• Gene Name: PSEN2
• Related Disease:
  Alzheimer disease 4
  Early-onset autosomal dominant Alzheimer disease
  Obsolete familial isolated dilated cardiomyopathy
  Dilated cardiomyopathy
• UniProt ID: PSN2_HUMAN
• PDB ID: 7Y5X; 7Y5Z
• EC Number: 3.4.23.-
• Pfam ID: PF01080
• Sequence:
  MLTFMASDSEEEVCDERTSLMSAESPTPRSCQEGRQGPEDGENTAQWRSQENEEDGEEDP
  DRYVCSGVPGRPPGLEEELTLKYGAKHVIMLFVPVTLCMIVVVATIKSVRFYTEKNGQLI
  YTPFTEDTPSVGQRLLNSVLNTLIMISVIVVMTIFLVVLYKYRCYKFIHGWLIMSSLMLL
  FLFTYIYLGEVLKTYNVAMDYPTLLLTVWNFGAVGMVCIHWKGPLVLQQAYLIMISALMA
  LVFIKYLPEWSAWVILGAISVYDLVAVLCPKGPLRMLVETAQERNEPIFPALIYSSAMVW
  TVGMAKLDPSSQGALQLPYDPEMEEDSYDSFGEPSYPEVFEPPLTGYPGEELEEEEERGV
  KLGLGDFIFYSVLVGKAAATGSGDWNTTLACFVAILIGLCLTLLLLAVFKKALPALPISI
  TFGLIFYFSTDNLVRPFMDTLASHQLYI
• Function: Probable catalytic subunit of the gamma-secretase complex, an endoprotease complex that catalyzes the intramembrane cleavage of integral membrane proteins such as Notch receptors and APP (amyloid-beta precursor protein). Requires the other members of the gamma-secretase complex to have a protease activity. May play a role in intracellular signaling and gene expression or in linking chromatin to the nuclear membrane. May function in the cytoplasmic partitioning of proteins. The holoprotein functions as a calcium-leak channel that allows the passive movement of calcium from endoplasmic reticulum to cytosol and is involved in calcium homeostasis. Is a regulator of mitochondrion-endoplasmic reticulum membrane tethering and modulates calcium ions shuttling between ER and mitochondria.
• Tissue Specificity: Isoform 1 is seen in the placenta, skeletal muscle and heart while isoform 2 is seen in the heart, brain, placenta, liver, skeletal muscle and kidney.
• KEGG Pathway:
  Notch sig.ling pathway (hsa04330)
  Neurotrophin sig.ling pathway (hsa04722)
  Alzheimer disease (hsa05010)
  Pathways of neurodegeneration - multiple diseases (hsa05022)
• Reactome Pathway:
  Regulated proteolysis of p75NTR (R-HSA-193692)
  NRIF signals cell death from the nucleus (R-HSA-205043)
  Activated NOTCH1 Transmits Signal to the Nucleus (R-HSA-2122948)
  Constitutive Signaling by NOTCH1 PEST Domain Mutants (R-HSA-2644606)
  Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants (R-HSA-2894862)
  NOTCH2 Activation and Transmission of Signal to the Nucleus (R-HSA-2979096)
  EPH-ephrin mediated repulsion of cells (R-HSA-3928665)
  NOTCH3 Activation and Transmission of Signal to the Nucleus (R-HSA-9013507)
  NOTCH4 Activation and Transmission of Signal to the Nucleus (R-HSA-9013700)
  Noncanonical activation of NOTCH3 (R-HSA-9017802)
  Nuclear signaling by ERBB4 (R-HSA-1251985)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alzheimer disease 4	DISY96OF	Strong	Autosomal dominant	[1]
Early-onset autosomal dominant Alzheimer disease	DISFAUJO	Supportive	Autosomal dominant	[2]
Obsolete familial isolated dilated cardiomyopathy	DIS4FXO4	Supportive	Autosomal dominant	[3]
Dilated cardiomyopathy	DISX608J	Limited	Autosomal dominant	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Presenilin-2 (PSEN2).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Presenilin-2 (PSEN2).	[6]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Presenilin-2 (PSEN2).	[7]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Presenilin-2 (PSEN2).	[9]
Niclosamide	DMJAGXQ	Approved	Niclosamide decreases the expression of Presenilin-2 (PSEN2).	[10]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of Presenilin-2 (PSEN2).	[11]
Enzalutamide	DMGL19D	Approved	Enzalutamide affects the expression of Presenilin-2 (PSEN2).	[12]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of Presenilin-2 (PSEN2).	[13]
Nimesulide	DMR1NMD	Terminated	Nimesulide decreases the activity of Presenilin-2 (PSEN2).	[15]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of Presenilin-2 (PSEN2).	[16]
Glyphosate	DM0AFY7	Investigative	Glyphosate decreases the expression of Presenilin-2 (PSEN2).	[17]
Taurine	DMVW7N3	Investigative	Taurine decreases the expression of Presenilin-2 (PSEN2).	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Quercetin	DM3NC4M	Approved	Quercetin decreases the phosphorylation of Presenilin-2 (PSEN2).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Presenilin-2 (PSEN2).	[14]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Presenilin-2 (PSEN2).	[8]

References

• [1] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [2] Early-Onset Familial Alzheimer Disease C RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY. 1999 Sep 24 [updated 2012 Oct 18]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(?) [Internet]. Seattle (WA): University of Washington, Seattle; 1993C2024.
• [3] Mutations of presenilin genes in dilated cardiomyopathy and heart failure. Am J Hum Genet. 2006 Dec;79(6):1030-9. doi: 10.1086/509900. Epub 2006 Oct 24.
• [4] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [5] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [6] 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.
• [7] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [8] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [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] 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.
• [11] Cannabidiol Modulates the Expression of Alzheimer's Disease-Related Genes in Mesenchymal Stem Cells. Int J Mol Sci. 2016 Dec 23;18(1):26. doi: 10.3390/ijms18010026.
• [12] NOTCH signaling is activated in and contributes to resistance in enzalutamide-resistant prostate cancer cells. J Biol Chem. 2019 May 24;294(21):8543-8554. doi: 10.1074/jbc.RA118.006983. Epub 2019 Apr 2.
• [13] Estrogenic and antiestrogenic properties of resveratrol in mammary tumor models. Cancer Res. 2001 Oct 15;61(20):7456-63.
• [14] 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.
• [15] Inhibition of cyclooxygenase as potential novel therapeutic strategy in N141I presenilin-2 familial Alzheimer's disease. Mol Psychiatry. 2006 Feb;11(2):172-81. doi: 10.1038/sj.mp.4001773.
• [16] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.
• [17] Glyphosate-based herbicides at low doses affect canonical pathways in estrogen positive and negative breast cancer cell lines. PLoS One. 2019 Jul 11;14(7):e0219610. doi: 10.1371/journal.pone.0219610. eCollection 2019.
• [18] Taurine-responsive genes related to signal transduction as identified by cDNA microarray analyses of HepG2 cells. J Med Food. 2006 Spring;9(1):33-41. doi: 10.1089/jmf.2006.9.33.