Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTKL39RT)

• DOT Name: Presenilin-1 (PSEN1)
• Synonyms: PS-1; EC 3.4.23.-; Protein S182
• Gene Name: PSEN1
• Related Disease:
  Alzheimer disease 3
  Pick disease
  Semantic dementia
  Behavioral variant of frontotemporal dementia
  Early-onset autosomal dominant Alzheimer disease
  Obsolete familial isolated dilated cardiomyopathy
  Dilated cardiomyopathy
  Acne inversa, familial, 3
  Dilated cardiomyopathy 1U
• UniProt ID: PSN1_HUMAN
• PDB ID: 2KR6; 4UIS; 5A63; 5FN2; 5FN3; 5FN4; 5FN5; 6IDF; 6IYC; 6LQG; 6LR4; 7C9I; 7D8X; 7Y5T
• EC Number: 3.4.23.-
• Pfam ID: PF01080
• Sequence:
  MTELPAPLSYFQNAQMSEDNHLSNTVRSQNDNRERQEHNDRRSLGHPEPLSNGRPQGNSR
  QVVEQDEEEDEELTLKYGAKHVIMLFVPVTLCMVVVVATIKSVSFYTRKDGQLIYTPFTE
  DTETVGQRALHSILNAAIMISVIVVMTILLVVLYKYRCYKVIHAWLIISSLLLLFFFSFI
  YLGEVFKTYNVAVDYITVALLIWNFGVVGMISIHWKGPLRLQQAYLIMISALMALVFIKY
  LPEWTAWLILAVISVYDLVAVLCPKGPLRMLVETAQERNETLFPALIYSSTMVWLVNMAE
  GDPEAQRRVSKNSKYNAESTERESQDTVAENDDGGFSEEWEAQRDSHLGPHRSTPESRAA
  VQELSSSILAGEDPEERGVKLGLGDFIFYSVLVGKASATASGDWNTTIACFVAILIGLCL
  TLLLLAIFKKALPALPISITFGLVFYFATDYLVQPFMDQLAFHQFYI
• Function: 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 presence of the other members of the gamma-secretase complex for protease activity. Plays a role in Notch and Wnt signaling cascades and regulation of downstream processes via its role in processing key regulatory proteins, and by regulating cytosolic CTNNB1 levels. Stimulates cell-cell adhesion via its interaction with CDH1; this stabilizes the complexes between CDH1 (E-cadherin) and its interaction partners CTNNB1 (beta-catenin), CTNND1 and JUP (gamma-catenin). Under conditions of apoptosis or calcium influx, cleaves CDH1. This promotes the disassembly of the complexes between CDH1 and CTNND1, JUP and CTNNB1, increases the pool of cytoplasmic CTNNB1, and thereby negatively regulates Wnt signaling. Required for normal embryonic brain and skeleton development, and for normal angiogenesis. Mediates the proteolytic cleavage of EphB2/CTF1 into EphB2/CTF2. The holoprotein functions as a calcium-leak channel that allows the passive movement of calcium from endoplasmic reticulum to cytosol and is therefore involved in calcium homeostasis. Involved in the regulation of neurite outgrowth. Is a regulator of presynaptic facilitation, spike transmission and synaptic vesicles replenishment in a process that depends on gamma-secretase activity. It acts through the control of SYT7 presynaptic expression.
• Tissue Specificity: Detected in azurophile granules in neutrophils and in platelet cytoplasmic granules (at protein level) . Expressed in a wide range of tissues including various regions of the brain, liver, spleen and lymph nodes .
• KEGG Pathway:
  Wnt sig.ling pathway (hsa04310)
  Notch sig.ling pathway (hsa04330)
  Neurotrophin sig.ling pathway (hsa04722)
  Alzheimer disease (hsa05010)
  Pathways of neurodegeneration - multiple diseases (hsa05022)
  Human papillomavirus infection (hsa05165)
• Reactome Pathway:
  Degradation of the extracellular matrix (R-HSA-1474228)
  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)
  Neutrophil degranulation (R-HSA-6798695)
  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

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alzheimer disease 3	DISVT69G	Strong	Autosomal dominant	[1]
Pick disease	DISP6X50	Strong	Autosomal dominant	[1]
Semantic dementia	DISA7775	Strong	Autosomal dominant	[1]
Behavioral variant of frontotemporal dementia	DISQHX2V	Supportive	Autosomal dominant	[2]
Early-onset autosomal dominant Alzheimer disease	DISFAUJO	Supportive	Autosomal dominant	[3]
Obsolete familial isolated dilated cardiomyopathy	DIS4FXO4	Supportive	Autosomal dominant	[4]
Dilated cardiomyopathy	DISX608J	Disputed	Autosomal dominant	[5]
Acne inversa, familial, 3	DIS6VM84	Limited	Autosomal dominant	[6]
Dilated cardiomyopathy 1U	DISOD6L1	Limited	Autosomal dominant	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Presenilin-1 (PSEN1).	[7]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Presenilin-1 (PSEN1).	[8]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Presenilin-1 (PSEN1).	[9]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Presenilin-1 (PSEN1).	[10]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Presenilin-1 (PSEN1).	[11]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of Presenilin-1 (PSEN1).	[12]
Bortezomib	DMNO38U	Approved	Bortezomib decreases the expression of Presenilin-1 (PSEN1).	[13]
Menthol	DMG2KW7	Approved	Menthol decreases the expression of Presenilin-1 (PSEN1).	[14]
Enzalutamide	DMGL19D	Approved	Enzalutamide affects the expression of Presenilin-1 (PSEN1).	[15]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Presenilin-1 (PSEN1).	[16]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Presenilin-1 (PSEN1).	[17]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Presenilin-1 (PSEN1).	[19]
SB-431542	DM0YOXQ	Preclinical	SB-431542 increases the expression of Presenilin-1 (PSEN1).	[20]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Presenilin-1 (PSEN1).	[22]
Deguelin	DMXT7WG	Investigative	Deguelin increases the expression of Presenilin-1 (PSEN1).	[23]
Paraquat	DMR8O3X	Investigative	Paraquat increases the expression of Presenilin-1 (PSEN1).	[24]
Phorbol 12,13-butyrate	DMZWTY7	Investigative	Phorbol 12,13-butyrate increases the expression of Presenilin-1 (PSEN1).	[8]

2 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 decreases the methylation of Presenilin-1 (PSEN1).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Presenilin-1 (PSEN1).	[21]

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] Dementia with prominent frontotemporal features associated with L113P presenilin 1 mutation. Neurology. 2000 Nov 28;55(10):1577-8. doi: 10.1212/wnl.55.10.1577.
• [3] 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.
• [4] 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.
• [5] 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.
• [6] Gamma-secretase gene mutations in familial acne inversa. Science. 2010 Nov 19;330(6007):1065. doi: 10.1126/science.1196284. Epub 2010 Oct 7.
• [7] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [8] Regulation of secretases by all-trans-retinoic acid. FEBS J. 2009 May;276(9):2645-55. doi: 10.1111/j.1742-4658.2009.06992.x. Epub 2009 Mar 25.
• [9] Increased mitochondrial ROS formation by acetaminophen in human hepatic cells is associated with gene expression changes suggesting disruption of the mitochondrial electron transport chain. Toxicol Lett. 2015 Apr 16;234(2):139-50.
• [10] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [11] Functional gene expression profile underlying methotrexate-induced senescence in human colon cancer cells. Tumour Biol. 2011 Oct;32(5):965-76.
• [12] 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.
• [13] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [14] Repurposing L-menthol for systems medicine and cancer therapeutics? L-menthol induces apoptosis through caspase 10 and by suppressing HSP90. OMICS. 2016 Jan;20(1):53-64.
• [15] 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.
• [16] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [17] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [18] 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.
• [19] BET bromodomain inhibition as a novel strategy for reactivation of HIV-1. J Leukoc Biol. 2012 Dec;92(6):1147-54. doi: 10.1189/jlb.0312165. Epub 2012 Jul 16.
• [20] Activin/nodal signaling switches the terminal fate of human embryonic stem cell-derived trophoblasts. J Biol Chem. 2015 Apr 3;290(14):8834-48.
• [21] 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.
• [22] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [23] 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.
• [24] Curcumin attenuates paraquat-induced cell death in human neuroblastoma cells through modulating oxidative stress and autophagy. Neurosci Lett. 2017 Jan 1;636:40-47. doi: 10.1016/j.neulet.2016.10.050. Epub 2016 Oct 26.