Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTO5YQVK)

• DOT Name: Beta-secretase 2 (BACE2)
• Synonyms: EC 3.4.23.45; Aspartic-like protease 56 kDa; Aspartyl protease 1; ASP1; Asp 1; Beta-site amyloid precursor protein cleaving enzyme 2; Beta-site APP cleaving enzyme 2; Down region aspartic protease; DRAP; Memapsin-1; Membrane-associated aspartic protease 1; Theta-secretase
• Gene Name: BACE2
• UniProt ID: BACE2_HUMAN
• PDB ID: 2EWY; 3ZKG; 3ZKI; 3ZKM; 3ZKN; 3ZKQ; 3ZKS; 3ZKX; 3ZL7; 3ZLQ; 4BEL; 4BFB; 6JSZ; 6UJ0; 6UJ1; 7D5B; 7D5U; 7F1G; 7N4N
• EC Number: 3.4.23.45
• Pfam ID: PF00026
• Sequence:
  MGALARALLLPLLAQWLLRAAPELAPAPFTLPLRVAAATNRVVAPTPGPGTPAERHADGL
  ALALEPALASPAGAANFLAMVDNLQGDSGRGYYLEMLIGTPPQKLQILVDTGSSNFAVAG
  TPHSYIDTYFDTERSSTYRSKGFDVTVKYTQGSWTGFVGEDLVTIPKGFNTSFLVNIATI
  FESENFFLPGIKWNGILGLAYATLAKPSSSLETFFDSLVTQANIPNVFSMQMCGAGLPVA
  GSGTNGGSLVLGGIEPSLYKGDIWYTPIKEEWYYQIEILKLEIGGQSLNLDCREYNADKA
  IVDSGTTLLRLPQKVFDAVVEAVARASLIPEFSDGFWTGSQLACWTNSETPWSYFPKISI
  YLRDENSSRSFRITILPQLYIQPMMGAGLNYECYRFGISPSTNALVIGATVMEGFYVIFD
  RAQKRVGFAASPCAEIAGAAVSEISGPFSTEDVASNCVPAQSLSEPILWIVSYALMSVCG
  AILLVLIVLLLLPFRCQRRPRDPEVVNDESSLVRHRWK
• Function: Responsible for the proteolytic processing of the amyloid precursor protein (APP). Cleaves APP, between residues 690 and 691, leading to the generation and extracellular release of beta-cleaved soluble APP, and a corresponding cell-associated C-terminal fragment which is later released by gamma-secretase. It has also been shown that it can cleave APP between residues 671 and 672. Involved in the proteolytic shedding of PMEL at early stages of melanosome biogenesis. Cleaves PMEL within the M-beta fragment to release the amyloidogenic PMEL luminal fragment containing M-alpha and a small portion of M-beta N-terminus. This is a prerequisite step for subsequent processing and assembly of PMEL fibrils into amyloid sheets. Responsible also for the proteolytic processing of CLTRN in pancreatic beta cells.
• Tissue Specificity: Brain. Present in neurons within the hippocampus, frontal cortex and temporal cortex (at protein level). Expressed at low levels in most peripheral tissues and at higher levels in colon, kidney, pancreas, placenta, prostate, stomach and trachea. Expressed at low levels in the brain. Found in spinal cord, medulla oblongata, substantia nigra and locus coruleus. Expressed in the ductal epithelium of both normal and malignant prostate.
• KEGG Pathway: Alzheimer disease (hsa05010)
• BioCyc Pathway: MetaCyc:G66-33964-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 3 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Etoposide	DMNH3PG	Approved	Beta-secretase 2 (BACE2) affects the response to substance of Etoposide.	[15]
Mitomycin	DMH0ZJE	Approved	Beta-secretase 2 (BACE2) affects the response to substance of Mitomycin.	[15]
Mitoxantrone	DMM39BF	Approved	Beta-secretase 2 (BACE2) affects the response to substance of Mitoxantrone.	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Beta-secretase 2 (BACE2).	[1]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Beta-secretase 2 (BACE2).	[11]

13 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 Beta-secretase 2 (BACE2).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Beta-secretase 2 (BACE2).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Beta-secretase 2 (BACE2).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Beta-secretase 2 (BACE2).	[5]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Beta-secretase 2 (BACE2).	[6]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Beta-secretase 2 (BACE2).	[7]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Beta-secretase 2 (BACE2).	[8]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Beta-secretase 2 (BACE2).	[9]
Clozapine	DMFC71L	Approved	Clozapine increases the expression of Beta-secretase 2 (BACE2).	[10]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Beta-secretase 2 (BACE2).	[9]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Beta-secretase 2 (BACE2).	[12]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Beta-secretase 2 (BACE2).	[13]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Beta-secretase 2 (BACE2).	[14]

References

• [1] 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.
• [2] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [3] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [4] 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.
• [5] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [6] Persistent and non-persistent changes in gene expression result from long-term estrogen exposure of MCF-7 breast cancer cells. J Steroid Biochem Mol Biol. 2011 Feb;123(3-5):140-50.
• [7] 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.
• [8] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [9] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [10] Toxicoproteomics reveals an effect of clozapine on autophagy in human liver spheroids. Toxicol Mech Methods. 2023 Jun;33(5):401-410. doi: 10.1080/15376516.2022.2156005. Epub 2022 Dec 19.
• [11] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [12] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [13] 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.
• [14] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [15] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.