Beta-secretase 1

BACE1
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesBACE1, ASP2, BACE, HSPC104, beta-secretase 1
External IDsOMIM: 604252 MGI: 1346542 HomoloGene: 8014 GeneCards: BACE1
EC number3.4.23.46
Orthologs
SpeciesHumanMouse
Entrez

23621

23821

Ensembl

ENSG00000186318

ENSMUSG00000032086

UniProt

P56817

P56818

RefSeq (mRNA)

NM_001145947
NM_011792

RefSeq (protein)

NP_001139419
NP_035922

Location (UCSC)Chr 11: 117.29 – 117.32 MbChr 9: 45.84 – 45.86 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Beta-secretase 1, also known as beta-site amyloid precursor protein cleaving enzyme 1, beta-site APP cleaving enzyme 1 (BACE1), membrane-associated aspartic protease 2, memapsin-2, aspartyl protease 2, and ASP2, is an enzyme that in humans is encoded by the BACE1 gene.[5] Expression of BACE1 is observed mainly in neurons.

BACE1 is an aspartic acid protease important in the formation of myelin sheaths in peripheral nerve cells: in mice the expression of BACE1 is high in the postnatal stages, when myelination occurs.[6] The transmembrane protein contains two active site aspartate residues in its extracellular protein domain and may function as a dimer, its cytoplasmic tail is required for the correct maturation and an efficient intracellular trafficking, but doesn't affect the activity. It is produced as a pro-enzyme, the endoproteolitc removal occurs after BACE leaves Endoplasmic reticulum, in the Golgi apparatus. In addition the pro-peptide receives additional sugars to increase the molecular mass.[7] and the tail became a palmitoylated.

The BACE1 expression is influenced by the inflammatory state: during AD the cytokines reduce the PPAR1 an inhibitor of BACE1 mRNA).

Role in Alzheimer's disease

Processing of the amyloid precursor protein

BACE1 is the major beta secretase for the generation of amyloid-β peptides in the neurons.[8]

Generation of the 40 or 42 amino acid-long amyloid-β peptides that aggregate in the brain of Alzheimer's patients requires two sequential cleavages of the amyloid precursor protein (APP). Extracellular cleavage of APP by BACE1 creates a soluble extracellular fragment and a cell membrane-bound fragment referred to as C99. Cleavage of C99 within its transmembrane domain by γ-secretase releases the intracellular domain of APP and produces amyloid-β. Since gamma-secretase cleaves APP closer to the cell membrane than BACE1 does, it removes a fragment of the amyloid-β peptide. Initial cleavage of APP by α-secretase rather than BACE1 prevents eventual generation of amyloid-β, forming P3, this demonstrates that BACE1 and Alpha secretase compete for the APP processing.

Unlike APP and the presenilin proteins important in γ-secretase, no known mutations in the gene encoding BACE1 cause early-onset, familial Alzheimer's disease, which is a rare form of the disorder. However, levels of this enzyme have been shown to be elevated in the far more common late-onset sporadic Alzheimer's. BACE2 is a close homolog of BACE1 with no reported APP cleavage in vivo.

The physiological purpose of BACE's cleavage of APP and other transmembrane proteins is unknown: some studies observed that BACE1 is involved in myelination (it is co-express with neuregulin 1 type III). In a manner analogous to APP processing, the VGSC subunit beta is a substrate for BACE1.[9]

However a single residue mutation in APP reduces the ability of BACE1 to cleave it to produce amyloid-beta and reduces the risk of Alzheimer's disease and other cognitive declines.[10][11]

BACE inhibitors

Drugs to block this enzyme (BACE inhibitors) in theory would prevent the buildup of beta-amyloid and (per the Amyloid hypothesis) may help slow or stop Alzheimer's disease.[12]

For Alzheimer's disease

Several companies are in the early stages of development and testing of this potential class of treatment.[13][14] In March 2008 phase I results were reported for CoMentis Inc's candidate CTS-21166.[15]

In April 2012 Merck & Co., Inc reported phase I results for its candidate verubecestat (MK-8931).[16] Merck began a Phase II/III trial of MK-8931 in December, 2012 estimated to be completed in July 2019.[17] In February 2017, Merck halted its late-stage trial of verubecestat for mild to moderate Alzheimer's disease after it was reported as having "virtually no chance" of working according to an independent panel of experts. This came just three months after Eli Lilly & Co. announced its own setback with solanezumab. The results of Merck's trial of verubecestat on patients with early stage Alzheimer's are still expected in February 2019.

In September 2014 AstraZeneca and Eli Lilly and Company announced an agreement to codevelop lanabecestat (AZD3293).[18] A pivotal Phase II/III clinical trial of lanabecestat started in late 2014,[19] but was halted in 2018 before its planned conclusion due to poor results.[20]

Another BACE1 inhibitor that has reached phase II trials is the Eli Lilly's inhibitor LY2886721. The data on phase I trial were first presented at the Alzheimer's Association International conference in 2012. Daily dosing during 2 weeks, reduced BACE1 activity by 50–75% and CSF Aβ42 by 72% (Willis et al., 2012; Bowman Rogers and Strobel, 2013). Recently, Lilly reported that the phase II trial of LY2886721 was terminated due to liver abnormalities that were found in 4 out of 45 patients (Rogers, 2013). This toxicity, however, does not have to be related to the working mechanism of the inhibitor, but can represent off-target effects as the livers of BACE1 knockout mice are normal.

Potential side effects

Tests in mice have indicated that BACE proteases, specifically BACE1, are necessary for the proper function of muscle spindles.[21] These results raise the possibility that BACE inhibiting drugs currently being investigated for the treatment of Alzheimer's may have significant side effects related to impaired motor coordination,[22] though BACE1 knockout mice are healthy.[23]

Relationship to plasmepsin

BACE1 is distantly related to the pathogenic aspartic-acid protease plasmepsin, which is a potential target for future anti-malarial drugs.[24]

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000186318 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000032086 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ Vassar R, Bennett BD, Babu-Khan S, Kahn S, Mendiaz EA, Denis P, Teplow DB, Ross S, Amarante P, Loeloff R, Luo Y, Fisher S, Fuller J, Edenson S, Lile J, Jarosinski MA, Biere AL, Curran E, Burgess T, Louis JC, Collins F, Treanor J, Rogers G, Citron M (Oct 1999). "Beta-secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE". Science. 286 (5440): 735–41. doi:10.1126/science.286.5440.735. PMID 10531052.
  6. ↑ Willem M, Garratt AN, Novak B, Citron M, Kaufmann S, Rittger A, DeStrooper B, Saftig P, Birchmeier C, Haass C (Oct 2006). "Control of peripheral nerve myelination by the beta-secretase BACE1". Science. 314 (5799): 664–6. Bibcode:2006Sci...314..664W. doi:10.1126/science.1132341. PMID 16990514. S2CID 8432207. Lay summary – The Scientist. {{cite journal}}: Cite uses deprecated parameter |lay-url= (help)
  7. ↑ Capell, Anja; Steiner, Harald; Willem, Michael; Kaiser, Hartmut; Meyer, Carmen; Walter, Jochen; Lammich, Sven; Multhaup, Gerd; Haass, Christian (2000-10-06). "Maturation and Pro-peptide Cleavage of β-Secretase". Journal of Biological Chemistry. 275 (40): 30849–30854. doi:10.1074/jbc.M003202200. ISSN 0021-9258. PMID 10801872.
  8. ↑ Cai, Huaibin; Wang, Yanshu; McCarthy, Diane; Wen, Hongjin; Borchelt, David R.; Price, Donald L.; Wong, Philip C. (March 2001). "BACE1 is the major β-secretase for generation of Aβ peptides by neurons". Nature Neuroscience. 4 (3): 233–234. doi:10.1038/85064. ISSN 1546-1726. PMID 11224536. S2CID 11973104.
  9. ↑ Kim, Doo Yeon; Carey, Bryce W.; Wang, Haibin; Ingano, Laura A. M.; Binshtok, Alexander M.; Wertz, Mary H.; Pettingell, Warren H.; He, Ping; Lee, Virginia M.-Y.; Woolf, Clifford J.; Kovacs, Dora M. (July 2007). "BACE1 regulates voltage-gated sodium channels and neuronal activity". Nature Cell Biology. 9 (7): 755–764. doi:10.1038/ncb1602. ISSN 1465-7392. PMC 2747787. PMID 17576410.
  10. ↑ "Alzheimer's-fighting gene may inspire treatments". July 2012.
  11. ↑ Jonsson T, Atwal JK, Steinberg S, Snaedal J, Jonsson PV, Bjornsson S, Stefansson H, Sulem P, Gudbjartsson D, Maloney J, Hoyte K, Gustafson A, Liu Y, Lu Y, Bhangale T, Graham RR, Huttenlocher J, Bjornsdottir G, Andreassen OA, Jönsson EG, Palotie A, Behrens TW, Magnusson OT, Kong A, Thorsteinsdottir U, Watts RJ, Stefansson K (Aug 2012). "A mutation in APP protects against Alzheimer's disease and age-related cognitive decline". Nature. 488 (7409): 96–9. Bibcode:2012Natur.488...96J. doi:10.1038/nature11283. PMID 22801501. S2CID 4333449.
  12. ↑ Pradeepkiran, JA; Reddy, AP; Yin, X; Manczak, M; Reddy, PH (2020). "Protective Effects of BACE1 Inhibitory Ligand Molecules Against Amyloid Beta-Induced Synaptic and Mitochondrial Toxicities in Alzheimer's Disease". Human Molecular Genetics. 29 (1): 49–69. doi:10.1093/hmg/ddz227. PMC 7001603. PMID 31595293.
  13. ↑ Walker LC, Rosen RF (Jul 2006). "Alzheimer therapeutics-what after the cholinesterase inhibitors?". Age and Ageing. 35 (4): 332–5. doi:10.1093/ageing/afl009. PMID 16644763.
  14. ↑ Baxter EW, Conway KA, Kennis L, Bischoff F, Mercken MH, Winter HL, Reynolds CH, Tounge BA, Luo C, Scott MK, Huang Y, Braeken M, Pieters SM, Berthelot DJ, Masure S, Bruinzeel WD, Jordan AD, Parker MH, Boyd RE, Qu J, Alexander RS, Brenneman DE, Reitz AB (Sep 2007). "2-Amino-3,4-dihydroquinazolines as inhibitors of BACE-1 (beta-site APP cleaving enzyme): Use of structure based design to convert a micromolar hit into a nanomolar lead". Journal of Medicinal Chemistry. 50 (18): 4261–4. doi:10.1021/jm0705408. PMID 17685503.
  15. ↑ "CoMentis BACE Inhibitor Debuts". April 2008.
  16. ↑ "Merck Presents Results of a Phase I Clinical Trial Evaluating Investigational BACE inhibitor MK-8931 at American Academy of Neurology". April 2012. Archived from the original on 2012-07-28.
  17. ↑ "Merck Initiates Phase II/III Study of Investigational BACE Inhibitor, MK-8931, for Treatment of Alzheimer's Disease". December 2012.
  18. ↑ "AstraZeneca and Lilly announce alliance to develop and commercialise BACE inhibitor AZD3293 for Alzheimer's disease". 16 Sep 2014. Retrieved 8 Oct 2014.
  19. ↑ "AstraZeneca and Lilly move Alzheimer's drug into big trial". Reuters. December 2014. Archived from the original on 2015-10-25. Retrieved 2017-06-30.
  20. ↑ "Update on Phase III Clinical Trials of lanabecestat". 12 June 2018. Retrieved 20 June 2018.
  21. ↑ Cheret, Cecil; Michael Willem; Florence R Fricker; Hagen Wende (June 2013). "Bace1 and Neuregulin-1 cooperate to control formation and maintenance of muscle spindles". EMBO Journal. 32 (14): 2015–28. doi:10.1038/emboj.2013.146. PMC 3715864. PMID 23792428.
  22. ↑ Pettersson, A.F.; Olsson, E.; Wahlund, L.-O. (2005). "Motor Function in Subjects with Mild Cognitive Impairment and Early Alzheimer's Disease". Dementia and Geriatric Cognitive Disorders. 19 (5–6): 299–304. doi:10.1159/000084555. ISSN 1420-8008. PMID 15785030. S2CID 36382718.
  23. ↑ Roberds SL, Anderson J, Basi G, Bienkowski MJ, Branstetter DG, Chen KS, Freedman SB, Frigon NL, Games D, Hu K, Johnson-Wood K, Kappenman KE, Kawabe TT, Kola I, Kuehn R, Lee M, Liu W, Motter R, Nichols NF, Power M, Robertson DW, Schenk D, Schoor M, Shopp GM, Shuck ME, Sinha S, Svensson KA, Tatsuno G, Tintrup H, Wijsman J, Wright S, McConlogue L (Jun 2001). "BACE knockout mice are healthy despite lacking the primary beta-secretase activity in brain: implications for Alzheimer's disease therapeutics". Human Molecular Genetics. 10 (12): 1317–24. doi:10.1093/hmg/10.12.1317. PMID 11406613.
  24. ↑ Russo I, Babbitt S, Muralidharan V, Butler T, Oksman A, Goldberg DE (Feb 2010). "Plasmepsin V licenses Plasmodium proteins for export into the host erythrocyte". Nature. 463 (7281): 632–6. Bibcode:2010Natur.463..632R. doi:10.1038/nature08726. PMC 2826791. PMID 20130644. Lay summary – sciencedaily.com. {{cite journal}}: Cite uses deprecated parameter |lay-url= (help)

Further reading

  • Hong L, He X, Huang X, Chang W, Tang J (2005). "Structural features of human memapsin 2 (beta-secretase) and their biological and pathological implications". Acta Biochimica et Biophysica Sinica. 36 (12): 787–92. doi:10.1093/abbs/36.12.787. PMID 15592644.
  • Johnston JA, Liu WW, Todd SA, Coulson DT, Murphy S, Irvine GB, Passmore AP (2006). "Expression and activity of beta-site amyloid precursor protein cleaving enzyme in Alzheimer's disease". Biochemical Society Transactions. 33 (Pt 5): 1096–100. doi:10.1042/BST20051096. PMID 16246054. S2CID 44248549.
  • Dominguez DI, Hartmann D, De Strooper B (2006). "BACE1 and presenilin: two unusual aspartyl proteases involved in Alzheimer's disease". Neuro-Degenerative Diseases. 1 (4–5): 168–74. doi:10.1159/000080982. PMID 16908986.
  • Zacchetti D, Chieregatti E, Bettegazzi B, Mihailovich M, Sousa VL, Grohovaz F, Meldolesi J (2007). "BACE1 expression and activity: relevance in Alzheimer's disease". Neuro-Degenerative Diseases. 4 (2–3): 117–26. doi:10.1159/000101836. PMID 17596706. S2CID 32898359.
  • The MEROPS online database for peptidases and their inhibitors: A01.004
  • beta-Secretase: Molecule of the Month, by David Goodsell, RCSB Protein Data Bank
  • Human BACE1 genome location and BACE1 gene details page in the UCSC Genome Browser.
  • Overview of all the structural information available in the PDB for UniProt: P56817 (Human Beta-secretase 1) at the PDBe-KB.
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