|Beta-site APP-cleaving enzyme 1|
PDB rendering based on .
|Symbols||; ASP2; BACE; HSPC104|
|External IDs||ChEMBL: GeneCards:|
|RNA expression pattern|
Beta-secretase 1 (BACE1), also known as beta-site amyloid precursor protein cleaving enzyme 1, beta-site APP cleaving enzyme 1, membrane-associated aspartic protease 2, memapsin-2, aspartyl protease 2, and ASP2, is an enzyme that in humans is encoded by the BACE1 gene.
BACE1 is an aspartic-acid protease important in the formation of myelin sheaths in peripheral nerve cells. The transmembrane protein contains two active site aspartate residues in its extracellular protein domain and may function as a dimer.
Role in Alzheimer's disease
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 alpha-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 alpha-secretase rather than BACE1 prevents eventual generation of amyloid-β.
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. The physiological purpose of BACE's cleavage of APP and other transmembrane proteins is unknown. BACE2 is a close homolog of BACE1 with no reported APP cleavage in vivo.
Drugs to block this enzyme (BACE inhibitors) in theory would prevent the build up of beta-amyloid and may help slow or stop Alzheimers disease.
In April 2012 Merck & Co., Inc reported phase I results for its candidate MK-8931. Merck began a Phase II/III trial of MK-8931 in December, 2012. In September 2014 AstraZeneca and Eli Lilly and Company announced an agreement to codevelop AZD3293. A pivotal Phase II/III clinical trial of AZD3293 started in late 2014 and is planned to recruit 1,500 patients and end in May 2019.
Tests in mice have indicated that BACE proteases, specifically BACE1, are necessary for the proper function of muscle spindles. 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, though BACE1 knockout mice are healthy.
Relationship to plasmepsin
- Hong, L.; Koelsch, G.; Lin, X.; Wu, S.; Terzyan, S.; Ghosh, A. K.; Zhang, X. C.; Tang, J. (2000). "Structure of the protease domain of memapsin 2 (beta-secretase) complexed with inhibitor". Science 290 (5489): 150–153. doi:10.1126/science.290.5489.150. PMID 11021803.
- Vassar R, Bennett B, Babu-Khan S, Kahn S, Mendiaz E, Denis P et al. (Oct 1999). "Beta-secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE". Science (New York, N.Y.) 286 (5440): 735–41. doi:10.1126/science.286.5440.735. PMID 10531052.
- Willem M, Garratt A, Novak B, Citron M, Kaufmann S, Rittger A et al. (Oct 2006). "Control of peripheral nerve myelination by the beta-secretase BACE1". Science (New York, N.Y.) 314 (5799): 664–6. Bibcode:2006Sci...314..664W. doi:10.1126/science.1132341. PMID 16990514. Lay summary – The Scientist.
- "Alzheimer's-fighting gene may inspire treatments". July 2012.
- Jonsson T, Atwal J, Steinberg S, Snaedal J, Jonsson P, Bjornsson S et al. (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.
- Walker L, Rosen R (Jul 2006). "Alzheimer therapeutics-what after the cholinesterase inhibitors?". Age and Ageing 35 (4): 332–5. doi:10.1093/ageing/afl009. PMID 16644763.
- Baxter E, Conway K, Kennis L, Bischoff F, Mercken M, Winter H et al. (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.
- "CoMentis BACE Inhibitor Debuts". April 2008.
- "Merck Presents Results of a Phase I Clinical Trial Evaluating Investigational BACE inhibitor MK-8931 at American Academy of Neurology". April 2012.
- "Merck Initiates Phase II/III Study of Investigational BACE Inhibitor, MK-8931, for Treatment of Alzheimer's Disease". December 2012.
- "AstraZeneca and Lilly announce alliance to develop and commercialise BACE inhibitor AZD3293 for Alzheimer’s disease". http://www.astrazeneca.com/. 16 Sep 2014. Retrieved 8 Oct 2014.
- "AstraZeneca and Lilly move Alzheimer's drug into big trial". December 2014.
- Cheret, Cecil; Michael Willem; Florence R Fricker; Hagen Wende (June 2013). of muscle spindles "Bace1 and Neuregulin-1 cooperate to control formation and maintenance of muscle spindles". European Molecular Biology Organization.
- Roberds S, Anderson J, Basi G, Bienkowski M, Branstetter D, Chen K et al. (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.
- Russo I, Babbitt S, Muralidharan V, Butler T, Oksman A, Goldberg D (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.
- Hong L, He X, Huang X, Chang W, Tang J (Dec 2004). "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 J, Liu W, Todd S, Coulson D, Murphy S, Irvine G et al. (Nov 2005). "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.
- Dominguez D, 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 V, Grohovaz F et al. (2007). "BACE1 expression and activity: relevance in Alzheimer's disease". Neuro-Degenerative Diseases 4 (2-3): 117–26. doi:10.1159/000101836. PMID 17596706.
- The MEROPS online database for peptidases and their inhibitors: A01.004
- beta-Secretase: Molecule of the Month, by David Goodsell, RCSB Protein Data Bank