Beta-secretase 1
Beta-secretase 1 (BACE1) also known as beta-site APP cleaving enzyme 1 (beta-site amyloid precursor protein cleaving enzyme 1), memapsin-2 (membrane-associated aspartic protease 2), and aspartyl protease 2 (ASP2) is an enzyme that in humans is encoded by the BACE1 gene.[2]
β-Secretase is an aspartic-acid protease important in the formation of myelin sheaths in peripheral nerve cells.[3] 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 BACE 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 BACE does, it removes a fragment of the amyloid-β peptide. Initial cleavage of APP by alpha-secretase rather than BACE prevents eventual generation of amyloid-β.
Unlike APP and the presenilin proteins important in γ-secretase, no known mutations in the gene encoding BACE 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.
However a single residue mutation in APP reduces the ability of BACE-1 to cleave it to produce amyloid-beta and reduces the risk of Alzheimers and other cognitive declines.[4][5]
BACE inhibitors
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. As of September 2007 Several companies are in the early stages of development and testing of this new potential class of treatment.[6][7] In March 2008 phase I results were reported for CTS-21166.[8] In April 2012 Merck reported phase I results for MK-8931.[9] Merck began a Phase II/III trial of MK-8931 in December, 2012.[10]
Tests in mice have indicated that BACE proteases, specifically BACE1, is necessary for the proper function of muscle spindles. [11] 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.
Relationship to plasmepsin
Beta secretase, a vertebrate (human) aspartic-acid protease, is distantly related to the pathogenic aspartic-acid protease plasmepsin, which is a potential target for future anti-malarial drugs.[12]
See also
References
- ↑ 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 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 (October 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.
- ↑ Willem M, Garratt AN, Novak B, Citron M, Kaufmann S, Rittger A, DeStrooper B, Saftig P, Birchmeier C, Haass C (October 2006). "Control of peripheral nerve myelination by the beta-secretase BACE1". Science 314 (5799): 664–6. doi:10.1126/science.1132341. PMID 16990514. Lay summary – The Scientist.
- ↑ "Alzheimer's-fighting gene may inspire treatments". July 2012.
- ↑ Jonsson et al. (2012). A mutation in APP protects against Alzheimer’s disease and age-related cognitive decline. doi:10.1038/nature11283.
- ↑ Walker LC, Rosen RF (July 2006). "Alzheimer therapeutics-what after the cholinesterase inhibitors?". Age Ageing 35 (4): 332–5. doi:10.1093/ageing/afl009. PMID 16644763.
- ↑ Baxter EW, Conway KA, Kennis L, Bischoff F, Mercken MH, Winter HL, Reynolds CH, Tongue 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 (September 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.
- ↑ 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.
- ↑ Russo I, Babbitt S, Muralidharan V, Butler T, Oksman A, Goldberg DE (February 2010). "Plasmepsin V licenses Plasmodium proteins for export into the host erythrocyte". Nature 463 (7281): 632–6. doi:10.1038/nature08726. PMC 2826791. PMID 20130644. Lay summary – sciencedaily.com.
Further reading
- Hong L, He X, Huang X et al. (2005). "Structural features of human memapsin 2 (beta-secretase) and their biological and pathological implications". Acta Biochim. Biophys. Sin. (Shanghai) 36 (12): 787–92. doi:10.1093/abbs/36.12.787. PMID 15592644.
- Johnston JA, Liu WW, Todd SA et al. (2006). "Expression and activity of beta-site amyloid precursor protein cleaving enzyme in Alzheimer's disease". Biochem. Soc. Trans. 33 (Pt 5): 1096–100. doi:10.1042/BST20051096. PMID 16246054.
- 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 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.
External links
- The MEROPS online database for peptidases and their inhibitors: A01.004
- beta-Secretase: Molecule of the Month, by David Goodsell, RCSB Protein Data Bank
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| |||||||||||||||||||||||||||||||||||||
| ||||||||||||||||||||