Beta-secretase 1

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Beta-site APP-cleaving enzyme 1
Protein BACE1 PDB 1fkn.png
PDB rendering based on 1fkn[1].
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols BACE1 ; ASP2; BACE; HSPC104
External IDs OMIM604252 MGI1346542 HomoloGene8014 ChEMBL: 4822 GeneCards: BACE1 Gene
EC number 3.4.23.46
RNA expression pattern
PBB GE BACE1 217904 s at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 23621 23821
Ensembl ENSG00000186318 ENSMUSG00000032086
UniProt P56817 P56818
RefSeq (mRNA) NM_001207048 NM_001145947
RefSeq (protein) NP_001193977 NP_001139419
Location (UCSC) Chr 11:
117.16 – 117.19 Mb
Chr 9:
45.84 – 45.86 Mb
PubMed search [1] [2]

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.[2]

BACE1 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[edit]

Processing of the amyloid precursor protein

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.

However a single residue mutation in APP reduces the ability of BACE1 to cleave it to produce amyloid-beta and reduces the risk of Alzheimers and other cognitive declines.[4][5]

BACE inhibitors[edit]

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.

Several companies are in the early stages of development and testing of this potential class of treatment.[6][7] In March 2008 phase I results were reported for CoMentis Inc's candidate CTS-21166.[8]

In April 2012 Merck & Co., Inc reported phase I results for its candidate MK-8931.[9] Merck began a Phase II/III trial of MK-8931 in December, 2012.[10] In September 2014 AstraZeneca and Eli Lilly and Company announced an agreement to codevelop AZD3293.[11] 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.[12]

Tests in mice have indicated that BACE proteases, specifically BACE1, are necessary for the proper function of muscle spindles.[13] 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,[citation needed] though BACE1 knockout mice are healthy.[14]

Relationship to plasmepsin[edit]

BACE1 is distantly related to the pathogenic aspartic-acid protease plasmepsin, which is a potential target for future anti-malarial drugs.[15]

References[edit]

  1. ^ 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.  edit
  2. ^ Vassar R, Bennett BD, Babu-Khan S, Kahn S, Mendiaz EA, 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. 
  3. ^ Willem M, Garratt AN, 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 summaryThe Scientist. 
  4. ^ "Alzheimer's-fighting gene may inspire treatments". July 2012. 
  5. ^ Jonsson T, Atwal JK, Steinberg S, Snaedal J, Jonsson PV, 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. 
  6. ^ 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. 
  7. ^ Baxter EW, Conway KA, Kennis L, Bischoff F, Mercken MH, Winter HL 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. 
  8. ^ "CoMentis BACE Inhibitor Debuts". April 2008. 
  9. ^ "Merck Presents Results of a Phase I Clinical Trial Evaluating Investigational BACE inhibitor MK-8931 at American Academy of Neurology". April 2012. 
  10. ^ "Merck Initiates Phase II/III Study of Investigational BACE Inhibitor, MK-8931, for Treatment of Alzheimer's Disease". December 2012. 
  11. ^ "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. 
  12. ^ "AstraZeneca and Lilly move Alzheimer's drug into big trial". December 2014. 
  13. ^ 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. 
  14. ^ Roberds SL, Anderson J, Basi G, Bienkowski MJ, Branstetter DG, Chen KS 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. 
  15. ^ 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 summarysciencedaily.com. 

Further reading[edit]

  • 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.  Check date values in: |year= / |date= mismatch (help)
  • Johnston JA, Liu WW, Todd SA, Coulson DT, Murphy S, Irvine GB 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.  Check date values in: |year= / |date= mismatch (help)
  • 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 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[edit]