Beta secretase
From Wikipedia, the free encyclopedia
β-Secretase — also called BACE1 (β-site of APP cleaving enzyme) or memapsin-2 — is an aspartic-acid protease important in the pathogenesis of Alzheimer's disease, and in the formation of myelin sheaths in peripheral nerve cells.[1] The transmembrane protein, contains two active site aspartate residues in its extracellular protein domain and may function as a dimer.
Contents |
[edit] Function in Alzheimer's
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 releases a soluble extracellular fragment and is followed by APP cleavage within its transmembrane domain by γ-secretase. The second cleavage releases the intracellular domain of APP and amyloid-β. Since α-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 α-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.
[edit] 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 the disease. Several companies are in the early stages of development and testing of this new potential class of treatment.[2][3]
[edit] References
- ^ The Scientist, 22 September 2006 Alzheimer's enzyme important for myelin [1], reporting on a paper published in Science.
- ^ LF Walker, RC Rosen. "Alzheimer therapeutics—what after the cholinesterase inhibitors?" Age and Ageing 2006 35(4): 332-335. PMID 16644763
- ^ Baxter, et al. (2007). "2-Aminoquinazolines as Inhibitors of BACE-1 (β-Amyloid Cleaving Enzyme): Use of Structural Biology to Convert a Micromolar HTS Hit to a Nanomolar Lead". J. Med. Chem. 50 (18): 4261–4264. doi:.
[edit] 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. 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:. 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:. 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:. PMID 17596706.
|
||||||||
