Beta secretase

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. [The Scientist, 22 September 2006 "Alzheimer's enzyme important for myelin" [http://www.the-scientist.com/news/display/24841/] , reporting on a paper published in Science.] The transmembrane protein, contains two active site aspartate residues in its extracellular protein domain and may function as a dimer.

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".

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. [LF Walker, RC Rosen. "Alzheimer therapeutics—what after the cholinesterase inhibitors?" "Age and Ageing" 2006 35(4): 332-335. PMID 16644763] [cite journal|author=Baxter, "et al."|title=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 |journal= J. Med. Chem. |year=2007|volume=50|issue=18|pages= 4261–4264|doi=10.1021/jm0705408]

References

Further reading

PBB_Further_reading
citations =
*cite journal | author=Hong L, He X, Huang X, "et al." |title=Structural features of human memapsin 2 (beta-secretase) and their biological and pathological implications. |journal=Acta Biochim. Biophys. Sin. (Shanghai) |volume=36 |issue= 12 |pages= 787–92 |year= 2005 |pmid= 15592644 |doi=
*cite journal | author=Johnston JA, Liu WW, Todd SA, "et al." |title=Expression and activity of beta-site amyloid precursor protein cleaving enzyme in Alzheimer's disease. |journal=Biochem. Soc. Trans. |volume=33 |issue= Pt 5 |pages= 1096–100 |year= 2006 |pmid= 16246054 |doi= 10.1042/BST20051096
*cite journal | author=Dominguez DI, Hartmann D, De Strooper B |title=BACE1 and presenilin: two unusual aspartyl proteases involved in Alzheimer's disease. |journal=Neuro-degenerative diseases |volume=1 |issue= 4-5 |pages= 168–74 |year= 2006 |pmid= 16908986 |doi= 10.1159/000080982
*cite journal | author=Zacchetti D, Chieregatti E, Bettegazzi B, "et al." |title=BACE1 expression and activity: relevance in Alzheimer's disease. |journal=Neuro-degenerative diseases |volume=4 |issue= 2-3 |pages= 117–26 |year= 2007 |pmid= 17596706 |doi= 10.1159/000101836

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