Beta-secretase 1

From Infogalactic: the planetary knowledge core
Jump to: navigation, search

<templatestyles src="Module:Infobox/styles.css"></templatestyles>

Beta-site APP-cleaving enzyme 1
250px
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
File: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:
117.29 – 117.32 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

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

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 estimated to be completed in July 2019.[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

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

References

  1. Lua error in package.lua at line 80: module 'strict' not found.
  2. Lua error in package.lua at line 80: module 'strict' not found.
  3. Lua error in package.lua at line 80: module 'strict' not found.
  4. Lua error in package.lua at line 80: module 'strict' not found.
  5. Lua error in package.lua at line 80: module 'strict' not found.
  6. Lua error in package.lua at line 80: module 'strict' not found.
  7. Lua error in package.lua at line 80: module 'strict' not found.
  8. Lua error in package.lua at line 80: module 'strict' not found.
  9. Lua error in package.lua at line 80: module 'strict' not found.
  10. Lua error in package.lua at line 80: module 'strict' not found.
  11. Lua error in package.lua at line 80: module 'strict' not found.
  12. Lua error in package.lua at line 80: module 'strict' not found.
  13. Lua error in package.lua at line 80: module 'strict' not found.
  14. Lua error in package.lua at line 80: module 'strict' not found.
  15. Lua error in package.lua at line 80: module 'strict' not found.

Further reading

  • Lua error in package.lua at line 80: module 'strict' not found.
  • Lua error in package.lua at line 80: module 'strict' not found.
  • Lua error in package.lua at line 80: module 'strict' not found.
  • Lua error in package.lua at line 80: module 'strict' not found.

External links