Beta-site APP-cleaving enzyme 1
PDB rendering based on 1fkn[1].
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 1FKN, 1M4H, 1SGZ, 1TQF, 1UJJ, 1UJK, 1W50, 1W51, 1XN2, 1XN3, 1XS7, 1YM2, 1YM4, 2B8L, 2B8V, 2F3E, 2F3F, 2FDP, 2G94, 2HIZ, 2HM1, 2IQG, 2IRZ, 2IS0, 2NTR, 2OAH, 2OF0, 2OHK, 2OHL, 2OHM, 2OHN, 2OHP, 2OHQ, 2OHR, 2OHS, 2OHT, 2OHU, 2P4J, 2P83, 2P8H, 2PH6, 2PH8, 2Q11, 2Q15, 2QK5, 2QMD, 2QMF, 2QMG, 2QP8, 2QU2, 2QU3, 2QZK, 2QZL, 2VA5, 2VA6, 2VA7, 2VIE, 2VIJ, 2VIY, 2VIZ, 2VJ6, 2VJ7, 2VJ9, 2VKM, 2VNM, 2VNN, 2WEZ, 2WF0, 2WF1, 2WF2, 2WF3, 2WF4, 2WJO, 2XFI, 2XFJ, 2XFK, 2ZDZ, 2ZE1, 2ZHR, 2ZHS, 2ZHT, 2ZHU, 2ZHV, 2ZJH, 2ZJI, 2ZJJ, 2ZJK, 2ZJL, 2ZJM, 2ZJN, 3BRA, 3BUF, 3BUG, 3BUH, 3CIB, 3CIC, 3CID, 3CKP, 3CKR, 3DM6, 3DUY, 3DV1, 3DV5, 3EXO, 3FKT, 3H0B, 3HVG, 3HW1, 3I25, 3IGB, 3IN3, 3IN4, 3IND, 3INE, 3INF, 3INH, 3IVH, 3IVI, 3IXJ, 3IXK, 3K5C, 3K5D, 3K5F, 3K5G, 3KMX, 3KMY, 3KN0, 3KYR, 3L38, 3L3A, 3L58, 3L59, 3L5B, 3L5C, 3L5D, 3L5E, 3L5F, 3LHG, 3LNK, 3LPI, 3LPJ, 3LPK, 3MSJ, 3MSK, 3MSL, 3N4L, 3NSH, 3OHF, 3OHH, 3OOZ, 3PI5, 3QBH, 3QI1, 3R1G, 3R2F, 3RSV, 3RSX, 3RTH, 3RTM, 3RTN, 3RU1, 3RVI, 3S2O, 3S7L, 3S7M, 3SKF, 3SKG, 3TPJ, 3TPL, 3TPP, 3TPR, 3U6A, 3UDH, 3UDJ, 3UDK, 3UDM, 3UDN, 3UDP, 3UDQ, 3UDR, 3UDY, 3UFL, 4ACU, 4ACX, 4DH6, 4DJU, 4DJV, 4DJW, 4DJX, 4DJY
Identifiers
Symbols	BACE1; ASP2; BACE; HSPC104
External IDs	OMIM: 604252 MGI: 1346542 HomoloGene: 8014 ChEMBL: 4822 GeneCards: BACE1 Gene
EC number	3.4.23.46
Gene Ontology Molecular function • aspartic-type endopeptidase activity • peptidase activity • beta-aspartyl-peptidase activity • enzyme binding Cellular component • membrane fraction • endosome • endoplasmic reticulum • Golgi apparatus • trans-Golgi network • integral to plasma membrane • cell surface • membrane • integral to membrane • axon • cytoplasmic vesicle membrane • cytoplasmic vesicle Biological process • proteolysis • membrane protein ectodomain proteolysis • beta-amyloid metabolic process Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	23621	23821
Ensembl	ENSG00000186318	ENSMUSG00000032086
UniProt	P56817	P56818
RefSeq (mRNA)	NM_001207048.1	NM_001145947.1
RefSeq (protein)	NP_001193977.1	NP_001139419.1
Location (UCSC)	Chr 11: 117.16 – 117.19 Mb	Chr 9: 45.65 – 45.67 Mb
PubMed search	[1]	[2]
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Processing of the amyloid precursor protein

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 pathogenesis of Alzheimer's disease, and 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 [link]

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.

BACE inhibitors [link]

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.^[4][5]

Relationship to plasmepsin [link]

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.^[6]

See also [link]

• Beta-secretase 2

References [link]

External links [link]

• The MEROPS online database for peptidases and their inhibitors: A01.004

Further reading [link]

v t e PDB gallery 1fkn: Structure of Beta-Secretase Complexed with Inhibitor   1m4h: Crystal Structure of Beta-secretase complexed with Inhibitor OM00-3   1sgz: Crystal Structure of Unbound Beta-Secretase Catalytic Domain.   1tqf: Crystal structure of human Beta secretase complexed with inhibitor   1w50: APO STRUCTURE OF BACE (BETA SECRETASE)   1w51: BACE (BETA SECRETASE) IN COMPLEX WITH A NANOMOLAR NON-PEPTIDIC INHIBITOR   1xn2: New substrate binding pockets for beta-secretase.   1xn3: Crystal structure of Beta-secretase bound to a long inhibitor with additional upstream residues.   1xs7: Crystal Structure of a cycloamide-urethane-derived novel inhibitor bound to human brain memapsin 2 (beta-secretase).   1ym2: Crystal structure of human beta secretase complexed with NVP-AUR200   1ym4: Crystal structure of human beta secretase complexed with NVP-AMK640   2b8l: Crystal structure of human beta secretase complexed with inhibitor   2b8v: Crystal structure of human Beta-secretase complexed with L-L000430,469   2f3e: Crystal Structure of the Bace complex with AXQ093, a macrocyclic inhibitor   2f3f: Crystal Structure of the Bace complex with BDF488, a macrocyclic inhibitor   2fdp: Crystal structure of beta-secretase complexed with an amino-ethylene inhibitor   2g94: Crystal structure of beta-secretase bound to a potent and highly selective inhibitor.   2hiz: Crystal Structure of human beta-secretase (BACE) in the presence of an inhibitor   2hm1: Crystal Structure of human beta-secretase (BACE) in the presence of an inhibitor (2)   2iqg: Crystal Structure of Hydroxyethyl Secondary Amine-based Peptidomimetic Inhibitor of Human Beta-Secretase (BACE)   2irz: Crystal structure of human Beta-secretase complexed with inhibitor   2is0: Crystal structure of human Beta-secretase complexed with inhibitor   2of0: X-ray crystal structure of beta secretase complexed with compound 5   2ohk: X-ray crystal structure of beta secretase complexed with 1-amino-isoquinoline   2ohl: X-ray crystal structure of beta secretase complexed with 2-aminoquinoline   2ohm: X-ray crystal structure of beta secretase complexed with N~3~-benzylpyridine-2,3-diamine   2ohn: X-ray crystal structure of beta secretase complexed with 4-(4-fluorobenzyl)piperidine   2ohp: X-ray crystal structure of beta secretase complexed with compound 3   2ohq: X-ray crystal structure of beta secretase complexed with compound 4   2ohr: X-ray crystal structure of beta secretase complexed with compound 6a   2ohs: X-ray crystal structure of beta secretase complexed with compound 6b   2oht: X-ray crystal structure of beta secretase complexed with compound 7   2ohu: X-ray crystal structure of beta secretase complexed with compound 8b   2ph6: Crystal Structure of Human Beta Secretase Complexed with inhibitor