- Beta-secretase 1
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.
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. 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
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.
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.
Relationship to plasmepsin
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.
- Beta-secretase 2
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PDB gallery1fkn: Structure of Beta-Secretase Complexed with Inhibitor1m4h: Crystal Structure of Beta-secretase complexed with Inhibitor OM00-31sgz: Crystal Structure of Unbound Beta-Secretase Catalytic Domain.1tqf: Crystal structure of human Beta secretase complexed with inhibitor1w50: APO STRUCTURE OF BACE (BETA SECRETASE)1w51: BACE (BETA SECRETASE) IN COMPLEX WITH A NANOMOLAR NON-PEPTIDIC INHIBITOR1xn2: 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-AUR2001ym4: Crystal structure of human beta secretase complexed with NVP-AMK6402b8l: Crystal structure of human beta secretase complexed with inhibitor2b8v: Crystal structure of human Beta-secretase complexed with L-L000430,4692f3e: Crystal Structure of the Bace complex with AXQ093, a macrocyclic inhibitor2f3f: Crystal Structure of the Bace complex with BDF488, a macrocyclic inhibitor2fdp: Crystal structure of beta-secretase complexed with an amino-ethylene inhibitor2g94: 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 inhibitor2hm1: 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 inhibitor2is0: Crystal structure of human Beta-secretase complexed with inhibitor2of0: X-ray crystal structure of beta secretase complexed with compound 52ohk: X-ray crystal structure of beta secretase complexed with 1-amino-isoquinoline2ohl: X-ray crystal structure of beta secretase complexed with 2-aminoquinoline2ohm: X-ray crystal structure of beta secretase complexed with N~3~-benzylpyridine-2,3-diamine2ohn: X-ray crystal structure of beta secretase complexed with 4-(4-fluorobenzyl)piperidine2ohp: X-ray crystal structure of beta secretase complexed with compound 32ohq: X-ray crystal structure of beta secretase complexed with compound 42ohr: X-ray crystal structure of beta secretase complexed with compound 6a2ohs: X-ray crystal structure of beta secretase complexed with compound 6b2oht: X-ray crystal structure of beta secretase complexed with compound 72ohu: X-ray crystal structure of beta secretase complexed with compound 8b2ph6: Crystal Structure of Human Beta Secretase Complexed with inhibitor Hydrolase: proteases (EC 3.4) 3.4.11-19: ExopeptidaseDipeptidase (1, 2, 3)Dipeptidyl peptidase (Cathepsin C, Dipeptidyl peptidase-4) · Tripeptidyl peptidase (Tripeptidyl peptidase I, Tripeptidyl peptidase II)Serine type carboxypeptidases: Cathepsin A · DD-transpeptidaseMetallocarboxypeptidases: Carboxypeptidase (A, A2, B, C, E, Glutamate II)Other/ungrouped 3.4.21-24: Endopeptidase
Serine proteases · Cysteine protease · Aspartic acid protease · MetalloendopeptidasesOther/ungrouped: Amyloid precursor protein secretase (Alpha secretase, Beta-secretase 1, Beta-secretase 2, Gamma secretase)
3.4.99: Unknown VertebratePepsin · Chymosin · Renin · Signal peptide peptidase · Beta secretase (1, 2) Pathogenic Plant CathepsinD · ECategories:
- Human proteins
- Integral membrane proteins
- EC 3.4.23
- Alzheimer's disease
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