Biochemical Inhibition of the Acetyltransferases ATase1 and ATase2 Reduces β-Secretase (BACE1) Levels and Aβ Generation

Autor: Yun Ding, Mi Hee Ko, Shahriar Salamat, Yun Luo, Noël R. Peters, Luigi Puglielli, Frank W. Kotch, Mariana Pehar
Rok vydání: 2012
Předmět:
Lysine Acetyltransferases
PC12 Cells
Biochemistry
Mice
0302 clinical medicine
Neurobiology
Cricetinae
Amyloid precursor protein
Aspartic Acid Endopeptidases
Enzyme Inhibitors
Neurons
0303 health sciences
Lysine Acetylation
Neurodegenerative Diseases
BACE1
Up-Regulation
3. Good health
medicine.anatomical_structure
Amyloid Precursor Protein
Neuroglia
medicine.symptom
Alzheimer's disease
Amyloid
Mice
Transgenic
CHO Cells
Biology
Gene Expression Regulation
Enzymologic
03 medical and health sciences
Cricetulus
Acetyl Coenzyme A
Alzheimer Disease
Acetyltransferases
mental disorders
medicine
Animals
Humans
Molecular Biology
030304 developmental biology
Amyloid beta-Peptides
Cell Biology
medicine.disease
Rats
Mechanism of action
biology.protein
Amyloid Precursor Protein Secretases
Amyloid precursor protein secretase
030217 neurology & neurosurgery
Neuroscience
Zdroj: The Journal of Biological Chemistry
ISSN: 0021-9258
Popis: Background: The acetyltransferases ATase1 and ATase2 regulate the levels of BACE1, which is involved in the pathogenesis of Alzheimer disease (AD). Results: Both ATases are up-regulated in the brain of AD patients. ATase1/ATase2 inhibitors were identified. Structure-activity relationship, mechanisms of action, and biological effects were determined. Conclusion: ATase1/ATase2 inhibitors down-regulate levels and activity of BACE1. Significance: ATase1/ATase2 are potential targets to prevent AD.
The cellular levels of β-site APP cleaving enzyme 1 (BACE1), the rate-limiting enzyme for the generation of the Alzheimer disease (AD) amyloid β-peptide (Aβ), are tightly regulated by two ER-based acetyl-CoA:lysine acetyltransferases, ATase1 and ATase2. Here we report that both acetyltransferases are expressed in neurons and glial cells, and are up-regulated in the brain of AD patients. We also report the identification of first and second generation compounds that inhibit ATase1/ATase2 and down-regulate the expression levels as well as activity of BACE1. The mechanism of action involves competitive and non-competitive inhibition as well as generation of unstable intermediates of the ATases that undergo degradation.
Databáze: OpenAIRE
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