Biochemical inhibition of the acetyltransferases ATase1 and ATase2 reduces β-secretase (BACE1) levels and Aβ generation.
Biochemical inhibition of the acetyltransferases ATase1 and ATase2 reduces β-secretase (BACE1) levels and Aβ generation.
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DOI：
10.1074/jbc.m111.310136
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发表时间：
2012-03-09
期刊：
影响因子：
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通讯作者：
Puglielli L
中科院分区：
文献类型：
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作者：
Ding Y;Ko MH;Pehar M;Kotch F;Peters NR;Luo Y;Salamat SM;Puglielli L
背景：乙酰转移酶ATase 1和ATase 2调节BACE 1的水平，参与阿尔茨海默病（Alzheimer disease，AD）的发病。结果：AD患者脑组织中两种AT酶均表达上调。鉴定了ATase 1/ATase 2抑制剂。构效关系，作用机制和生物效应进行了测定。结论：ATase 1/ATase 2抑制剂下调BACE 1的水平和活性。意义：ATase 1/ATase 2是预防AD的潜在靶点。β位点APP裂解酶1（BACE 1）是阿尔茨海默病（AD）淀粉样β肽（Aβ）生成的限速酶，其细胞水平受两种基于ER的乙酰辅酶A（赖氨酸乙酰转移酶，ATase 1和ATase 2）的严格调节。在这里，我们报告说，这两种乙酰转移酶都在神经元和神经胶质细胞中表达，并且在AD患者的大脑中上调。我们还报道了第一代和第二代化合物的鉴定，其抑制ATase 1/ATase 2并下调BACE 1的表达水平和活性。作用机制包括竞争性和非竞争性抑制以及产生不稳定的AT酶中间体，这些中间体进行降解。
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.