1 Department of Food Science and Nutrition, Dong-A University , Saha-gu, Busan, Korea.
J Med Food. 2014 Feb;17(2):284-9. doi: 10.1089/jmf.2013.2968.
In our ongoing research to find therapeutic compounds for Alzheimer's disease (AD) from natural resources, the inhibitory activity of the BACE1 enzyme by Tenebrio molitor larvae and its major compounds were evaluated. The T. molitor larvae extract and its fractions exhibited strong BACE1 suppression. The major components of hexane fraction possessing both high yield and strong BACE1 inhibition were determined by thin layer chromatography, gas chromatography, and nuclear magnetic resonance analysis. A remarkable composition of unsaturated long chain fatty acids, including oleic acid and linoleic acid, were identified. Oleic acid, in particular, noncompetitively attenuated BACE1 activity with a half-maximal inhibitory concentration (IC₅₀) value of 61.31 μM and Ki value of 34.3 μM. Furthermore, the fatty acids were stably interacted with BACE1 at different allosteric sites of the enzyme bound with the OH of CYS319 and the NH₃ of TYR320 for oleic acid and with the C=O group of GLN304 for linoleic acid. Here, we first revealed novel pharmacophore features of oleic acids and linoleic acid to BACE1 by in silico docking studies. The present findings would clearly suggest potential guidelines for designing novel BACE1 selective inhibitors.
在我们从自然资源中寻找治疗阿尔茨海默病（AD）的治疗化合物的持续研究中，评估了黄粉虫幼虫及其主要化合物对 BACE1 酶的抑制活性。黄粉虫幼虫提取物及其馏分表现出强烈的 BACE1 抑制作用。通过薄层层析、气相色谱和核磁共振分析确定了具有高产量和强 BACE1 抑制作用的正己烷馏分的主要成分。鉴定出含有油酸和亚油酸等不饱和长链脂肪酸的显著成分。特别是油酸，非竞争性地减弱 BACE1 活性，半数最大抑制浓度（IC₅₀）值为 61.31 μM，Ki 值为 34.3 μM。此外，脂肪酸与 BACE1 稳定相互作用，油酸与酶结合的 CYS319 的 OH 和 TYR320 的 NH₃ 以及亚油酸与 GLN304 的 C=O 基团位于不同的变构部位。在这里，我们首次通过计算机对接研究揭示了油酸和亚油酸对 BACE1 的新型药效团特征。这些发现将为设计新型 BACE1 选择性抑制剂提供明确的指导原则。
