Identification of Chaulmoogric Acid as a Small Molecule Activator of Protein Phosphatase 5
Identification of Chaulmoogric Acid as a Small Molecule Activator of Protein Phosphatase 5
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DOI：
10.1007/s12010-009-8647-3
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发表时间：
2010-03-01
影响因子：
3
通讯作者：
Zhang, Bin
中科院分区：
文献类型：
--
作者：
Cher, Charmian;Tremblay, Marie-Helene;Zhang, Bin
蛋白磷酸酶5(PP5)是一种重要的蛋白磷酸酶，在中枢神经系统中大量表达。最近的研究表明，阿尔茨海默病(AD)患者大脑皮层PP5活性显著降低，提示小分子PP5激活剂可能对AD具有治疗潜力。我们利用微源化合物文库对PP5激活剂进行了生化筛选。圆二色谱(CD)和限制性蛋白分解研究结果表明，Chaulmoogric酸结合到PP5的四肽重复序列区域，导致螺旋含量完全丧失。这些结果表明了与花生四烯酸不同的作用机制，花生四烯酸是一种已知的PP5去磷酸化活性激活剂。当两种化合物在较低浓度下联合使用时，也观察到了PP5酶活性的协同激活。因此，进一步的构效关系研究可能有助于发现与内源性花生四烯酸协同激活PP5的小分子。
Protein phosphatase 5 (PP5) is an important protein phosphatase that is abundantly expressed in the central nervous system. Recent studies showed that PP5 activity in the neocortex from patients with Alzheimer's disease (AD) is decreased significantly, suggesting that small molecule PP5 activator may have therapeutic potential for AD. We performed a biochemical screening for PP5 activators with the microsource compound library. Chaulmoogric acid was identified to be an effective activator with EC50 value of 134.5 mu M. Importantly, results from circular dichroism (CD) and limited proteolysis study showed that chaulmoogric acid binds to a region of tetratricopeptide repeat (TPR) domain of PP5 resulting in complete loss of helical contents. These results demonstrate a different mechanism of action from that of arachidonic acid, a known activator for PP5 dephosphorylation activity. Synergistic activation of PP5 enzymatic activity was also observed with combined application of both compounds at relatively low concentrations. Therefore, further structure activity relationship study of chaulmoogric acid may facilitate the discovery of small molecules that can synergize with endogenous arachidonic acid for PP5 activation.