Potent and selective inhibition of the tumor marker AKR1B10 by bisdemethoxycurcumin: Probing the active site of the enzyme with molecular modeling and site-directed mutagenesis
Potent and selective inhibition of the tumor marker AKR1B10 by bisdemethoxycurcumin: Probing the active site of the enzyme with molecular modeling and site-directed mutagenesis
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DOI：
10.1016/j.bbrc.2009.08.107
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发表时间：
2009-11-06
影响因子：
3.1
通讯作者：
Hara, Akira
中科院分区：
文献类型：
--
作者：
Matsunaga, Toshiyuki;Endo, Satoshi;Hara, Akira
AKR1B10 是醛酮还原酶 (AKR) 超家族的人类成员，与醛糖还原酶 (AR) 具有高度序列同一性，最近被确定为治疗多种癌症的治疗靶点。我们比较了植物成分对重组 AKR1B10 和 AR 的抑制作用。姜黄素、厚朴酚、和厚朴酚和白藜芦醇对AKR1B10有抑制作用，IC(50)值为0.06-5μM，低于其对AR的抑制作用。其中，双去甲氧基姜黄素是最有效的竞争性抑制剂（K(i) = 22 nM），选择性最高（与 AR 相比为 85 倍），在细胞水平上是有效的抑制剂。相比之下，去甲氧基姜黄素和姜黄素的效力和选择性要低 3 倍以上。 AKR1B10-NADP(+) 复合物中类姜黄素的分子对接研究和假定结合残基的定点诱变表明，Gln114、Val301 和 Gln303 对于确定类姜黄素的抑制效力和选择性非常重要。 (C) 2009 Elsevier Inc. 保留所有权利。
A human member of the aldo-keto reductase (AKR) superfamily, AKR1B10, shares high sequence identity with aldose reductase (AR), and was recently identified as a therapeutic target in the treatment of several types of cancer. We have compared the inhibitory effects of plant components on recombinant AKR1B10 and AR. AKR1B10 was inhibited by curcuminoids, magnolol, honokiol and resveratrol, with IC(50) values of 0.06-5 mu M, which were lower than their values for AR. Among them, bisdemethoxycurcumin was the most potent competitive inhibitor (K(i) = 22 nM) with the highest selectivity (85-fold versus AR), and acted as an effective inhibitor in cellular level. In contrast, demethoxycurcumin and curcumin showed >3-fold less potency and selectivity. Molecular docking studies of the curcuminoids in the AKR1B10-NADP(+) complex and site-directed mutagenesis of the putative binding residues suggest that Gln114, Val301 and Gln303 are important for determining the inhibitory potency and selectivity of the curcuminoids. (C) 2009 Elsevier Inc. All rights reserved.