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首页> 外文期刊>Biochemistry >Indolequinone Inhibitors of NRH:Quinone Oxidoreductase 2. Characterization of the Mechanism of Inhibition in both Cell-Free and Cellular Systems
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Indolequinone Inhibitors of NRH:Quinone Oxidoreductase 2. Characterization of the Mechanism of Inhibition in both Cell-Free and Cellular Systems

机译：NRH：醌氧化还原酶的吲哚醌抑制剂。2在无细胞和细胞系统中抑制机理的表征

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摘要

We describe a series of indolequinones as efficient mechanism- based inhibitors of NRH:quinone oxidoreductase 2 (NQO2) for use either in cellular or cell-free systems. Compounds were designed to be reduced in the active site of the enzyme leading to loss of a substituted phenol leaving group and generation of a reactive iminium electrophile. Inhibition of NQO2 activity was assessed in both cell-free systems and the human leukemia K562 cell line. Inhibition of recombinant human NQO2 by the indolequinones was NRH-dependent, with kinetic parameters characteristic of mechanism-based inhibition and partition ratios as low as 2.0. Indolequinones inhibited NQO2 activity in K562 cells at nanomolar concentrations that did not inhibit NQO1 and were nontoxic to cells. Computation-based molecular modeling simulations demonstrated favorable conformations of indolequinones positioned directly above and in parallel with the isoalloxazine ring of FAD, and mass spectrometry extended our previous finding of adduction of the FAD in the active site of NQO2 by an indolequinone-derived iminium electrophile to the wider series of indolequinone inhibitors. Modeling combined with biochemical testing identified key structural parameters for effective inhibition, including a 5-aminoalkylamino side chain. Hydrogen bonding of the terminal amine nitrogen in the aminoalkylamino side chain was found to be critical for the correct orientation of the inhibitors in the active site. These indolequinones were irreversible inhibitors and were found to be at least 1 order of magnitude more potent than any previously documented competitive inhibitors of NQO2 and represent the first mechanism-based inhibitors of NQO2 to be characterized in cellular systems.
机译：我们将一系列吲哚醌作为NRH：醌氧化还原酶2（NQO2）的有效机理基础抑制剂，用于细胞或无细胞系统。设计化合物使其在酶的活性位点还原，从而导致取代的苯酚离去基团丢失并产生反应性亚胺基亲电子试剂。在无细胞系统和人类白血病K562细胞系中均评估了NQO2活性的抑制作用。吲哚醌对重组人NQO2的抑制作用是NRH依赖性的，其动力学参数具有基于机理的抑制作用，分配比低至2.0。吲哚醌以不抑制NQO1且对细胞无毒的纳摩尔浓度抑制K562细胞中的NQO2活性。基于计算的分子建模模拟表明，吲哚醌在FAD的异四恶嗪环正上方并与之平行排列的构象良好，而质谱法将我们先前发现的由吲哚醌衍生的亚胺基亲电子试剂将FAD在NQO2的活性位点内加成的构象扩展到了各种吲哚醌抑制剂。建模与生化测试相结合，确定了有效抑制的关键结构参数，包括5-氨基烷基氨基侧链。发现氨基烷基氨基侧链中的末端胺氮的氢键对于抑制剂在活性位点的正确取向至关重要。这些吲哚醌是不可逆的抑制剂，并且其效力比任何先前记录的NQO2竞争性抑制剂强至少1个数量级，并且代表了首个在细胞系统中表征的基于机理的NQO2抑制剂。

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