Bongkrekic Acid Analogue, Lacking One of the Carboxylic Groups of its Parent Compound, Shows Moderate but pH-insensitive Inhibitory Effects on the Mitochondrial ADP/ATP Carrier
Bongkrekic Acid Analogue, Lacking One of the Carboxylic Groups of its Parent Compound, Shows Moderate but pH-insensitive Inhibitory Effects on the Mitochondrial ADP/ATP Carrier
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Bongkrekic Acid 类似物缺乏其母体化合物的一个羧基，对线粒体 ADP/ATP 载体显示出中等但 pH 不敏感的抑制作用
DOI：
10.1111/cbdd.12594
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发表时间：
2015
期刊：
影响因子：
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通讯作者：
Yasuo Shinohara
中科院分区：
文献类型：
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作者：
Atsushi Yamamoto;Keisuke Hasui;Hiroshi Matsuo;Katsuhiro Okuda;Masato Abe;Kenji Matsumoto;Kazuki Harada;Yuya Yoshimura;Takenori Yamamoto;Kazuto Ohkura;Mitsuru Shindo;Yasuo Shinohara
Bongkrekic酸是从柯氏伯克氏菌中分离出来的，已知能特异性抑制线粒体ADP/ATP载体。然而，它与航母的互动方式仍然难以捉摸。在这项研究中，我们测试了17种bongkrekic酸类似物对线粒体ATP/ATP载体的抑制作用，这些类似物是从其全合成过程中获得的中间体中提取的。粗略筛选这些化学物质，通过测量它们对线粒体ATP合成的抑制作用，发现其中4种，KH‐1,KH‐7，KH‐16和KH‐17，具有中等抑制作用。进一步表征这4种类似物对线粒体功能的作用表明，KH‐16具有中度；KH‐1和KH‐17，弱；和KH‐7，线粒体内膜通透性和抑制电子传递的副作用都可以忽略不计，这表明只有KH‐7对线粒体ADP/ATP载体有特异性抑制作用。虽然母体bongkrekic酸对其作用表现出强烈的pH依赖性，但KH‐7的抑制作用对反应介质的pH几乎不敏感，这表明bongkrekic酸的3个羧基对其pH依赖性作用的重要性。KH‐7对线粒体ADP/ATP载体的直接抑制作用也被清楚地证明。
Bongkrekic acid, isolated fromBurkholderia cocovenenans, is known to specifically inhibit the mitochondrial ADP/ATP carrier. However, the manner of its interaction with the carrier remains elusive. In this study, we tested the inhibitory effects of 17 bongkrekic acid analogues, derived from the intermediates obtained during its total synthesis, on the mitochondrial ATP/ATP carrier. Rough screening of these chemicals, performed by measuring their inhibitory effects on the mitochondrial ATP synthesis, revealed that 4 of them, KH‐1, KH‐7, KH‐16, and KH‐17, had moderate inhibitory effects. Further characterization of the actions of these 4 analogues on mitochondrial function showed that KH‐16 had moderate; KH‐1 and KH‐17, weak; and KH‐7, negligible side effects of both permeabilization of the mitochondrial inner membrane and inhibition of the electron transport, indicating that only KH‐7 had a specific inhibitory effect on the mitochondrial ADP/ATP carrier. Although the parental bongkrekic acid showed a strong pH dependency of its action, the inhibitory effect of KH‐7 was almost insensitive to the pH of the reaction medium, indicating the importance of the 3 carboxyl groups of bongkrekic acid for its pH‐dependent action. A direct inhibitory effect of KH‐7 on the mitochondrial ADP/ATP carrier was also clearly demonstrated.