KH-17, a simplified derivative of bongkrekic acid, weakly inhibits the mitochondrial ADP/ATP carrier from both sides of the inner mitochondrial membrane
KH-17, a simplified derivative of bongkrekic acid, weakly inhibits the mitochondrial ADP/ATP carrier from both sides of the inner mitochondrial membrane
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KH-17 是 bongkrekic 酸的简化衍生物，从线粒体内膜两侧微弱抑制线粒体 ADP/ATP 载体
DOI：
10.1111/cbdd.14194
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发表时间：
2023
影响因子：
3
通讯作者：
Shinohara Yasuo
中科院分区：
文献类型：
--
作者：
Takegawa Kazuto;Ito Takeshi;Yamamoto Atsushi;Yamazaki Naoshi;Shindo Mitsuru;Shinohara Yasuo
已知有两种天然产物，bongkrekic acid和carboxyloxide，在10− 6 M的浓度范围内，分别从基质侧和胞质侧特异性抑制线粒体ADP/ATP载体。在本研究中，我们研究了一种合成的bongkrekic酸衍生物KH-17对线粒体ADP/ATP载体的作用方式，KH-17缺少三个甲基，一个甲氧基和五个内部双键。在微酸性pH下，KH-17抑制线粒体[3 H]ADP摄取，但其抑制作用比其母体化合物米松酸弱约10倍。KH-17的主要作用位点通过使用亚线粒体颗粒的实验被证实为ADP/ATP载体的基质侧，亚线粒体颗粒具有线粒体内膜的内向外方向。然而，当我们将KH-17加入到中性pH的线粒体中时，它对[3 H]ADP摄取有微弱的抑制作用，其抑制强度与米松酸相似。这些结果表明，KH-17不仅从基质侧而且从胞质侧弱抑制ADP/ATP载体。为了确定这种解释是否正确，我们在两种[3 H]ADP浓度下检查了KH-17和羧甲苷对线粒体[3 H]ADP摄取的影响。我们发现KH-17和羧甲苷在较低的[3 H]ADP浓度下表现出较强的抑制作用。因此，我们得出结论，米酵菌酸衍生物KH-17从线粒体内膜的两侧微弱地抑制线粒体ADP/ATP载体。这些结果表明，消除三个甲基，一个甲氧基，和五个内部双键存在于bongkrekic酸改变其对线粒体ADP/ATP载体的作用方式。我们的数据将有助于提高我们的理解之间的相互作用bongkrekic酸和线粒体ADP/ATP载体。
Two natural products, bongkrekic acid and carboxyatractyloside, are known to specifically inhibit the mitochondrial ADP/ATP carrier from its matrix side and cytosolic side, respectively, in concentration ranges of 10−6M. In the present study, we investigated the manner of action of a synthetic bongkrekic acid derivative, KH‐17, lacking three methyl groups, one methoxy group, and five internal double bonds, on the mitochondrial ADP/ATP carrier. At slightly acidic pH, KH‐17 inhibited mitochondrial [3H]ADP uptake, but its inhibitory action was about 10 times weaker than that of its parental compound, bongkrekic acid. The main site of action of KH‐17 was confirmed as the matrix side of the ADP/ATP carrier by experiments using submitochondrial particles, which have an inside‐out orientation of the inner mitochondrial membrane. However, when we added KH‐17 to mitochondria at neutral pH, it had a weak inhibitory effect on [3H]ADP uptake, and its inhibitory strength was similar to that of bongkrekic acid. These results indicated that KH‐17 weakly inhibits the ADP/ATP carrier not only from the matrix side but also from the cytosolic side. To ascertain whether this interpretation was correct, we examined the effects of KH‐17 and carboxyatractyloside on mitochondrial [3H]ADP uptake at two [3H]ADP concentrations. We found that both KH‐17 and carboxyatractyloside showed a stronger inhibitory effect at the lower [3H]ADP concentration. Therefore, we concluded that the bongkrekic acid derivative, KH‐17, weakly inhibits the mitochondrial ADP/ATP carrier from both sides of the inner mitochondrial membrane. These results suggested that the elimination of three methyl groups, one methoxy group, and five internal double bonds present in bongkrekic acid altered its manner of action towards the mitochondrial ADP/ATP carrier. Our data will help to improve our understanding of the interaction between bongkrekic acid and the mitochondrial ADP/ATP carrier.