Natural tetramic acids elicit multiple inhibitory actions against mitochondrial machineries presiding over oxidative phosphorylation
Natural tetramic acids elicit multiple inhibitory actions against mitochondrial machineries presiding over oxidative phosphorylation
复制标题
天然特特拉姆酸对负责氧化磷酸化的线粒体机制产生多种抑制作用
DOI：
10.1093/bbb/zbab176
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Miyoshi Hideto
中科院分区：
文献类型：
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作者：
Unten Yufu;Murai Masatoshi;Sakai Katsuyuki;Asami Yukihiro;Yamamoto Takenori;Masuya Takahiro;Miyoshi Hideto
通过氧化磷酸化来控制ATP合成的线粒体机制是有希望的药物靶点。Fusaramin是从Fusarium concentricum FKI-7550中分离得到的一种3-酰基特特拉姆酸，是酵母线粒体氧化磷酸化的抑制剂，但其作用靶点尚未确定。在抑制氧化磷酸化的浓度范围内，Fusaramin显著干扰酵母线粒体对[3 H]ADP的摄取。一种特异性标记电压依赖性阴离子通道1（VDAC 1）的光反应性fusaramin衍生物（pFS-5），可促进ADP/ATP跨线粒体外膜运输。这些结果强烈表明，fusaramin的氧化磷酸化的抑制主要归因于VDAC 1功能的损害。Fusaramin还抑制FoF 1-ATP合酶和泛喹啉-细胞色素氧化还原酶（复合物III）的浓度高于VDAC抑制所需的浓度。考虑到其他特特拉姆酸衍生物被报道抑制FoF 1-ATP合酶和复合物III，发现天然特特拉姆酸引起针对线粒体机制的多种抑制作用。
The mitochondrial machineries presiding over ATP synthesis via oxidative phosphorylation are promising druggable targets. Fusaramin, a 3-acyl tetramic acid isolated fromFusarium concentricumFKI-7550, is an inhibitor of oxidative phosphorylation inSaccharomyces cerevisiaemitochondria, although its target has yet to be identified. Fusaramin significantly interfered with [3H]ADP uptake by yeast mitochondria at the concentration range inhibiting oxidative phosphorylation. A photoreactive fusaramin derivative (pFS-5) specifically labeled voltage-dependent anion channel 1 (VDAC1), which facilitates trafficking of ADP/ATP across the outer mitochondrial membrane. These results strongly suggest that the inhibition of oxidative phosphorylation by fusaramin is predominantly attributable to the impairment of VDAC1 functions. Fusaramin also inhibited FoF1-ATP synthase and ubiquinol-cytochromecoxidoreductase (complex III) at concentrations higher than those required for the VDAC inhibition. Considering that other tetramic acid derivatives are reported to inhibit FoF1-ATP synthase and complex III, natural tetramic acids were found to elicit multiple inhibitory actions against mitochondrial machineries.