Ascochlorin is a novel, specific inhibitor of the mitochondrial cytochrome bc1 complex.
Ascochlorin is a novel, specific inhibitor of the mitochondrial cytochrome bc1 complex.
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DOI：
10.1016/j.bbabio.2009.12.003
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发表时间：
2010-03
影响因子：
4.3
通讯作者：
Minagawa, Nobuko
中科院分区：
文献类型：
--
作者：
Berry, Edward A.;Huang, Li-shar;Lee, Dong-Woo;Daldal, Fevzi;Nagai, Kazuo;Minagawa, Nobuko
Ascochlorin是由植物病原真菌Ascochyta viciae产生的类异戊二烯抗生素。与通过作用于泛醇结合结构域特异性抑制锥虫交替氧化酶的子囊呋喃酮类似，子囊二氢蛋白在结构上也与泛醇相关。当添加到从大鼠肝脏分离的线粒体制剂，或酵母毕赤酵母（汉逊酵母）异常，子囊二氢菌素抑制电子传递通过辅酶Q的方式可比抗霉素A和stigmatellin，表明这种抗生素作用于细胞色素bc1复合物。与子囊二氢酚相比，子囊呋喃酮对相同活性的抑制作用要小得多。一方面，与气位抑制剂抗霉素A和funiculosin一样，子囊二氢酚在H.异常的核编码的交替氧化酶基因的表达比测试的Qo位点抑制剂强得多。另一方面，它抑制细胞色素B的还原和超氧阴离子的产生，在抗霉素A3的存在下，以类似于Qo位点抑制剂myxothiazol的方式。这些结果表明，子囊二氢酚可能在真菌细胞色素bc1复合物的Qi和Qo位点上起作用。事实上，改变的电子顺磁共振（EPR）线的形状的Rieske铁硫蛋白，和光诱导的时间分辨细胞色素B和C还原动力学的红细菌capsulatus细胞色素bc1复合物中存在的子囊二氢卟酚证明，这种抑制剂可以结合到两个Qo和Qi网站的细菌酶。使用纯化的牛细胞色素bc1复合物的其他实验表明，子囊二氢卟酚通过Qi和Qo位点抑制泛醌对细胞色素B的还原。此外，鸡细胞色素bc1复合物的晶体结构与过量的子囊二氢卟酚处理揭示了明确的电子密度，可以归因于子囊二氢卟酚结合在齐和Qo网站。总体研究结果清楚地表明，子囊二氯酚是一种不寻常的细胞色素bc1抑制剂，在这两个酶的活性位点的行为。
Ascochlorin is an isoprenoid antibiotic that is produced by the phytopathogenic fungus Ascochyta viciae. Similar to ascofuranone, which specifically inhibits trypanosome alternative oxidase by acting at the ubiquinol binding domain, ascochlorin is also structurally related to ubiquinol. When added to the mitochondrial preparations isolated from rat liver, or the yeast Pichia (Hansenula) anomala, ascochlorin inhibited the electron transport via CoQ in a fashion comparable to antimycin A and stigmatellin, indicating that this antibiotic acted on the cytochrome bc1 complex. In contrast to ascochlorin, ascofuranone had much less inhibition on the same activities. On the one hand, like the Qi site inhibitors antimycin A and funiculosin, ascochlorin induced in H. anomala the expression of nuclear-encoded alternative oxidase gene much more strongly than the Qo site inhibitors tested. On the other hand, it suppressed the reduction of cytochrome b and the generation of superoxide anion in the presence of antimycin A3 in a fashion similar to the Qo site inhibitor myxothiazol. These results suggested that ascochlorin might act at both the Qi and the Qo sites of the fungal cytochrome bc1 complex. Indeed, the altered electron paramagnetic resonance (EPR) line shape of the Rieske iron-sulfur protein, and the light-induced time resolved cytochrome b and c reduction kinetics of Rhodobacter capsulatus cytochrome bc1 complex in the presence of ascochlorin demonstrated that this inhibitor can bind to both the Qo and Qi sites of the bacterial enzyme. Additional experiments using purified bovine cytochrome bc1 complex showed that ascochlorin inhibits reduction of cytochrome b by ubiquinone through both Qi and Qo sites. Moreover, crystal structure of chicken cytochrome bc1 complex treated with excess ascochlorin revealed clear electron densities that could be attributed to ascochlorin bound at both the Qi and Qo sites. Overall findings clearly show that ascochlorin is an unusual cytochrome bc1 inhibitor that acts at both of the active sites of this enzyme.
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