Yabunaka Hiromi, Kenmochi Atsushi, Nakatogawa Yasushi, Sakamoto Kimitoshi, Miyoshi Hideto
Division of Applied Life Sciences, Graduate School of Agriculture, Kyoto University, Kita-shirakawa, Sakyo-ku, 606-8502, Kyoto, Japan.
Biochim Biophys Acta. 2002 Dec 2;1556(2-3):106-12. doi: 10.1016/s0005-2728(02)00341-9.
We synthesized novel ubiquinone analogs by hybridizing the natural ubiquinone ring (2,3-dimethoxy-5-methyl-1,4-benzoquinone) and hydrophobic phenoxybenzamide unit, and named them hybrid ubiquinones (HUs). The HUs worked as electron transfer substrates with bovine heart mitochondrial succinate-ubiquinone oxidoreductase (complex II) and ubiquinol-cytochrome c oxidoreductase (complex III), but not with NADH-ubiquinone oxidoreductase (complex I). With complex I, they acted as inhibitors in a noncompetitive manner against exogenous short-chain ubiquinones irrespective of the presence of the natural ubiquinone ring. Elongation of the distance between the ubiquinone ring and the phenoxybenzamide unit did not recover the electron accepting activity. The structure/activity study showed that high structural specificity of the phenoxybenzamide moiety is required to act as a potent inhibitor of complex I. These findings indicate that binding of the HUs to complex I is mainly decided by some specific interaction of the phenoxybenzamide moiety with the enzyme. It is of interest that an analogous bulky and hydrophobic substructure can be commonly found in recently registered synthetic pesticides the action site of which is mitochondrial complex I.
我们通过将天然泛醌环（2,3-二甲氧基-5-甲基-1,4-苯醌）与疏水性苯氧基苯甲酰胺单元杂交合成了新型泛醌类似物，并将它们命名为杂交泛醌（HUs）。HUs可作为牛心线粒体琥珀酸-泛醌氧化还原酶（复合体II）和泛醇-细胞色素c氧化还原酶（复合体III）的电子传递底物，但不能作为NADH-泛醌氧化还原酶（复合体I）的电子传递底物。对于复合体I，无论天然泛醌环是否存在，它们都以非竞争性方式对外源短链泛醌起抑制剂作用。泛醌环与苯氧基苯甲酰胺单元之间距离的延长并不能恢复电子接受活性。结构/活性研究表明，苯氧基苯甲酰胺部分需要具有高结构特异性才能作为复合体I的有效抑制剂。这些发现表明，HUs与复合体I的结合主要由苯氧基苯甲酰胺部分与该酶的某些特定相互作用决定。有趣的是，在最近注册的合成农药中通常可以发现类似的庞大且疏水的亚结构，其作用位点是线粒体复合体I。
