Miyoshi H, Ohshima M, Shimada H, Akagi T, Iwamura H, McLaughlin J L
Division of Applied Life Sciences, Graduate School of Agriculture, Kyoto University, Japan.
Biochim Biophys Acta. 1998 Jul 20;1365(3):443-52. doi: 10.1016/s0005-2728(98)00097-8.
The annonaceous acetogenins are the most potent of the known inhibitors of bovine heart mitochondrial complex I. These inhibitors act, at the terminal electron transfer step of the enzyme, in a similar way to the usual complex I inhibitors, such as piericidin A and rotenone; however, structural similarities are not apparent between the acetogenins and these known complex I inhibitors. A systematic set of isolated natural acetogenins was prepared and examined for their inhibitory actions with bovine heart mitochondrial complex I to identify the essential structural factors of these inhibitors for the exhibition of potent activity. Despite their very potent activity, the structural requirements of the acetogenins are not particularly rigid and remain somewhat ambiguous. The most common structural units, such as adjacent bis-tetrahydrofuran (THF) rings and hydroxyl groups in the 4- and/or 10-positions, were not essential for exhibiting potent activity. The stereochemistry surrounding the THF rings, surprisingly, seemed to be unimportant, which was corroborated by an exhaustive conformational space search analysis, indicating that the model compounds, with different stereochemical arrangements around the THF moieties, were in fairly good superimposition. Proper length and flexibility of the alkyl spacer moiety, which links the THF and the alpha, beta-unsaturated gamma-lactone ring moieties, were essential for the potent activity. This probably results from some sort of specific conformation of the spacer moiety which regulates the two ring moieties to locate into an optimal spatial position on the enzyme. It is, therefore, suggested that the structural specificity of the acetogenins, required for optimum inhibition, differs significantly from that of the common complex I inhibitors in which essential structural units are compactly arranged and conveniently defined. The structure-activity profile for complex I inhibition is discussed in comparison with those for other biological activities.
番荔枝内酯是已知的对牛心线粒体复合物I最有效的抑制剂。这些抑制剂在该酶的末端电子传递步骤中发挥作用，其方式与常见的复合物I抑制剂（如杀粉蝶菌素A和鱼藤酮）相似；然而，番荔枝内酯与这些已知的复合物I抑制剂之间没有明显的结构相似性。制备了一组系统的天然分离番荔枝内酯，并检测它们对牛心线粒体复合物I的抑制作用，以确定这些抑制剂发挥强效活性所需的基本结构因素。尽管番荔枝内酯具有很强的活性，但其结构要求并非特别严格，仍有些不明确。最常见的结构单元，如相邻的双四氢呋喃（THF）环以及4位和/或10位的羟基，对于发挥强效活性并非必不可少。令人惊讶的是，THF环周围的立体化学似乎并不重要，详尽的构象空间搜索分析证实了这一点，这表明围绕THF部分具有不同立体化学排列的模型化合物具有相当好的重叠性。连接THF和α,β-不饱和γ-内酯环部分的烷基间隔部分的适当长度和灵活性对于强效活性至关重要。这可能是由于间隔部分的某种特定构象，它调节两个环部分在酶上定位到最佳空间位置。因此，有人提出，最佳抑制所需的番荔枝内酯的结构特异性与常见的复合物I抑制剂有很大不同，在常见的复合物I抑制剂中，基本结构单元紧密排列且易于确定。与其他生物活性的结构-活性关系相比，讨论了复合物I抑制的结构-活性关系。
