Crucial structural factors and mode of action of polyene Amides as inhibitors for mitochondrial NADH-Ubiquinone oxidoreductase (Complex I)
Crucial structural factors and mode of action of polyene Amides as inhibitors for mitochondrial NADH-Ubiquinone oxidoreductase (Complex I)
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DOI：
10.1021/bi7010306
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发表时间：
2007-09-11
期刊：
影响因子：
2.9
通讯作者：
Miyoshi, Hideto
中科院分区：
文献类型：
--
作者：
Yoshida, Takehiko;Murai, Masatoshi;Miyoshi, Hideto
天然抗生素多烯酰胺类如粘素酰胺类是线粒体复合物I的有效抑制剂。由于这一系列化合物由于扩展的π-共轭骨架而显著不稳定，因此尚未对其抑制作用进行详细表征。为了阐明多烯化合物与配合物1的作用机制和结合方式，需要确定每个官能团在抑制作用中的作用。本文合成了一系列酰胺类似物，并以牛心脏线粒体复合物I为底物进行了构效关系研究。关于左手部分，许多天然产物共有的天然π-共辄骨架对于抑制作用不是必需的，并且可以被更简单的子结构如共辄二烯取代。左手部分的几何形状和形状被证明是重要的抑制，这表明该部分可能结合到一个狭窄的疏水口袋中的酶，而不仅仅是分配到脂质膜相。关于抑制剂的右侧部分，2-甲基、酰胺NH和（S）-1 '-甲基的存在对于活性是至关重要的，这表明与酰胺基团相邻的两个甲基精细地调节酰胺基团的氢键结合能力。相反，2 ′-OH基团的修饰对活性没有显著影响，这表明该官能团的作用不是作为酶的氢键供体，而是作为亲水性锚，将右侧部分引导到膜表面或膜表面附近。详细的表征的作用机制表明，多烯酰胺共享一个共同的结合域与其他复合物I抑制剂，虽然他们的结合位置（或方式）的域内可能有很大的不同，从其他抑制剂。
Natural antibiotic polyene amides such as myxalamides are potent inhibitors of mitochondrial complex I. Because of the significant instability of this series of compounds due to an extended pi-conjugation skeleton, a detailed characterization of their inhibitory action has not been performed. To elucidate the action mechanism as well as binding manner of polyene an-tides with complex 1, identification of the roles of each functional group in the inhibitory action is needed. We here synthesized a series of amide analogues and carried out structure-activity studies with bovine heart mitochondrial complex I. With respect to the left-hand portion, the natural pi-conjugation skeleton common to many natural products is not required for the inhibition and can be substituted with a simpler substructure such as a conjugated diene. The geometry and shape of the left-hand portion were shown to be important for the inhibition, suggesting that this portion may bind to a narrow hydrophobic pocket in the enzyme rather than merely partitioning into the lipid membrane phase. Concerning the right-hand portion of the inhibitor, the presence of the 2-methyl, amide NH, and (S)-1'-methyl groups was crucial for the activity, suggesting that both methyl groups neighboring the amide group finely adjust the hydrogen-bonding ability of the amide group. in contrast, modifications of the 2'-OH group did not significantly influence the activity, suggesting that the role of this functional group is not to serve as a hydrogen bond donor to the enzyme but to act as a hydrophilic anchor directing the right-hand portion at or near the membrane surface. Detailed characterization of the action mechanism indicated that the polyene amides share a common binding domain with other complex I inhibitors, though their binding position (or manner) within the domain may differ considerably from that of other inhibitors.