Synthesis and Inhibition Mechanism of lac-Acetogenins, a Novel Type of Inhibitor of Bovine Heart Mitochondrial Complex I
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- 作者：Naoya Ichimaru ; Masatoshi Murai ; Masato Abe ; Takeshi Hamada ; Yohsuke Yamada ; Sae Makino ; Takaaki Nishioka ; Hidefumi Makabe ; Asami Makino ; Toshihide Kobayashi ; and Hideto Miyoshi
- 刊名：Biochemistry
- 出版年：2005
- 出版时间：January 18, 2005
- 年：2005
- 卷：44
- 期：2
- 页码：816 - 825
- 全文大小：173K
- 年卷期：v.44,no.2(January 18, 2005)
- ISSN：1520-4995
文摘
We have synthesized 
lac-acetogenins that are new acetogenin mimics possessing two n-alkyltails without an 
,
-unsaturated 
-lactone ring and suggested that their inhibition mechanism may bedifferent from that of common acetogenins [Hamada et al. (2004) Biochemistry 43, 3651-3658]. Toelucidate the inhibition mechanism of lac-acetogenins in more detail, we carried out wide structuralmodifications of original lac-acetogenins and characterized the inhibitory action with bovine heartmitochondrial complex I. In contrast to common acetogenins, both the presence of adjacent bis-THFrings and the stereochemistry around the hydroxylated bis-THF rings are important structural factors requiredfor potent inhibition. The inhibitory potency of a derivative possessing an n-butylphenyl ether structure(compound 7) appeared to be superior to that of the original lac-acetogenins and equivalent to that ofbullatacin, one of the most potent natural acetogenins. Double-inhibitor titration of steady-state complexI activity showed that the extent of inhibition of compound 7 and bullatacin is not additive, suggestingthat the binding sites of the two inhibitors are not identical. Competition tests using a fluorescent ligandindicated that the binding site of compound 7 does not overlap with that of other complex I inhibitors.The effects of compound 7 on superoxide production from complex I are also different from those ofother complex I inhibitors. Our results clearly demonstrate that lac-acetogenins are a novel type ofinhibitor acting at the terminal electron-transfer step of bovine complex I.
lac-acetogenins that are new acetogenin mimics possessing two n-alkyltails without an ,-unsaturated -lactone ring and suggested that their inhibition mechanism may bedifferent from that of common acetogenins [Hamada et al. (2004) Biochemistry 43, 3651-3658]. Toelucidate the inhibition mechanism of lac-acetogenins in more detail, we carried out wide structuralmodifications of original lac-acetogenins and characterized the inhibitory action with bovine heartmitochondrial complex I. In contrast to common acetogenins, both the presence of adjacent bis-THFrings and the stereochemistry around the hydroxylated bis-THF rings are important structural factors requiredfor potent inhibition. The inhibitory potency of a derivative possessing an n-butylphenyl ether structure(compound 7) appeared to be superior to that of the original lac-acetogenins and equivalent to that ofbullatacin, one of the most potent natural acetogenins. Double-inhibitor titration of steady-state complexI activity showed that the extent of inhibition of compound 7 and bullatacin is not additive, suggestingthat the binding sites of the two inhibitors are not identical. Competition tests using a fluorescent ligandindicated that the binding site of compound 7 does not overlap with that of other complex I inhibitors.The effects of compound 7 on superoxide production from complex I are also different from those ofother complex I inhibitors. Our results clearly demonstrate that lac-acetogenins are a novel type ofinhibitor acting at the terminal electron-transfer step of bovine complex I.