Essential structural factors of annonaceous acetogenins as potent inhibitors of mitochondrial complex I.
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.
Division of Applied Life Sciences, Graduate School of Agriculture, Kyoto University, Japan. miyoshi@kais.kyoto-u.ac.jp
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Miyoshi
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Ohshima
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Shimada
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Akagi
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Iwamura
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McLaughlin
D000818:Animals; D002417:Cattle; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D005663:Furans / Q000737:chemistry* / Q000494:pharmacology*; D007700:Kinetics; D007783:Lactones / Q000737:chemistry* / Q000494:pharmacology*; D008929:Mitochondria, Heart / Q000201:enzymology; D008958:Models, Molecular; D008968:Molecular Conformation; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000037:antagonists & inhibitors*; D010944:Plants / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D005663:Furans; D007783:Lactones; C112079:isomurisolenin; D016660:NAD(P)H Dehydrogenase (Quinone)