Synthesis and inhibition mechanism of Delta lac-acetogenins, a novel type of inhibitor of bovine heart mitochondrial complex I.
We have synthesized Deltalac-acetogenins that are new acetogenin mimics possessing two n-alkyl tails without an alpha,beta-unsaturated gamma-lactone ring and suggested that their inhibition mechanism may be different from that of common acetogenins [Hamada et al. (2004) Biochemistry 43, 3651-3658]. To elucidate the inhibition mechanism of Deltalac-acetogenins in more detail, we carried out wide structural modifications of original Deltalac-acetogenins and characterized the inhibitory action with bovine heart mitochondrial complex I. In contrast to common acetogenins, both the presence of adjacent bis-THF rings and the stereochemistry around the hydroxylated bis-THF rings are important structural factors required for 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 Deltalac-acetogenins and equivalent to that of bullatacin, one of the most potent natural acetogenins. Double-inhibitor titration of steady-state complex I activity showed that the extent of inhibition of compound 7 and bullatacin is not additive, suggesting that the binding sites of the two inhibitors are not identical. Competition tests using a fluorescent ligand indicated 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 of other complex I inhibitors. Our results clearly demonstrate that Deltalac-acetogenins are a novel type of inhibitor acting at the terminal electron-transfer step of bovine complex I.
Ichimaru
Naoya
N
Division of Applied Life Sciences, Graduate School of Agriculture, Kyoto University, Sakyo-ku, Kyoto 606-8502, Japan.
Murai
Masatoshi
M
Abe
Masato
M
Hamada
Takeshi
T
Yamada
Yohsuke
Y
Makino
Sae
S
Nishioka
Takaaki
T
Makabe
Hidefumi
H
Makino
Asami
A
Kobayashi
Toshihide
T
Miyoshi
Hideto
H
D054378:Acetogenins; D000818:Animals; D001667:Binding, Competitive; D002417:Cattle; D042967:Electron Transport Complex I / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D005233:Fatty Alcohols / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D005663:Furans / Q000737:chemistry; D007783:Lactones / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D008929:Mitochondria, Heart / Q000201:enzymology*; D011485:Protein Binding; D013050:Spectrometry, Fluorescence; D013329:Structure-Activity Relationship; D013481:Superoxides / Q000378:metabolism; D017186:Titrimetry
D054378:Acetogenins; D004791:Enzyme Inhibitors; D005233:Fatty Alcohols; D005663:Furans; D007783:Lactones; D013481:Superoxides; C018674:tetrahydrofuran; D042967:Electron Transport Complex I