title: Synthesis and inhibition mechanism of Delta lac-acetogenins, a novel type of inhibitor of bovine heart mitochondrial complex I.
abstract: 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.
authors.affiliation: Division of Applied Life Sciences, Graduate School of Agriculture, Kyoto University, Sakyo-ku, Kyoto 606-8502, Japan.
authors.forename: Naoya
authors.initials: N
authors.lastname: Ichimaru
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Murai
authors.forename: Masato
authors.initials: M
authors.lastname: Abe
authors.forename: Takeshi
authors.initials: T
authors.lastname: Hamada
authors.forename: Yohsuke
authors.initials: Y
authors.lastname: Yamada
authors.forename: Sae
authors.initials: S
authors.lastname: Makino
authors.forename: Takaaki
authors.initials: T
authors.lastname: Nishioka
authors.forename: Hidefumi
authors.initials: H
authors.lastname: Makabe
authors.forename: Asami
authors.initials: A
authors.lastname: Makino
authors.forename: Toshihide
authors.initials: T
authors.lastname: Kobayashi
authors.forename: Hideto
authors.initials: H
authors.lastname: Miyoshi
mesh_terms: 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
chemical_list: D054378:Acetogenins; D004791:Enzyme Inhibitors; D005233:Fatty Alcohols; D005663:Furans; D007783:Lactones; D013481:Superoxides; C018674:tetrahydrofuran; D042967:Electron Transport Complex I