title: Synthesis and inhibitory action of novel acetogenin mimics with bovine heart mitochondrial complex I.
abstract: Studies on the inhibition mechanism of acetogenins, the most potent inhibitors of complex I, are useful to elucidate the structural and functional features of the terminal electron-transfer step of this enzyme. We synthesized acetogenin mimics that possess two alkyl tails without a gamma-lactone ring, named Deltalac-acetogenin, and examined their inhibitory action on bovine heart mitochondrial complex I. Unexpectedly, the Deltalac-acetogenin carrying two n-undecanyl groups (compound 3) elicited very potent inhibition comparable to that of bullatacin. The inhibitory potency of compound 3 markedly decreased with shortening the length of either or both alkyl tails, indicating that symmetric as well as hydrophobic properties of the inhibitor are important for the inhibition. Both acetylation and deoxygenation of either or both of two OH groups adjacent to the tetrahydrofuran (THF) rings resulted in a significant decrease in inhibitory potency. These structural dependencies of the inhibitory action of Deltalac-acetogenins are in marked contrast to those of ordinary acetogenins. Double-inhibitor titration of steady-state complex I activity showed that inhibition of compound 3 and bullatacin are not additive, though the inhibition site of both inhibitors is downstream of iron-sulfur cluster N2. Our results indicate that the mode of inhibitory action of Deltalac-acetogenins differs from that of ordinary acetogenins. Therefore, Deltalac-acetogenins can be regarded as a novel type of inhibitor acting on the terminal electron-transfer step of complex I.
authors.affiliation: Division of Applied Life Sciences, Graduate School of Agriculture, Kyoto University, Sakyo-ku, Kyoto 606-8502, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Hamada
authors.forename: Naoya
authors.initials: N
authors.lastname: Ichimaru
authors.forename: Masato
authors.initials: M
authors.lastname: Abe
authors.forename: Daisuke
authors.initials: D
authors.lastname: Fujita
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kenmochi
authors.forename: Takaaki
authors.initials: T
authors.lastname: Nishioka
authors.forename: Klaus
authors.initials: K
authors.lastname: Zwicker
authors.forename: Ulrich
authors.initials: U
authors.lastname: Brandt
authors.forename: Hideto
authors.initials: H
authors.lastname: Miyoshi
mesh_terms: D054378:Acetogenins; D000818:Animals; D002417:Cattle; D004578:Electron Spin Resonance Spectroscopy; D042967:Electron Transport Complex I / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000138:chemical synthesis*; D005233:Fatty Alcohols / Q000138:chemical synthesis*; D005663:Furans / Q000138:chemical synthesis; D006571:Heterocyclic Compounds / Q000138:chemical synthesis; D007506:Iron-Sulfur Proteins / Q000378:metabolism; D007783:Lactones / Q000138:chemical synthesis*; D008929:Mitochondria, Heart / Q000201:enzymology*; D018716:Molecular Mimicry; D010084:Oxidation-Reduction; D013329:Structure-Activity Relationship; D013367:Submitochondrial Particles / Q000201:enzymology
chemical_list: D054378:Acetogenins; D004791:Enzyme Inhibitors; D005233:Fatty Alcohols; D005663:Furans; D006571:Heterocyclic Compounds; D007506:Iron-Sulfur Proteins; D007783:Lactones; C061022:bullatacin; D042967:Electron Transport Complex I