title: Mode of inhibitory action of Deltalac-acetogenins, a new class of inhibitors of bovine heart mitochondrial complex I.
abstract: We have revealed that Deltalac-acetogenins, a new class of inhibitors of bovine heart mitochondrial complex I (NADH-ubiquinone oxidoreductase), act differently from ordinary inhibitors such as rotenone and piericidin A [Ichimaru et al. (2005) Biochemistry 44, 816-825]. Since a detailed study of these unique inhibitors might provide new insight into the terminal electron transfer step of the enzyme, we further characterized their inhibitory action using the most potent Deltalac-acetogenin derivative (compound 1). Unlike ordinary complex I inhibitors, 1 had a dose-response curve for inhibition of the reduction of exogenous short-chain ubiquinones that was difficult to explain with a simple bimolecular association model. The inhibitory effect of 1 on ubiquinol-NAD(+) oxidoreductase activity (reverse electron transfer) was much weaker than that on NADH oxidase activity (forward electron transfer), indicating a direction-specific effect. These results suggest that the binding site of 1 is not identical to that of ubiquinone and the binding of 1 to the enzyme secondarily (or indirectly) disturbs the redox reaction of ubiquinone. Using endogenous and exogenous ubiquinone as an electron acceptor of complex I, we investigated the effect of 1 in combination with different ordinary inhibitors on the superoxide production from the enzyme. The results indicated that the level of superoxide production induced by 1 is significantly lower than that induced by ordinary inhibitors probably because of fewer electron leaks from the ubisemiquinone radical to molecular oxygen and that the site of inhibition by 1 is downstream of that by ordinary inhibitors. The unique inhibitory action of hydrophobic Deltalac-acetogenins may be closely associated with the dynamic function of the membrane domain of complex I.
authors.affiliation: Division of Applied Life Sciences, Graduate School of Agriculture, Kyoto University, Sakyo-ku, Kyoto 606-8502, Japan.
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Murai
authors.forename: Naoya
authors.initials: N
authors.lastname: Ichimaru
authors.forename: Masato
authors.initials: M
authors.lastname: Abe
authors.forename: Takaaki
authors.initials: T
authors.lastname: Nishioka
authors.forename: Hideto
authors.initials: H
authors.lastname: Miyoshi
mesh_terms: D054378:Acetogenins; D000818:Animals; D002417:Cattle; D004305:Dose-Response Relationship, Drug; D042967:Electron Transport Complex I / Q000037:antagonists & inhibitors*; D004583:Electrons; D005233:Fatty Alcohols / Q000737:chemistry / Q000494:pharmacology*; D007783:Lactones / Q000737:chemistry / Q000494:pharmacology*; D008564:Membrane Potentials / Q000187:drug effects; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000201:enzymology; D009097:Multienzyme Complexes / Q000378:metabolism; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism; D011522:Protons; D013367:Submitochondrial Particles / Q000187:drug effects / Q000201:enzymology; D013481:Superoxides / Q000378:metabolism
chemical_list: D054378:Acetogenins; D005233:Fatty Alcohols; D007783:Lactones; D009097:Multienzyme Complexes; D011522:Protons; D013481:Superoxides; C023107:NADH oxidase; D009247:NADH, NADPH Oxidoreductases; D042967:Electron Transport Complex I