title: Bongkrekic acid analogue, lacking one of the carboxylic groups of its parent compound, shows moderate but pH-insensitive inhibitory effects on the mitochondrial ADP/ATP carrier.
abstract: Bongkrekic acid, isolated from Burkholderia cocovenenans, is known to specifically inhibit the mitochondrial ADP/ATP carrier. However, the manner of its interaction with the carrier remains elusive. In this study, we tested the inhibitory effects of 17 bongkrekic acid analogues, derived from the intermediates obtained during its total synthesis, on the mitochondrial ATP/ATP carrier. Rough screening of these chemicals, performed by measuring their inhibitory effects on the mitochondrial ATP synthesis, revealed that 4 of them, KH-1, KH-7, KH-16, and KH-17, had moderate inhibitory effects. Further characterization of the actions of these 4 analogues on mitochondrial function showed that KH-16 had moderate; KH-1 and KH-17, weak; and KH-7, negligible side effects of both permeabilization of the mitochondrial inner membrane and inhibition of the electron transport, indicating that only KH-7 had a specific inhibitory effect on the mitochondrial ADP/ATP carrier. Although the parental bongkrekic acid showed a strong pH dependency of its action, the inhibitory effect of KH-7 was almost insensitive to the pH of the reaction medium, indicating the importance of the 3 carboxyl groups of bongkrekic acid for its pH-dependent action. A direct inhibitory effect of KH-7 on the mitochondrial ADP/ATP carrier was also clearly demonstrated.
authors.affiliation: Faculty of Pharmaceutical Sciences, Suzuka University of Medical Science, Minamitamagakicho-3500, Suzuka, Mie, 513-8670, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Yamamoto
authors.affiliation: Interdisciplinary Graduate School of Engineering Sciences, Kyushu University, 6-1 Kasuga-koen, Kasuga, 816-8580, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Hasui
authors.affiliation: Interdisciplinary Graduate School of Engineering Sciences, Kyushu University, 6-1 Kasuga-koen, Kasuga, 816-8580, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Matsuo
authors.affiliation: Institute for Materials Chemistry and Engineering, Kyushu University, Kasugakoen-6, Kasuga, Fukuoka, 816-8580, Japan.
authors.forename: Katsuhiro
authors.initials: K
authors.lastname: Okuda
authors.affiliation: Institute for Materials Chemistry and Engineering, Kyushu University, Kasugakoen-6, Kasuga, Fukuoka, 816-8580, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Abe
authors.affiliation: Institute for Materials Chemistry and Engineering, Kyushu University, Kasugakoen-6, Kasuga, Fukuoka, 816-8580, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Matsumoto
authors.affiliation: Institute for Genome Research, Tokushima University, Kuramotocho-3, Tokushima, 770-8503, Japan.|Faculty of Pharmaceutical Sciences, Tokushima University, Shomachi-1, Tokushima, 770-8505, Japan.
authors.forename: Kazuki
authors.initials: K
authors.lastname: Harada
authors.affiliation: Institute for Genome Research, Tokushima University, Kuramotocho-3, Tokushima, 770-8503, Japan.|Faculty of Pharmaceutical Sciences, Tokushima University, Shomachi-1, Tokushima, 770-8505, Japan.
authors.forename: Yuya
authors.initials: Y
authors.lastname: Yoshimura
authors.affiliation: Institute for Genome Research, Tokushima University, Kuramotocho-3, Tokushima, 770-8503, Japan.|Faculty of Pharmaceutical Sciences, Tokushima University, Shomachi-1, Tokushima, 770-8505, Japan.
authors.forename: Takenori
authors.initials: T
authors.lastname: Yamamoto
authors.affiliation: Faculty of Pharmaceutical Sciences, Suzuka University of Medical Science, Minamitamagakicho-3500, Suzuka, Mie, 513-8670, Japan.
authors.forename: Kazuto
authors.initials: K
authors.lastname: Ohkura
authors.affiliation: Institute for Materials Chemistry and Engineering, Kyushu University, Kasugakoen-6, Kasuga, Fukuoka, 816-8580, Japan.
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Shindo
authors.affiliation: Institute for Genome Research, Tokushima University, Kuramotocho-3, Tokushima, 770-8503, Japan.|Faculty of Pharmaceutical Sciences, Tokushima University, Shomachi-1, Tokushima, 770-8505, Japan.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Shinohara
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001865:Bongkrekic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006863:Hydrogen-Ion Concentration; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000378:metabolism; D000226:Mitochondrial ADP, ATP Translocases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats
chemical_list: D004791:Enzyme Inhibitors; D001865:Bongkrekic Acid; D000255:Adenosine Triphosphate; D000226:Mitochondrial ADP, ATP Translocases
keywords: ADP/ATP carrier; bongkrekic acid; mitochondria; mitochondrial solute carrier (SLC25a)