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ID 113787
Title Alternative
pH-resistant Inhibitor of Mitochondrial ADP/ATP Carrier
Author
Yamamoto, Atsushi Suzuka University of Medical Science
Hasui, Keisuke Kyushu University
Matsuo, Hiroshi Kyushu University
Okuda, Katsuhiro Kyushu University
Abe, Masato Kyushu University
Matsumoto, Kenji Kyushu University
Harada, Kazuki Tokushima University
Yoshimura, Yuya Tokushima University
Ohkura, Kazuto Suzuka University of Medical Science
Shindo, Mitsuru Kyushu University
Keywords
ADP/ATP carrier
bongkrekic acid(BKA)
mitochondria
mitochondrial solute carrier (SLC25a)
Content Type
Journal Article
Description
Bongkrekic acid (BKA), 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 the present 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, done by measuring their inhibitory effects on the mitochondrial ATP synthesis, revealed that 4 of them, KH-1, 7, 16, and 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 BKA for its pH- dependent action. A direct inhibitory effect of KH-7 on the mitochondrial ADP/ATP carrier was also clearly demonstrated.
Journal Title
Chemical Biology & Drug Design
ISSN
17470277
17470285
NCID
AA12108214
AA12571955
Publisher
John Wiley & Sons
Volume
86
Issue
5
Start Page
1304
End Page
1322
Published Date
2015-05-29
Rights
This is the peer reviewed version of the following article: Yamamoto, A. , Hasui, K. , Matsuo, H. , Okuda, K. , Abe, M. , Matsumoto, K. , Harada, K. , Yoshimura, Y. , Yamamoto, T. , Ohkura, K. , Shindo, M. and Shinohara, Y. (2015), 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. Chem Biol Drug Des, 86: 1304-1322, which has been published in final form at https://doi.org/10.1111/cbdd.12594. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions.
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DOI (Published Version)
URL ( Publisher's Version )
FullText File
language
eng
TextVersion
Author
departments
Institute of Advanced Medical Sciences