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(5): 1304-22, 2015 Nov.
Article
en En
| MEDLINE
| ID: mdl-26032198
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.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Ácido Bongcréquico
/
Mitocondrias Hepáticas
/
Translocasas Mitocondriales de ADP y ATP
/
Inhibidores Enzimáticos
Límite:
Animals
Idioma:
En
Revista:
Chem Biol Drug Des
Asunto de la revista:
BIOQUIMICA
/
FARMACIA
/
FARMACOLOGIA
Año:
2015
Tipo del documento:
Article
País de afiliación:
Japón