TITLE

Uncoupling Mechanism of Glycoside Antibiotic Aculeximycin in Isolated Rat-Liver Mitochondria

AUTHOR(S)
Miyoshi, Hideto; Tamaki, Motohito; Murata, Hideaki; Ikemoto, Takaya; Shibuya, Toshiro; Harada, Ken-ichi; Suzuki, Makoto; Iwamura, Hajime
PUB. DATE
January 1996
SOURCE
Journal of Biochemistry;1996, Vol. 119 Issue 2, p274
SOURCE TYPE
Academic Journal
DOC. TYPE
Article
ABSTRACT
Effects of basic glycoside antibiotic aculeximycin (ACM) on the oxidative phosphorylation of rat-liver mitochondria were examined. ACM was shown to be a potent uncoupler of the oxidative phosphorylation. To cause the same extent of respiration release, higher concentration of ACM was required in phosphate (P1)-free medium than in P1 medium. During the uncoupling caused by ACM in P1 medium, large amplitude swelling and oxidation of intramitochondrial NAD(P)H occurred, indicating that ACM remarkably enhances permeability of the inner mitochondrial membrane. The P1 uptake via P1/H+ symporter was shown to play an important, but not essential, role in the uncoupling by ACM, indicating the increase in membrane permeability is mostly due to acceleration of P1/H+ influx through P1/H+symporter activated by ACM. ACM is the first naturally occurring antibiotic, to our knowledge, which activates P1/H+ symporter. However, since the inhibition of P1/H+ symporter by N-ethylmaleimide did not completely abolish the uncoupling activity of ACM, and ACM induced the uncoupling even in P1-free medium, an increase in the membrane permeability for other ions, such as Na+ and K+, due to a different action mechanism has also to be considered. On the other hand, positively charged amine local anesthetics, like dibucaine, prevented the uncoupling activity by ACM in both P1 and P1, -free medium. The uncoupling activity of iV-diacetylated ACM lacking free ami no groups was ca. l/12Oth that of ACM, indicating that positively charged amino groups are important for the uncoupling activity. It is suggested that some specific interactions between positively charged amino groups of ACM and the binding site, which is probably negatively charged, are triggers that affect the permeability of the inner mitochondrial membrane. Amine local anesthetics may mask the negative charge of the binding site, thereby interfering with ACM binding.
ACCESSION #
80117212

 

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