The effect of alkylguanidines on mitochondrial metabolism.
نویسنده
چکیده
In 1955 Hollunger (1) showed that with isolated mitochondria, guanidine, methylguanidine, and asym-dimethylguanidine inhibited the adenosine diphosphate-stimulated oxidation of those substrates with diphosphopyridine nucleotide-linked dehydrogenases, whereas succinate oxidation was far less affected. When dinitrophenol was used to stimulate respiration, no marked inhibition was noted. Hollunger claimed that methylguanidine was less effective than the unsubstituted compound, but Pressman (2) has reported that the monosubstituted guanidines were more potent inhibitors and were more effective with increasing length of the alkyl chain. Since Lardy, Johnson, and McMurray (3) have shown that oligomycin inhibits the adenosine diphosphate-, but not the dinitrophenol-stimulated oxidation of various substrates by mitochondria, the guanidines and oligomycin share some common properties. However, the two compounds differ in their effects on succinate oxidation. Oligomycin has been shown to inhibit at the phosphorylation site between cytochromes b and c, and also at that in the vicinity of the cytochrome oxidase, and it has been deduced that it also acts at the site between diphosphopyridine nucleotide and cytochrome b (4). Guanidine and the monosubstituted derivatives are restricted in their sites of action to the latter step (1, 2). In the course of experiments with the guanidine derivative galegine (4-methyl-3-butenylguanidine) it was noted that inhibition of adenosine diphosphate-stimulated oxidation occurred more readily and at lower concentrations of alkylguanidine when the mitochondria were not actively respiring, i.e. when they were in the “resting” condition (State 4 of Chance and Williams (5)). These findings indicate that the alkylguanidines combine with an energy-rich intermediate involved in the phosphorylation process. In contrast, oligomycin inhibited oxidation equally well in both the active and resting phases of respiration. The effects of galegine on pyridine nucleotide reduction and oxidation in mitochondria and the effects of this compound on the energy-linked reduction of pyridine nucleotide are described.
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ورودعنوان ژورنال:
- The Journal of biological chemistry
دوره 238 شماره
صفحات -
تاریخ انتشار 1963