Inhibitors and Activators of the Mitochondrial Reduced Diphosphopyridine Nucleotide Dehydrogenase

Abstract

Abstract The inhibitor response properties of the mitochondrial DPNH dehydrogenase have been studied with both the particle-bound and the soluble forms of the enzyme. Electron transfer from the particle-bound DPNH dehydrogenase to the respiratory chain is inhibited by barbiturates, Demerol, rotenone, and piericidin A, whereas the activities of the soluble enzyme are essentially unaffected by these inhibitors. In contrast, the ferricyanide reductase, as well as other diaphorase activities, of the soluble DPNH dehydrogenase is inhibited by mercurials, whereas the bound dehydrogenase appears to be protected against such mercurial attack. o-Phenanthroline interacts with the soluble dehydrogenase, inhibits its activities, and causes the release of labile sulfide from the enzyme. However, other bidentate iron chelators such as bathophenanthroline sulfonate and Tiron do not inhibit the enzyme but interact with it and protect it against inhibition by o-phenanthroline. These studies have indicated that in DPNH dehydrogenase the complex among iron, labile sulfide groups, and cysteine sulfur residues must have a tetrahedral structure. Adenosine phosphates inhibit DPNH dehydrogenase in the same manner as does DPN, but adenosine, nicotinamide mononucleotide, and NMNH are not inhibitory. Guanidinium compounds activate the soluble DPNH dehydrogenase, but inhibit the coenzyme Q reductase activity of the particulate DPNH-coenzyme Q reductase (Complex I). The activating effect of guanidinium compounds on the soluble dehydrogenase is associated not only with an increase in the value of Vmax, but also with a substantial decrease in the value of Kmdpnh (3-fold at 50 mm guanidine).