Inhibitor Probes of the Quinone Binding Sites of Mammalian Complex II and Escherichia coli Fumarate Reductase

Continuing our previous studies to develop selective and effective probes of the quinone chemistry in the respiratory chain, we investigated four 2-alkyl-4,6-dinitrophenol derivatives as inhibitors of quinone reduction and oxidation in beef heart succinate dehydrogenase and E. coli fumarate reductase

Victoria Yankovskaya; Sergei O. Sablin; Rona R. Ramsay; Thomas P. Singer; Brian A.C. Ackrell; Gary Cecchini; Hideto Miyoshi

2002

Scholarcy highlights

  • Unit containing an 8a-histidyl-FAD moiety, and an iron-sulfur subunit with three distinct Fe-S clusters that transport electrons between the FAD and bound quinones, and two transmembrane polypeptides which contain the quinone binding sites
  • The anchor subunits show very little sequence homology among species, which probably accounts for the fact that thenoyltrifluoroacetone and carboxanilides, two types of highly potent inhibitors of electron transfer to quinone in the mammalian succinate dehydrogenase complex, do not inhibit E. coli fumarate reductase
  • This report compares the structurepotency relationships of several 2-alkyl-4,6-dinitrophenols as inhibitors of quinone reduction and quinol oxidation by beef heart complex II and by wild-type and mutant forms of E. coli fumarate reductase impaired by single amino acid substitutions at the putative QA1 and QB binding sites
  • Inhibition of Mammalian Succinate Dehydrogenase by 2-Substituted 4,6-Dinitrophenols—The 2-alkyl-4,6-dinitrophenol derivatives shown in Table I were tested for their effects on quinone reduction and quinol oxidation by the enzyme
  • In contrast to the incomplete inhibition noted in our earlier study, with the more potent inhibitors and the extended range of concentrations used in the present work, complete inhibition of membrane-bound succinate dehydrogenase was attained
  • Continuing our previous studies to develop selective and effective probes of the quinone chemistry in the respiratory chain, we investigated four 2-alkyl-4,6-dinitrophenol derivatives as inhibitors of quinone reduction and oxidation in beef heart succinate dehydrogenase and E. coli fumarate reductase
  • In the reverse direction, based on the Ki values obtained from the complementary series of experiments using quinone reduction as the test assay, which are presented, it is clear that substitution of Glu-29 with Asp increased the potency of all of the 2-alkyl-substituted dinitrophenol derivatives some 14 –20-fold

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