Mitochondrial complex II, the succinate:ubiquinone oxidoreductase (SQR, EC 1.3.5.1), catalyzes the oxidation of succinate to fumarate as a partial reaction of the tricarboxylic acid cycle (TCA). Since it transfers the electrons to the terminal acceptor ubiquinone, the SQR physically links the TCA cycle to the respiratory chain where the redox equivalents are available for respiratory energy conservation.  SQR has been solubilized from housefly flight muscle mitochondria and purified through ion-exchange chromatography or native (�clear-native�) electrophoresis. Enzyme kinetic data are presented that acrylonitrile insecticides and acaricides inhibit purified housefly complex II by interfering with quinone reduction. Inhibition is mixed-mode with respect to the quinone substrate indicating that the inhibitor binds to the free enzyme as well as to the enzyme-substrate complex. The X-ray structure of thiapronil bound to chicken complex II reveals characteristic features of quinoid inhibitors. A bifurcated H-bond is established between the carbonyl-/enol-oxygen and residues TyrD58 and TrpB173 of the transmembrane subunit SdhD and the ISP, respectively. Two fungicidal SQR inhibitors, flutolaniland fluopyram, inhibit Caenorhabditis elegans complex II. Interestingly, both compounds are at least 1000-times less active on the mammalian ortholog isolated from rat heart. An intriguing feature of nematodes is the expression of a complex II isoform catalyzing the reverse reaction, quinol-dependent fumarate reduction, under hypoxic conditions. Anaerobic respiration through fumarate reductase (QFR) requires rhodoquinone, which has a much more negative standard redox potential than ubiquinone. Interestingly, flutolanil and fluopyram inhibit both SQR and QFR activities of the parasitic nematode Haemonchus contortus, suggesting that the quinone sites of aerobic and anaerobic complex II are similar. Our enzyme kinetic studies have been substantiated by recently published X-ray structural data of QFR isolated from the parasitic nematode, Ascaris suum.

Mitochondrial respiratory complex II: Molecular target of novel active ingredients for pest management

248th National Meeting (2014)

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