Fig. 1: The distinct rhodoquinone-dependent metabolism of parasitic helminths is an attractive target for anthelmintic development.
From: Identification of a family of species-selective complex I inhibitors as potential anthelmintics
a Ubiquinone-coupled aerobic electron transport chain (ETC). Electrons generated from the oxidation of NADH and succinate enter the ETC through complexes I and II. Electrons are first transferred to the electron carrier, ubiquinone (UQ) and are ultimately shuttled through complexes III and IV, where they exit the ETC through the reduction of O2. Electron-coupled proton translocation at complexes I, III and IV establishes the proton motive force necessary to drive ATP synthase. b Rhodoquinone-coupled anaerobic ETC (Rhodoquinone-dependent metabolism). Electrons from the oxidation of NADH still enter the ETC through the activity of complex I, but are transferred to an alternative electron carrier, rhodoquinone (RQ). In contrast to aerobic conditions, RQ shuttles electrons to complex II, where acting in reverse as a fumarate reductase, fumarate is used as the terminal electron acceptor instead of oxygen. Complex I acts as the sole proton pump to establish the proton gradient to drive the synthesis of ATP by ATP synthase. c Key targets for inhibitors of RQ-dependent metabolism. Compounds capable of targeting complex I (sole electron entry point, sole proton pump), complex II (key electron exit point), and RQ synthesis (anaerobic specific electron carrier) are likely to act as anthelmintic candidates. d L1 wild-type and kynu-1 (RQ-deficient) mutant worms treated with 200 µM KCN for 15 h. Survival and overall health of worms were assessed relative to untreated controls by monitoring worm motility over the course of 3 h following the removal of KCN. e L1 wild-type worms treated with 12.5 µM rotenone (complex I inhibitor) or 25 µM wact-11 (complex II inhibitor) in combination with 200 µM KCN for 15 h. Survival and overall health of worms were assessed relative to DMSO controls by monitoring worm motility over the course of 3 h following the removal of KCN. All data are the mean of at least three biological replicates; shaded regions are SEM.
