The Toxoplasma gondii type-II NADH dehydrogenase TgNDH2-I is inhibited by 1-hydroxy-2-alkyl-4(1H)quinolones |
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Authors: | San San Lin,Ahmad Saleh,Uwe Groß |
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Affiliation: | a Institute of Medical Microbiology, University of Göttingen, Kreuzbergring 57, Göttingen D-37075, Germany b Johann Wolfgang Goethe-Universität, Fachbereich Medizin, Zentrum der Biologischen Chemie, Molekulare Bioenergetik, Centre of Excellence Frankfurt “Macromolecular Complexes”, Frankfurt am Main, Germany |
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Abstract: | The apicomplexan parasite Toxoplasma gondii does not possess complex I of the mitochondrial respiratory chain, but has two genes encoding rotenone-insensitive, non-proton pumping type-II NADH dehydrogenases (NDH2s). The absence of such “alternative” NADH dehydrogenases in the human host defines these enzymes as potential drug targets. TgNDH2-I and TgNDH2-II are constitutively expressed in tachyzoites and bradyzoites and are localized to the mitochondrion as shown by epitope tagging. Functional expression of TgNDH2-I in the yeast Yarrowia lipolytica as an internal enzyme, with the active site facing the mitochondrial matrix, permitted growth in the presence of the complex I inhibitor DQA. Bisubstrate kinetics of TgNDH2-I measured within Y. lipolytica mitochondrial membrane preparations were in accordance with a ping-pong mechanism. Using inhibition kinetics we demonstrate here that 1-hydroxy-2-alkyl-4(1)quinolones with long alkyl chains of C12 (HDQ) and C14 are high affinity inhibitors for TgNDH2-I, while compounds with shorter side chains (C5 and C6) displayed significantly higher IC50 values. The efficiency of the various quinolone derivatives to inhibit TgNDH2-I enzyme activity mirrors their inhibitory potency in vivo, suggesting that a long acyl site chain is critical for the inhibitory potential of these compounds. |
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Keywords: | HFF, human foreskin fibroblasts HDQ, 1-Hydroxy-2-Dodecyl-4(1H)Quinolone HHQ, 1-Hydroxy-2-Hexyl-4(1H)Quinolone HPQ, 1-Hydroxy-2-Pentyl-4(1H)Quinolone HTQ, 1-Hydroxy-2-Tetradecyl-4(1H)Quinolone |
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