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Title: The Toxoplasma gondii type-II NADH dehydrogenase TgNDH2-I is inhibited by 1-hydroxy-2-alkyl-4(1H)quinolones.
Authors: Lin SS1, Kerscher S, Saleh A, Brandt U, Gross U, Bohne W.
Keywords: Alternative (type-II) NADH dehydrogenase (NDH2)Toxoplasma gondiiInhibition kineticsPing-pong mechanism1-Hydroxy-2-alkyl-4(1)quinoloneHDQ
Issue Date: 9-Apr-2008
Publisher: Biochimica et Biophysica Acta (BBA) - Bioenergetics, ScienceDirect
Citation: Lin et al., 2008 S.S. Lin, S. Kerscher, A. Saleh, U. Brandt, U. Gross, W. Bohne The Toxoplasma gondii type-II NADH dehydrogenase TgNDH2-I is inhibited by 1-hydroxy-2-alkyl-4(1H)quinolones Biochim Biophys Acta, 1777 (2008), pp. 1455-1462
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 C(12) (HDQ) and C(14) are high affinity inhibitors for TgNDH2-I, while compounds with shorter side chains (C(5) and C(6)) displayed significantly higher IC(50) 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.
Description: Resaerch Article on drug discovery for malaria and toxoplasmosis
ISSN: 0005-2728
Appears in Collections:Applied science faculty

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