Journal
BIOCHIMICA ET BIOPHYSICA ACTA-BIOENERGETICS
Volume 1777, Issue 11, Pages 1455-1462Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.bbabio.2008.08.006
Keywords
Alternative (type-II) NADH dehydrogenase (NDH2); Toxoplasma gondii; Inhibition kinetics; Ping-pong mechanism; 1-Hydroxy-2-alkyl-4(1)quinolone; HDQ
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Funding
- Deutsche Forschungsgemeinschaft [130 1557/3-1]
- Croucher foundation [SFB472, Teilprojekt P2, EXC115]
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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 Using inhibition kinetics we demonstrate here that 1-hydroxy-2-alkyl-4(1)quinolones with long mechanism. 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. (C) 2008 Elsevier B.V. All rights reserved.
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