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Antimicrobial Agents and Chemotherapy, May 2006, p. 1841-1851, Vol. 50, No. 5
0066-4804/06/$08.00+0     doi:10.1128/AAC.50.5.1841-1851.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Functional Characterization and Target Validation of Alternative Complex I of Plasmodium falciparum Mitochondria

Giancarlo A. Biagini,1* Parnpen Viriyavejakul,1 Paul M. O'Neill,2 Patrick G. Bray,1 and Stephen A. Ward1*

Liverpool School of Tropical Medicine, Pembroke Place, Liverpool L35 QA,1 Departments of Chemistry and Pharmacology, University of Liverpool, Liverpool L69 7ZD, United Kingdom2

Received 24 January 2006/ Accepted 3 February 2006

This study reports on the first characterization of the alternative NADH:dehydrogenase (also known as alternative complex I or type II NADH:dehydrogenase) of the human malaria parasite Plasmodium falciparum, known as PfNDH2. PfNDH2 was shown to actively oxidize NADH in the presence of quinone electron acceptors CoQ1 and decylubiquinone with an apparent Km for NADH of approximately 17 and 5 µM, respectively. The inhibitory profile of PfNDH2 revealed that the enzyme activity was insensitive to rotenone, consistent with recent genomic data indicating the absence of the canonical NADH:dehydrogenase enzyme. PfNDH2 activity was sensitive to diphenylene iodonium chloride and diphenyl iodonium chloride, known inhibitors of alternative NADH:dehydrogenases. Spatiotemporal confocal imaging of parasite mitochondria revealed that loss of PfNDH2 function provoked a collapse of mitochondrial transmembrane potential ({Psi}m), leading to parasite death. As with other alternative NADH:dehydrogenases, PfNDH2 lacks transmembrane domains in its protein structure, and therefore, it is proposed that this enzyme is not directly involved in mitochondrial transmembrane proton pumping. Rather, the enzyme provides reducing equivalents for downstream proton-pumping enzyme complexes. As inhibition of PfNDH2 leads to a depolarization of mitochondrial {Psi}m, this enzyme is likely to be a critical component of the electron transport chain (ETC). This notion is further supported by proof-of-concept experiments revealing that targeting the ETC's Q-cycle by inhibition of both PfNDH2 and the bc1 complex is highly synergistic. The potential of targeting PfNDH2 as a chemotherapeutic strategy for drug development is discussed.

* Corresponding author. Mailing address: Liverpool School of Tropical Medicine, Pembroke Place, Liverpool L35QA, United Kingdom. Phone: 44 1517053151. Fax: 44 1517053371. E-mail for Giancarlo A. Biagini: Biagini{at}liv.ac.uk. E-mail for Stephen A. Ward: saward{at}liv.ac.uk.

Antimicrobial Agents and Chemotherapy, May 2006, p. 1841-1851, Vol. 50, No. 5
0066-4804/06/$08.00+0     doi:10.1128/AAC.50.5.1841-1851.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

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