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Functional characterization and target validation of alternative complex I of Plasmodium falciparum mitochondria

Biagini, Giancarlo ORCID: https://orcid.org/0000-0001-6356-6595, Viriyavejakul, P., O'Neill, P. M., Bray, Patrick and Ward, Steve ORCID: https://orcid.org/0000-0003-2331-3192 (2006) 'Functional characterization and target validation of alternative complex I of Plasmodium falciparum mitochondria'. Antimicrobial Agents and Chemotherapy, Vol 50, Issue 5, pp. 1841-1851.

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Abstract

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 CoQ, and decylubiquinone with an apparent K-m for NADH of approximately 17 and 5 IxM, 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 bc(1), complex is highly synergistic. The potential of targeting PfNDH2 as a chemotherapeutic strategy for drug development is discussed.

Item Type: Article
Subjects: QU Biochemistry > Cells and Genetics > QU 350 Cellular structures
QU Biochemistry > Cells and Genetics > QU 375 Cell physiology
QX Parasitology > Protozoa > QX 135 Plasmodia
WC Communicable Diseases > Tropical and Parasitic Diseases > WC 750 Malaria
Faculty: Department: Groups (2002 - 2012) > Molecular & Biochemical Parasitology Group
Digital Object Identifer (DOI): https://doi.org/10.1128/AAC.50.5.1841-1851.2006
Depositing User: Martin Chapman
Date Deposited: 05 Sep 2011 13:52
Last Modified: 06 Feb 2018 13:01
URI: https://archive.lstmed.ac.uk/id/eprint/1453

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