Biosynthesis of ubiquinones by malarial parasites. I. Isolation of 14C-labeled ubiquinones from cultures of rhesus monkey blood infected with Plasmodium knowlesi

Skelton, Frederick S.; Lunan, Kenneth D.; Folkers, Karl; Schnell, Jerome V.; Siddiqui, Wasim A.; Geiman, Quentin M.

doi:10.1021/bi00831a064

Cited by 30 publications

(9 citation statements)

References 12 publications

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“…The reaction was functionally isolated from other respiratory complexes by the action of atovaquone and cyanide for complexes III and IV, respectively. The native ubiquinone of P. falciparum is CoQ 8 (42,43), but as this is too hydrophobic and cannot be used as an exogenous substrate, we assayed PfNDH2 activity using the more hydrophilic short-chain analogs CoQ 1 (with only one isoprenoid unit in the side chain) and DB, which contains a 10-carbon linear saturated side chain. Quinone-dependent oxidation of NADH displayed Michaelis-Menten kinetics ( (Table 1).…”

Section: Resultsmentioning

confidence: 99%

“…P. falciparum mitochondria use a different homolog of ubiquinone (CoQ 8 ) than their mammalian host (42,43), and several antimalarial drugs show specificity for parasite CoQ, including the hydroxynaphthoquinones (13, 50). This strategy led to the development of atovaquone (20), an inhibitor of complex III (or bc 1 complex), which has been successful clinically, especially in combination with proguanil (Malarone), for the treatment of chloroquine-resistant infections (31).…”

Section: As Inhibition Of Pfndh2 Leads To a Depolarization Of Mitochomentioning

confidence: 99%

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

Biagini

Viriyavejakul

O’Neill

et al. 2006

Antimicrob Agents Chemother

116

110

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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 1 and decylubiquinone with an apparent K m for NADH of approximately 17 and 5 M, 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 (⌿ 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 ⌿ 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.New empirical estimates put the number of episodes of clinical Plasmodium falciparum malaria in the range of half a billion per year (44). It is estimated that, from these infections, approximately 2.7 million deaths occur per year, mostly among young children under the age of five (6). Unfortunately, these staggering figures are on the increase, largely as a result of parasite multidrug resistance (45). A number of strategies have been proposed to deal with this global health problem, one of which is the development of novel drugs for new parasite targets (4).In search of new antimalarial drug targets, we have focused on the electron transport chain (ETC) of the malaria parasite mitochondrion. The recently completed malaria genome project revealed that P. falciparum mitochondria lack the conventional rotenone-sensitive complex I (or NADH:dehydrogenase) found in most mammalian mitochondria but instead contain an alternative complex I (or type II NADH:dehydrogenase) (22). The activity of this enzyme has yet to be biochemically confirmed in the human malaria parasite P. falciparum; however, it has recently been detected in the rodent malaria parasite Plasmodium yoelii (49). Alternative NADH: dehydrogenases have been described in some detail for plants, fungi, and bacteria (25, 32, 33, 36, 40, 53). Type II NADH: dehydrogenases are ro...

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Section: Resultsmentioning

confidence: 99%

Section: As Inhibition Of Pfndh2 Leads To a Depolarization Of Mitochomentioning

confidence: 99%

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

Biagini

Viriyavejakul

O’Neill

et al. 2006

Antimicrob Agents Chemother

116

110

View full text Add to dashboard Cite

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“…Ubiquinones and dolichols are the dominant extraplastidial end products of the isoprenoid synthesis pathway in Plasmodium spp. [57][58][59][60]. In addition, several proteins of P. falciparum are modified by the attachment of farnesyl or geranylgeranyl residues [61,62].…”

Section: Isoprenoid Synthesismentioning

confidence: 99%

The Plastid-Like Organelle of Apicomplexan Parasites as Drug Target

Wiesner

Reichenberg²,

Heinrich³

et al. 2008

CPD

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Apicomplexan parasites infectious to humans include Plasmodium spp., Babesia spp., Toxoplasma gondii, Cryptosporidium spp., Isospora belli and Cyclospora cayetanensis. With exception of Cryptosporidium spp., these parasites possess a non-photosynthetic plastid-like organelle called apicoplast. The apicoplast possesses a small circular genome and harbours prokaryotic-type biochemical pathways. As the most important metabolic functions, the mevalonate independent 1-deoxy-D-xylulose 5-phosphate pathway of isoprenoid synthesis and the type II fatty acid synthesis system are operative inside the apicoplast. Classical antibacterial drugs such as ciprofloxacin, tetracycline, doxycycline, clindamycin and spiramycin inhibit the apicoplast-located gyrase and translation machinery, respectively, and are currently used in the clinic for the treatment of infections with apicomplexan parasites. As an inhibitor of isoprenoid synthesis, fosmidomycin was proven to be effective against acute P. falciparum malaria in clinical phase II studies. Triclosan, an inhibitor of fatty acid synthesis, was active in a malaria mouse model. In vitro antimalarial activity was shown for inhibitors of peptide deformylase and the import of apicoplast-targeted proteins. Work on various other inhibitors of apicoplast-located biochemical processes is ongoing.

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“…Biosynthesis of isoprenoids in P. falciparum -The first reports demonstrating the biosynthesis of isoprenoids in Plasmodium were published by Rietz et al (1967) and Skelton et al (1969), showing the occurrence of ubiquinones-8 and 9 in Plasmodium lophurae and the identification of ubiquinone-8 biosynthesised by P. knowlesi, Plasmodium cynomolgi, and Plasmodium berghei. Afterwards, Mbaya et al (1990) showed that schizont extracts of P. falciparum biosynthesised isoprenoid until the farnesyl pyrophosphate step upon incubation with […”

Section: Mep Pathway In P Falciparum -Various Attemptsmentioning

confidence: 99%