Coenzyme Q. 114. Biosynthesis of coenzymes Q by malarial parasites. 2. Coenzyme Q synthesis in blood cultures of monkeys infected with malarial parasites (Plasmodium falciparum and P. knowlesi)

Schnell, Jerome V.; Siddiqui, Wasim A.; Geiman, Quentin M.

doi:10.1021/jm00293a002

Cited by 30 publications

(20 citation statements)

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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

117

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

117

110

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“…Schnell et al [29] found the presence of coenzyme Q 8 and coenzyme Q 9 in P. falciparum by using [ 14 C]PHBA to label the benzoquinone ring in infected blood from the monkey species Aotus trivirgatus. We suggest that, as coenzyme Q acts as an antioxidant, the host's organism could be forcing the parasite to produce di¡erent homologs in order to resist di¡erent kinds of oxidative damage imposed by the immune system [30].…”

Section: Discussionmentioning

confidence: 99%

Characterization of the isoprenoid chain of coenzyme Q in Plasmodium falciparum

Macedo¹

2002

FEMS Microbiology Letters

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Little is known about isoprenoid biosynthesis in parasitic protozoa. The presence of dolichol and isoprenylated proteins has been detected in Plasmodium falciparum, but no studies are available about the biosynthesis of the isoprenic side chain attached to the benzoquinone ring of coenzyme Q. In the present study, using metabolic labelling with different intermediates, we demonstrated the presence of an active isoprenoid pathway for the biosynthesis of the isoprenic chain of coenzyme Q. Our results show that P. falciparum is able to synthesize different homologs (coenzyme Q(8) and coenzyme Q(9)), depending on the given intermediate. Parasites treated with nerolidol at doses 2.2 times below the IC(50) showed a decreased ability to synthesize the isoprenic chain attached to coenzyme Q at all intraerythrocytic stages. Treatment with nerolidol arrested development of the intraerythrocytic stages of the parasites, indicating that the drug may have an antimalarial potential.

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“…The addition of these isoprenoids to 4-hydroxybenzoate is performed by 4-hydroxybenzoate octaprenyltransferase (EC 2.5.1.39, PlasmoDB ID PF3D7_0607500) (118,119). Labeling studies in P. falciparum identify coenzyme Q isoforms coenzyme Q8 and Q9, which have 8 and 9 isoprene units (40-carbon and 45-carbon), respectively, in their side chains (120,121). Incorporation of labeled FPP results in the detection of coenzyme Q8, and incorporation of labeled GGPP detects coenzyme Q9 (120).…”

Section: Coenzyme Q (Ubiquinone)mentioning

confidence: 99%

Isoprenoid Biosynthesis in Plasmodium falciparum

2014

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bMalaria kills nearly 1 million people each year, and the protozoan parasite Plasmodium falciparum has become increasingly resistant to current therapies. Isoprenoid synthesis via the methylerythritol phosphate (MEP) pathway represents an attractive target for the development of new antimalarials. The phosphonic acid antibiotic fosmidomycin is a specific inhibitor of isoprenoid synthesis and has been a helpful tool to outline the essential functions of isoprenoid biosynthesis in P. falciparum. Isoprenoids are a large, diverse class of hydrocarbons that function in a variety of essential cellular processes in eukaryotes. In P. falciparum, isoprenoids are used for tRNA isopentenylation and protein prenylation, as well as the synthesis of vitamin E, carotenoids, ubiquinone, and dolichols. Recently, isoprenoid synthesis in P. falciparum has been shown to be regulated by a sugar phosphatase. We outline what is known about isoprenoid function and the regulation of isoprenoid synthesis in P. falciparum, in order to identify valuable directions for future research.

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Coenzyme Q. 114. Biosynthesis of coenzymes Q by malarial parasites. 2. Coenzyme Q synthesis in blood cultures of monkeys infected with malarial parasites (Plasmodium falciparum and P. knowlesi)

Cited by 30 publications

References 1 publication

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

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

Characterization of the isoprenoid chain of coenzyme Q in Plasmodium falciparum

Isoprenoid Biosynthesis in Plasmodium falciparum

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