Structural features of Plasmodium cytochrome b that may underlie susceptibility to 8-aminoquinolines and hydroxynaphthoquinones

Vaidya, Akhil B.; Lashgari, Monir S.; Pologe, Laura G.; Morrisey, Joanne M.

doi:10.1016/0166-6851(93)90088-f

Cited by 112 publications

(82 citation statements)

References 31 publications

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“…Based upon these results, it was concluded that atovaquone acts at the cytochrome bc 1 complex of the malarial respiratory chain. Unique structural features of the parasite cytochrome b a were speculated as being responsible for the therapeutic value of some of the hydroxynaphthoquinones as antimalarials (16). Because malarial mitochondria do not seem to contribute much to the ATP pool, it has long been suggested that the main purpose for these organelles was to dispose of electrons generated by dihydroorotate dehydrogenase (7)(8)(9), an essential enzyme in pyrimidine biosynthesis.…”

Section: Discussionmentioning

confidence: 99%

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Atovaquone, a Broad Spectrum Antiparasitic Drug, Collapses Mitochondrial Membrane Potential in a Malarial Parasite

Srivastava¹,

Rottenberg

Vaidya³

1997

Journal of Biological Chemistry

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377

267

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At present, approaches to studying mitochondrial functions in malarial parasites are quite limited because of the technical difficulties in isolating functional mitochondria in sufficient quantity and purity. We have developed a flow cytometric assay as an alternate means to study mitochondrial functions in intact erythrocytes infected with Plasmodium yoelii, a rodent malaria parasite. By using a very low concentration (2 nM) of a lipophilic cationic fluorescent probe, 3,3dihexyloxa-carbocyanine iodide, we were able to measure mitochondrial membrane potential(⌬⌿ m ) in live intact parasitized erythrocytes through flow cytometry. The accumulation of the probe into parasite mitochondria was dependent on the presence of a membrane potential since inclusion of carbonyl cyanide m-chlorophenylhydrazone, a protonophore, dissipated the membrane potential and abolished the probe accumulation. We tested the effect of standard mitochondrial inhibitors such as myxothiazole, antimycin, cyanide and rotenone. All of them except rotenone collapsed the ⌬⌿ m and inhibited respiration. The assay was validated by comparing the EC 50 of these compounds for inhibiting ⌬⌿ m and respiration. This assay was used to investigate the effect of various antimalarial drugs such as chloroquine, tetracycline and a broad spectrum antiparasitic drug atovaquone. We observed that only atovaquone collapsed ⌬⌿ m and inhibited parasite respiration within minutes after drug treatment. Furthermore, atovaquone had no effect on mammalian ⌬⌿ m . This suggests that atovaquone, shown to inhibit mitochondrial electron transport, also depolarizes malarial mitochondria with consequent cellular damage and death.Plasmodium spp. are obligate intracellular parasites, spending a major portion of their life cycle within erythrocytes and converting these relatively inactive cells into metabolically thriving active hosts. At present, our knowledge of mechanisms by which the parasite accomplishes these changes is limited, as is our understanding of metabolic processes associated with parasitism. It is generally believed that glycolysis is the main source of ATP in erythrocytic stages of malarial parasites with little or no contribution by mitochondria to the cellular ATP pool (1, 2). A lack of tricarboxylic acid cycle enzymes (3-6) and an acristate mitochondrial morphology has led to the suggestion that mitochondria in malaria parasite act mainly to serve as an electron disposal sink for dihydroorotate dehydrogenase, a critical enzyme in pyrimidine biosynthesis (7-9). It is well established through studies in other systems that, in addition to oxidative phosphorylation, mitochondria are also central to many other physiological activities such as the metabolism of molecules such as amino acids, lipids, and heme, as well as intracellular Ca 2ϩ homeostasis (10). These functions are achieved by the action of gene products encoded by both mitochondrial and nuclear genomes. Because most of the mitochondrial proteins are encoded by the nuclear genome and imported into mitochon...

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Section: Discussionmentioning

confidence: 99%

“…have been sequenced and found to encode at least three components of the electron transport chain, viz. subunits 1 and 3 of cytochrome c oxidase, and apocytochrome b (13)(14)(15)(16). In addition, mitochondrial preparations have been shown to contain ubiquinone cytochrome c oxidoreductase (bc 1 complex) (17), and cytochrome c oxidase activities (18 -20).…”

mentioning

confidence: 99%

Atovaquone, a Broad Spectrum Antiparasitic Drug, Collapses Mitochondrial Membrane Potential in a Malarial Parasite

Srivastava¹,

Rottenberg

Vaidya³

1997

Journal of Biological Chemistry

Self Cite

377

267

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“…In addition to the cytoplasmic ribosomal RNA genes encoded within the nuclear genome, T. gondii, like other coccidian parasites (35), appears to contain at least two additional classes of ribosomal RNA genes, encoded by the mitochondrial genome (present as a tandemly repeated 6-kb linear sequence in Plasmodium species [26]), and a plastid-like genome (a 35-kb circular molecule; [9,29,36,37]). At this stage it is not possible to directly link the cycloheximide-resistant spots with either the mitochondrion or the plastid-like genomes, but the observation that the Plasmodium mitchondrial DNA is much more heavily transcribed than the 35-kb plastid-like circle (Vaidya, A., personal communication) argues in favor of a mitochondrial origin (38). While the functional mitochondrial genome has not yet been cloned from Toxoplasma, both the P. falciparum mitochondrial genome and sequences suspected to be derived from the T. gondii mitochondrial genome are available for examination, and both of these sequences predict that mitochondrial ribosomes in the phylum Apicomplexa are resistant to macrolide and licosamide antibiotics.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of cytoplasmic and organellar protein synthesis in Toxoplasma gondii. Implications for the target of macrolide antibiotics.

Beckers¹,

Roos²,

Donald³

et al. 1995

J. Clin. Invest.

117

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IntroductionWe Combining cycloheximide treatment with two-dimensional gel analysis revealed a small subset of parasite proteins likely to be synthesized on mitochondrial ribosomes. Synthesis of these proteins was inhibited by 100 jM tetracycline, but not by 100 jpM azithromycin or clindamycin. Ribosomal DNA sequences believed to be derived from the T. gondii mitochondrial genome predict macrolide/lincosamide resistance. PCR amplification of total T. gondii DNA identified an additional class of prokaryotic-type ribosomal genes, similar to the plastid-like ribosomal genes of the Plasmodium falciparum. Ribosomes encoded by these genes are predicted to be sensitive to the lincosamide/macrolide class of antibiotics, and may serve as the functional target for azithromycin, clindamycin, and other protein synthesis inhibitors in Toxoplasma and related parasites. (J. Clin. Invest. 1995. 95:367-376)

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“…Two transcripts slightly larger than 2.3 kb were reported in P. falciparum, but no functional attribution was made (109). The whereabouts and nature of promoters in this genome are unknown.…”

Section: Gene Expressionmentioning

confidence: 95%

Extrachromosomal DNA in the Apicomplexa

Wilson¹,

Gardner²,

Rangachari³

et al. 1993

Toxoplasmosis

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Structural features of Plasmodium cytochrome b that may underlie susceptibility to 8-aminoquinolines and hydroxynaphthoquinones

Cited by 112 publications

References 31 publications

Atovaquone, a Broad Spectrum Antiparasitic Drug, Collapses Mitochondrial Membrane Potential in a Malarial Parasite

Atovaquone, a Broad Spectrum Antiparasitic Drug, Collapses Mitochondrial Membrane Potential in a Malarial Parasite

Inhibition of cytoplasmic and organellar protein synthesis in Toxoplasma gondii. Implications for the target of macrolide antibiotics.

Extrachromosomal DNA in the Apicomplexa

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