Transient silencing of <i>Plasmodium falciparum</i> bifunctional glucose‐6‐phosphate dehydrogenase− 6‐phosphogluconolactonase

Crooke, Almudena; Díez, Amalia; Mason, Philip J.; Bautista, José M.

doi:10.1111/j.1742-4658.2006.05174.x

Cited by 28 publications

(21 citation statements)

References 54 publications

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“…These data suggest that PfPKA activity might be necessary for the completion of the asexual cycle, or the reinvasion of erythrocytes. For further dsRNA experiments, we decided to analyze the treated parasites at the maximum of PfPKAc expression which occurs at the schizont stage according to previous studies (Wu et al 1995;Crooke et al 2006).…”

Section: Resultsmentioning

confidence: 99%

Phenotypic and transcriptomic analyses of Plasmodium falciparum protein kinase A catalytic subunit inhibition

2009

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The emergence and dissemination of drug-resistant malaria parasites represent one of the most important problems in malaria case management. Plasmodium falciparum is the causative agent of the most lethal form of human malaria. The molecular mechanisms that control the life cycle of the malaria parasite are still poorly understood. The published genome sequence (P. falciparum strain 3D7) reveals that several homologs of eukaryotic signaling proteins, such as protein kinases and phosphatases, are conserved in P. falciparum. Proteins kinases are now widely recognized as valuable drug targets in protozoan parasites. In this study, gene silencing with double-stranded RNA (dsRNA) and microarray techniques were used to study the biological function of the cAMP-dependent protein kinase catalytic subunit (PfPKAc) in the parasite erythrocytic life cycle. Treatment of parasites with PfPKAc dsRNA resulted in a marked reduction of endogenous PfPKAc mRNA associated with a compensatory decrease of PfPKAr mRNA followed by morphological changes in schizont stages and cell cycle arrest. The global effects of gene silencing were also investigated using a P. falciparum pan-genomic microarray. Transcriptomic analysis showed that the expression of 329 genes was altered in response to downregulation of PfPKAc mRNA particularly genes in specific metabolic pathways linked with merozoite invasion processes, the calcium/calmodulin signaling, and kinases network and mitochondrial functions.

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Section: Resultsmentioning

confidence: 99%

Phenotypic and transcriptomic analyses of Plasmodium falciparum protein kinase A catalytic subunit inhibition

2009

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“…Growth of P. falciparum with RNAimediated silencing of PfGluPho arrests at the trophozoite stage and results in increased gametocyte formation, highlighting the importance of PfGluPho for Plasmodium parasites. Furthermore, it was shown that PfGluPho silencing was accompanied by enhanced transcription of thioredoxin reductase, pointing to a key role of PfGluPho in responding to oxidative stress (68). However, studies on RNAi in Plasmodium parasites raise questions about the significance of RNAi-based study results, because the RNAi machinery is missing in Plasmodium (69).…”

Section: P Falciparum's G6pdmentioning

confidence: 99%

Glucose‐6‐phosphate metabolism in Plasmodium falciparum

2012

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Malaria is still one of the most threatening diseases worldwide. The high drug resistance rates of malarial parasites make its eradication difficult and furthermore necessitate the development of new antimalarial drugs. Plasmodium falciparum is responsible for severe malaria and therefore of special interest with regard to drug development. Plasmodium parasites are highly dependent on glucose and very sensitive to oxidative stress; two observations that drew interest to the pentose phosphate pathway (PPP) with its key enzyme glucose‐6‐phosphate dehydrogenase (G6PD). A central position of the PPP for malaria parasites is supported by the fact that human G6PD deficiency protects to a certain degree from malaria infections. Plasmodium parasites and the human host possess a complete PPP, both of which seem to be important for the parasites. Interestingly, there are major differences between parasite and human G6PD, making the enzyme of Plasmodium a promising target for antimalarial drug design. This review gives an overview of the current state of research on glucose‐6‐phosphate metabolism in P. falciparum and its impact on malaria infections. Moreover, the unique characteristics of the enzyme G6PD in P. falciparum are discussed, upon which its current status as promising target for drug development is based. © 2012 IUBMB IUBMB Life, 64(7): 603–611, 2012

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“…This indicates either that PfGluPho is essential in blood stage parasites or that loss of this enzyme is highly deleterious. A previous analysis of PfGluPho attempted to ablate GluPho function by knocking down the PfGluPho transcript via antisense silencing or by overexpression of PfGluPho dsRNA [20]. These methods are not routinely used in P. falciparum genetic manipulation, and the method by which they are proposed to work is unclear.…”

Section: Pfglupho Is Essential For Blood Parasite Stage Growthmentioning

confidence: 99%

Plasmodium falciparum glucose‐6‐phosphate dehydrogenase 6‐phosphogluconolactonase is a potential drug target

et al. 2015

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The malarial parasite Plasmodium falciparum is exposed to substantial redox challenges during its complex life cycle. In intraerythrocytic parasites, haemoglobin breakdown is a major source of reactive oxygen species. Deficiencies in human glucose‐6‐phosphate dehydrogenase, the initial enzyme in the pentose phosphate pathway (PPP), lead to a disturbed redox equilibrium in infected erythrocytes and partial protection against severe malaria. In P. falciparum, the first two reactions of the PPP are catalysed by the bifunctional enzyme glucose‐6‐phosphate dehydrogenase 6‐phosphogluconolactonase (PfGluPho). This enzyme differs structurally from its human counterparts and represents a potential target for drugs. In the present study we used epitope tagging of endogenous PfGluPho to verify that the enzyme localises to the parasite cytosol. Furthermore, attempted double crossover disruption of the PfGluPho gene indicates that the enzyme is essential for the growth of blood stage parasites. As a further step towards targeting PfGluPho pharmacologically, ellagic acid was characterised as a potent PfGluPho inhibitor with an IC50 of 76 nm. Interestingly, pro‐oxidative drugs or treatment of the parasites with H2O2 only slightly altered PfGluPho expression or activity under the conditions tested. Furthermore, metabolic profiling suggested that pro‐oxidative drugs do not significantly perturb the abundance of PPP intermediates. These data indicate that PfGluPho is essential in asexual parasites, but that the oxidative arm of the PPP is not strongly regulated in response to oxidative challenge.

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Transient silencing of Plasmodium falciparum bifunctional glucose‐6‐phosphate dehydrogenase− 6‐phosphogluconolactonase

Cited by 28 publications

References 54 publications

Phenotypic and transcriptomic analyses of Plasmodium falciparum protein kinase A catalytic subunit inhibition

Phenotypic and transcriptomic analyses of Plasmodium falciparum protein kinase A catalytic subunit inhibition

Glucose‐6‐phosphate metabolism in Plasmodium falciparum

Plasmodium falciparum glucose‐6‐phosphate dehydrogenase 6‐phosphogluconolactonase is a potential drug target

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