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Parasite-induced permeation of nucleosides in Plasmodium falciparum malaria
1School of Biochemistry and Molecular Genetics, University of New South Wales, Sydney, Australia.
Abstract:
A mechanism which mediates the transport of the nonphysiological nucleoside, L-adenosine, was demonstrated in Plasmodium falciparum infected erythrocytes and naturally released merozoites. L-Adenosine was not a substrate for influx in freed intraerythrocytic parasites or in normal human erythrocytes nor was L-adenosine transported in a variety of cell types including other parasitic protozoa such as Crithidia luciliae, Trichomonas vaginalis, Giardia intestinalis, or the mammalian cells, Buffalo Green Monkey and HeLa cells. L-Adenosine transport in P. falciparum infected cells was nonsaturable, with a rate of 0.13 +/- 0.01 pmol/microliter cell water per s per microM L-adenosine, yet the transport was inhibited by furosemide, phloridzin and piperine with IC50 values between 1-13 microM, distinguishing the transport pathway from simple diffusion. The channel-like permeation was selective as disaccharides were not permeable to parasitised cells. In addition, an unusual metabolic property of parasitic adenosine deaminase was found in that L-adenosine was metabolised to L-inosine by both P. falciparum infected erythrocytes and merozoites, an activity which was inhibited by 50 nM deoxycoformycin. No other cell type examined displayed this enzymic activity. The results further substantiate that nucleoside transport in P. falciparum infected cells was significantly altered compared to uninfected erythrocytes and that L-adenosine transport and metabolism was a biochemical property of Plasmodium infected cells and merozoites and not found in normal erythrocytes nor any of the other cell types investigated.
Insights
Plasmodium falciparum infected cells and merozoites uniquely transport and metabolize L-adenosine, a nonphysiological nucleoside. This specific L-adenosine transport mechanism is not found in normal human cells or other parasitic protozoa.
Area of Science:
- Biochemistry
- Parasitology
- Cell Biology
Background:
- Nucleoside transport is crucial for cellular function.
- Plasmodium falciparum causes malaria, a significant global health concern.
- Understanding nutrient uptake in parasites is key to developing new treatments.
Purpose of the Study:
- To investigate the transport mechanism of the nonphysiological nucleoside L-adenosine in Plasmodium falciparum.
- To determine if L-adenosine transport and metabolism are unique to infected cells and merozoites.
- To characterize the biochemical properties of this transport pathway.
Main Methods:
- Utilized infected erythrocytes and purified merozoites of Plasmodium falciparum.
- Performed transport assays with radiolabeled L-adenosine.
- Investigated inhibition by specific compounds (furosemide, phloridzin, piperine) and enzyme activity (adenosine deaminase).
- Tested L-adenosine transport in various control cell types, including normal erythrocytes and other protozoa.
Main Results:
- Demonstrated a specific, non-saturable transport mechanism for L-adenosine in P. falciparum infected cells and merozoites.
- Identified inhibition of L-adenosine transport by furosemide, phloridzin, and piperine, suggesting a carrier-mediated process.
- Discovered that P. falciparum possesses an unusual adenosine deaminase activity, metabolizing L-adenosine to L-inosine, inhibited by deoxycoformycin.
- Confirmed that L-adenosine transport and metabolism were absent in normal human erythrocytes and other tested cell types.
Conclusions:
- Nucleoside transport and adenosine metabolism are significantly altered in Plasmodium falciparum infected cells.
- L-adenosine transport and metabolism represent a unique biochemical characteristic of Plasmodium infected cells and merozoites.
- These findings highlight potential targets for antimalarial drug development by exploiting parasite-specific metabolic pathways.