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Protein tyrosine kinase activity in human malaria parasite Plasmodium falciparum
1Malaria Research Centre, 22-Sham Nath Marg, Delhi 110 054, India.
Abstract:
Protein tyrosine kinases (PTKs) are believed to be implicated in the parasite growth, maturation and differentiation functions. Protein tyrosine kinase activity was found to be distributed in all the stages of P. falciparum parasite maturation. Membrane bound PTK activity was found to be increased during maturation process (ring stage to trophozoite stage) in chloroquine sensitive strains. In vivo conversion of the schizont stage to ring stage via release of merozoites was associated with a decrease in PTK activity. Chloroquine inhibited the membrane bound PTK activity in a dose dependent manner (IC50 = 45 microM). Kinetic studies show that chloroquine is a competitive inhibitor of PTK with respect to peptide substrate and noncompetitive with respect to ATP indicating that chloroquine inhibits PTK activity by binding with protein substrate binding site. The results suggest that maturation of malaria parasite is related to PTK and inhibition of this activity by chloroquine could provide a hypothesis to explain the mechanism of action of chloroquine.
Insights
Protein tyrosine kinases (PTKs) are crucial for malaria parasite development. Chloroquine inhibits PTK activity, suggesting a novel mechanism for this antimalarial drug.
Area of Science:
- Malariology
- Parasitology
- Biochemistry
Background:
- Protein tyrosine kinases (PTKs) play a role in parasite growth, maturation, and differentiation.
- PTK activity is present throughout all stages of Plasmodium falciparum parasite maturation.
Purpose of the Study:
- To investigate the role of PTK activity in malaria parasite maturation.
- To determine the effect of chloroquine on PTK activity.
Main Methods:
- Assessing PTK activity across different parasite maturation stages.
- Investigating the inhibitory effect of chloroquine on membrane-bound PTK.
- Conducting kinetic studies to elucidate the inhibition mechanism.
Main Results:
- Membrane-bound PTK activity increased during maturation (ring to trophozoite) in chloroquine-sensitive strains.
- PTK activity decreased during schizont-to-ring stage conversion.
- Chloroquine competitively inhibited PTK with respect to peptide substrate (IC50 = 45 µM).
Conclusions:
- Malaria parasite maturation is linked to PTK activity.
- Chloroquine's inhibition of PTK may explain its mechanism of action.
- PTK inhibition by chloroquine offers a new hypothesis for antimalarial drug action.