Abstract:
Polyamines and the enzymes involved in their biosynthesis are present at high levels in rapidly proliferating
cells, including cancer cells and protozoan parasites. Inhibition of polyamine biosynthesis in asexual
blood-stage malaria parasites causes cytostatic arrest of parasite development under in vitro conditions,
but does not cure infections in vivo. This may be due to replenishment of the parasite’s intracellular polyamine
pool via salvage of exogenous polyamines from the host. However, the mechanism(s) of polyamine
uptake by the intraerythrocytic parasite are not well understood. In this study, the uptake of the polyamines,
putrescine and spermidine, into Plasmodium falciparum parasites functionally isolated from their
host erythrocyte was investigated using radioisotope flux techniques. Both putrescine and spermidine
were taken up into isolated parasites via a temperature-dependent process that showed cross-competition
between different polyamines. There was also some inhibition of polyamine uptake by basic amino
acids. Inhibition of polyamine biosynthesis led to an increase in the total amount of putrescine and spermidine
taken up from the extracellular medium. The uptake of putrescine and spermidine by isolated
parasites was independent of extracellular Na+ but increased with increasing external pH. Uptake also
showed a marked dependence on the parasite’s membrane potential, decreasing with membrane depolarization
and increasing with membrane hyperpolarization. The data are consistent with polyamines
being taken up into the parasite via an electrogenic uptake process, energised by the parasite’s inwardly
negative membrane potential.
