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A number of different proteins on the surface of Plasmodium falciparum malaria parasites help the invaders bind to red blood cells. But once attached to host blood cells, the parasites need to shed the 'sticky' surface proteins that would otherwise interfere with entrance into the cell.
"What we have discovered is the parasite enzyme - we refer to it as a 'sheddase' - which sheds the sticky proteins," says Michael Blackman, National Institute for Medical Research. The enzyme, called PfSUB2, is required for the parasites to invade cells; without it, the parasites die.
Blackman's team has worked on malarial surface proteins for over 15 years. "We predicted that this enzyme must have the capacity to 'move' across the surface of the parasite, since the proteins that are shed are themselves distributed all over the parasite surface," he says.
A major challenge in the study was to visualise that motion. "To overcome this, we genetically modified the parasite by 'tagging' PfSUB2 so that we could visually follow its movement within the parasite. It was only by doing this that we were able to see that PfSUB2 is secreted onto and across the parasite surface," he says.
The enzyme is stored in and released from cellular compartments near the tip of the parasite, according to the study. Once on the surface, the enzyme attaches to a motor that shuttles it from front to back, liberating the sticky surface proteins. With these proteins removed, the parasite gains entrance into a red blood cell. The entire invasion lasts about 30 seconds.
By designing a specific inhibitor that impeded the ability to shed the sticky proteins, Blackman and his team interfered with the enzyme's normal functioning. A drug – yet to be designed – could possibly do the same, preventing the parasites from infecting blood cells.
"The most exciting practical implication of this work is that it identifies a potential drug target that is quite different from anything that is targeted by existing antimalarial drugs," Blackman says. "This is very important, since it is widely agreed that the best way to prevent the appearance of drug resistance in any pathogen is to use combinations of drugs that target distinct biochemical pathways."
Harris PK et al. Molecular identification of a malaria merozoite surface sheddase. PLoS Pathog 2005 1(3): e29. Full text
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16/8/06 [WTD023958] 'Sheddase' helps the malaria parasite invade red blood cells.doc