Researchers at UCSD have discovered that the single-cell parasite responsible for an estimated 1 million deaths per year worldwide from malaria has protein "wiring" that differs markedly from the cellular circuitry of other higher organisms, a finding which could lead to the development of antimalarial drugs that exploit that difference.
The scientists will report in the Nov. 3 issue of Nature a comparison of newly discovered protein-interactions in Plasmodium falciparum with protein interactions reported earlier in four other well studied model organisms -- yeast, a nematode worm, the fruit fly, and a bacterium that causes digestive-tract ulcers in humans. The authors of the study, Trey Ideker, a professor of bioengineering at UCSD's Jacobs School of Engineering, and two graduate students, Silpa Suthram and Taylor Sittler, said the malaria parasite's protein interactions "set it apart from other species."
"We've known since the Plasmodium genome was sequenced three years ago that 40 percent of its 5,300 proteins are significantly similar, or homologous, to proteins in other eukaryotes, but until now we didn't know that the malaria parasite assembles those proteins so uniquely," said Ideker. "Since our earlier research showed that yeast, worm, and fly have hundreds of both conserved proteins and protein interactions, we didn't initially believe our own analysis, which showed that there are only three Plasmodium protein interactions in common with yeast and none in common with the other species studied." The World Health Organization warns that malaria is a growing threat to health worldwide, particularly in poor countries. No malaria vaccine has been developed, and once powerful antimalarial drugs are less and less effective because Plasmodium falciparum has developed resistance to those drugs. Even mosquitoes that transmit malaria are developing resistance to the most commonly used insecticides.
"The demonstration that the Plasmodium protein network differs significantly from those of several model organisms is an intriguing result that could lead to the identification of novel drug targets for fighting malaria," said John Whitmarsh, acting director of the Center for Bioinformatics and Computational Biology at the National Institute of General Medical Sciences, which partially funded the work. "Ideker and his team have demonstrated the effectiveness of a computational approach based on mathematics for understanding complex biological interactions."
Researchers studying protein expression under controlled laboratory conditions have been slowed because techniques designed for other organisms work poorly with Plasmodium because 80 percent of its genome is comprised of only two of the four building blocks of DNA.
Stanly Fields, a professor of genomic sciences at the University of Washington who invented an ingenious way to identify pairs of proteins that physically interact with one another, modified his technique and added special culture conditions to enable his group to study Plasmodium. Fields's team and collaborators at Prolexys Pharmaceuticals of Salt Lake City, UT, discovered 2,846 interactions involving 1,312 Plasmodium falciparum proteins. The team provided data on those interactions to Ideker's group earlier and also reported the results in the Nov. 3 issue of Nature.