Ideal New Anti-Malaria Target Revealed In Parasite Protein Structure

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Main Category: Tropical Diseases
Also Included In: Biology / Biochemistry;  Medical Devices / Diagnostics
Article Date: 09 Jan 2012 - 12:00 PST

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Scientists have cracked the structure of a protein that is vital to the parasitePlasmodium falciparum, the one that causes the most deadly form of malaria. They suggest the protein, a key enzyme in the generation of cell membranes, could be an ideal target for anti-malaria drugs, particularly as the protein is not present in humans. 

The study was led by the Department of Biology at Washington University, St. Louis, Missouri, and a report on it appears as the "Paper of the Week" in the 6 January issue of The Journal of Biological Chemistry. 

In 2010, malaria killed 655,000 people worldwide. The disease is caused by five different species of Plasmodium, a parasite that lives in the gut of its primary host, the mosquito, but the deadliest form of malaria comes from being bitten by a mosquito carrying the species Plasmodium falciparum.

New drugs to combat malaria are desperately needed: not only is P. falciparum responsible for the most severe form of malaria, it is endemic in areas populated by about 40% of the people in the world, and drugs that used to work are losing their effectiveness, partly because counterfeiting has led to widespread resistance. 

In a biology lab at Washington University, researchers took six years and more to uncover the structure and function of the protein, an enzyme called PMT (short for phosphoethanolamine methyltransferase). 

In previous work they had already established that the enzyme's job is to add methyl groups to a starting molecule called phosophoethanolamine that is involved in making the cell membranes.

And even though there are similar proteins in other organisms, humans don't have it. 

These features make it an ideal target for developing new anti-malaria drugs.

Senior author Dr Joseph M. Jez, associate professor of biology in Arts & Sciences, told the press:

"What my lab does is crystallize proteins so that we can see what they look like in three dimensions."

"The idea is that if we know a protein's structure, it will be easier to design chemicals that would target the protein's active site and shut it down," he added.

The researchers have perfected an interesting way to crystallize a protein. They put a solution of a salt or something else that can dry out the protein at the bottom of a small well. Then, as Jez explains: "we put a drop of our liquid protein on a microscope cover slip and flip it over the top of the well, so the drop of protein is hanging upside down in the well".

This helps to slowly withdraw water from the protein, rather like making rock candy, except in the case of candy it's the string hanging into the jar of sugar solution that helps to withdraw water.

There is also another difference: in making rock candy, the sugar is not reluctant to form crystals, but in this process, the protein is highly reluctant.