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Pouch's newfound role tied to potential new treatment for malaria

University of Illinois at Urbana-Champaign

For a century, a tiny compartment called the volutin granule in yeast, fungi and bacteria was thought to be a storage granule with no active function. University of Illinois scientists, however, have found that the granule is really an organelle -- a live vacuole (a subcellular pouch) with a membrane and active enzymes -- and it may provide a new line of attack against malaria.

The researchers began studying the compartment in 1994 with funding from the National Institutes of Health. They labeled the organelle an acidocalcisome in recognition of its acidic and calcium components. They also found that it contains a pyrophosphatase, an enzyme that acts like a pump and allows protons to be transported inside it, and that the organelle has plant-like qualities.

In the April 1 issue of the Biochemical Journal, the researchers reported that the organelle exists in Plasmodium berghei, a malaria-causing organism. The new work -- funded by the Burroughs Wellcome Fund -- involved extensive molecular studies, including immunofluorescence microscopy, in which the organelle of the malaria parasite was compared with those in other parasites and plants.

"These so-called granules are not just storage granules. They have a function," said Roberto Docampo, a professor of veterinary pathobiology in the UI College of Veterinary Medicine. "These organelles have pumps for the uptake of protons to make them acidic, and for the uptake of calcium and other elements. The calcium is not bound permanently. It can be released as free calcium. It is involved in metabolism.

"Since the malaria parasites have this organelle, it means that the polyphosphates and pyrophosphates are important for the organism's existence, and that analogs of these compounds could be used for chemotherapy," Docampo said.

A new weapon against malaria is sorely needed, because the malaria parasite is rapidly becoming resistant to chloroquine, the most commonly used drug against malaria. In fact, resistance has been documented in more than 70 countries, mostly in Africa, Asia and Latin America.

Docampo and colleagues have found that analogs of pyrophosphate -- chemical compounds already used extensively to fight osteoporosis and other bone-related diseases -- have "potent effects" in disrupting metabolism in two other parasites (toxoplasma and trypanosomes).

"We believe that pyrophosphate analogs concentrate into these acidic calcium organelles and become toxic against the parasite but not the other host cells," Docampo said. "Since acidocalcisomes are alive and serve a function, we think that these drugs may kill the parasite. We haven't tested this against the malaria parasite in animals yet, but we believe these already existing analogs at least have potential in the treatment of malaria or in the development of specific drugs that could be used."

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