The deadly Leishmania parasite.
Credit: Malcolm McConville/University of Melbourne
SYDNEY: A parasite's eating habits - plotted in atomic detail - may help researchers to create more effective targeted drugs.
Leishmania is a parasite that infects around 12 million people across 88 countries and kills 500,000 people annually. New research by a team of Australian scientists has identified the metabolic pathways that are essential to the parasite's survival, right down to the particular atoms it uses as a food source.
The researchers made the discovery by labelling carbon atoms in the Leishmania parasites' food source and tracking how the energy was metabolised using nuclear magnetic resonance imaging. They hope this information can be applied to future drug design.
"The carbon-tracing method allows us to detect which nutrients the parasite uses to survive and see which metabolic pathways are active for a particular parasite," said Malcolm McConville, a molecular biochemist and deputy director of the Bio21 Institute at the University of Melbourne and co-author of the paper published in the current issue of The Journal of Biological Chemistry.
"From this, we can use the same approach to look at parasite metabolism in the host itself and develop drugs to fight them."
A pioneering method
"Before this method was developed, biochemists were making predictions based on the genomes, isolating an individual pathway and spending time developing drugs to act against it, only to find that it was redundant and the parasite didn't use [the pathway] anyway," said McConville.
"With the development of the carbon-tracing method, it allowed us to take a global approach by looking at as many metabolites as possible to see which pathways were actually being used, saving time and money."
They found that the tagged carbon was very quickly absorbed into certain metabolic pathways, namely the glycotic pathway and the pentose phosphate pathway. When the organism runs low on energy, atoms can be removed from the metabolic cycle but have to be replaced in order for proper functioning, a process known as anaplerosis.
Anaplerosis in the tricarboxyilic acid cycle (TCA cycle) plays an important role in the parasites' survival as it allows intermediates to leave the cycle in order to be converted into glucose or other fatty acids. By doing so, it allows the parasite to feed and sustain itself. As a result of this process, an enzyme in the TCA cycle called mitochondrial aconitase generates energy and also toxic compounds, which are damaging to cells.
Parasites unable to spread
The researchers were surprised to discover that the Leishmania parasite needs the mitochondrial aconitase enzyme to function, even though it seems counter-productive to its survival, as it lives in the very cells that contain toxic compounds.
By inhibiting the mitochondrial aconitase enzyme, the energy levels in cells were rapidly depleted and the parasites were unable to spread. When these energy reserves were replenished, the growth arrest stopped.
