Heme Metabolism in Malarial Parasites

Heme is an indispensable cofactor used for diverse purposes by many organisms. Amongst other roles, it is critically important for energy production via the electron transport chain, a wide variety of biotransformation reactions, and redox cell signaling. Organisms meet their heme requirement in two ways: biosynthesis and/or scavenging.

Heme metabolism in the malarial parasite is quite intriguing. On one hand, the parasite’s genome encodes a complete heme biosynthetic pathway and the individual genes all appear to be transcribed during parasite development in the red blood cell. On the other hand, the parasite takes up ~60% of the infected red blood cell’s hemoglobin content (~20 mM heme), and proteolytically degrades it to obtain an amino acid supply. Heme is released in the process, and a large fraction is detoxified by polymerization into an inert polymer, hemozoin. However, it is unclear if this conversion is quantitative. As a large quantity of heme is released, even a seemingly small fraction of this could completely satisfy the parasite’s heme requirement.

We are interested in quantitatively understanding the extent to which the parasite balances de novo heme biosynthesis with scavenging. To address this question, we are developing novel heme biosensors, and using mass spectrometric and biochemical approaches to gain quantitative and dynamic information on how heme from different sources is utilized. A thorough understanding of this question will be beneficial to drug development efforts. Indeed, some of the most potent and clinically efficacious antimalarials directly interact with heme to alter its metabolism by the parasite.