Malaria is a major global health problem. No vaccine is yet available, and disease amelioration currently relies on drug therapy and controlling the mosquito vector. However, drug therapy is becoming more problematic because existing drugs are losing their effectiveness as a result of parasites' resistance. Thus, development of new malaria drugs is vital.
Malaria parasites contain a nonphotosynthetic plastid homologous to the chloroplasts of plants. The malaria-causing organism belongs to a group of parasites that we believe originated from photosynthetic algae similar to the modern zooxanthellae, which live inside corals, anemones, jellyfish, and mollusks. Ancestors of the malaria parasite switched from symbiosis (i.e., living in partnership with their animal hosts) to parasitism about 400 million ago. The plastid was not lost, even though photosynthesis was discarded in favor of stealing nutrients from the animal hosts. It is noteworthy that only invertebrate animal hosts would have existed at that time. The parasites subsequently evolved alongside the animals, and malaria parasites are the modern descendants of these once-photosynthetic symbionts.
The parasite plastid synthesizes fatty acids, heme, iron sulfur clusters, and isoprenoid precursors. It is indispensable to the parasite, and therefore is an attractive target for antimalarial drugs. Because plastids originally derive from endosymbiotic cyanobacteria, they contain a large repertoire of bactera-type metabolic processes, which are fundamentally different from those of the human host. As a consequence, many antibacterials work as antimalarials.
Our lab has focused on understanding the metabolism, biogenesis, evolutionary origins, and basic cell biology of the plastid organelle in malaria parasites. We identified many of the pathways in the plastid and collaborated with groups sequencing the malaria parasite genome to identify 500 genes with roles in plastid function. We have also used fluorescent proteins such as GFP to visualize this curious organelle in live parasites, providing us with a dynamic view of its behavior in the parasite life cycle and allowing us to see how the plastid responds to drugs that perturb the organelle's activities and therefore kill the parasites.
How parasite plastid biosynthetic pathways are fueled in the absence of photosynthetic energy and carbon capture initially was not clear. We described a pair of parasite transporter proteins, PfiTPT and PfoTPT, that are homologues of plant chloroplast innermost membrane transporters responsible for moving phosphorylated C3, C5, and C6 compounds across the plant chloroplast envelope. PfiTPT was shown to be localized in the innermost membrane of the parasite plastid by virtue of its cleavable N-terminal targeting sequence. PfoTPT lacks such a targeting sequence but was shown to localize in the outermost parasite plastid membrane, with its termini projecting into the cytosol. We have characterized these membrane proteins in the parasite plastid and determined the membrane orientation for PfoTPT. PfiTPT and PfoTPT are proposed to act in tandem to transport phosphorylated C3 compounds from the parasite cytosol into the plastid, enabling the transporters to shunt, into the plastid, glycolytic derivatives of glucose scavenged from the host. This activity, in turn, provides carbon, reducing equivalents, and ATP to power the organelle. This work provides our first understanding of how the organelle exploits the host's supply of resources, enabling us to reconstruct a biochemical chain of transfers and modifications that link the metabolism of the plastid with that of the host.
We have also investigated how malaria parasites access nutrients from the human host. Pumps produced by the parasite pull in essential resources that fuel parasite growth. These pumps are the engines of the parasite, and knowing how they work allows us to design strategies to stall their motors.
Last updated September 2008
