Structure of Essential Malaria Parasite Enzyme Determined

Malaria is a major worldwide health threat.

The Science

The three-dimensional structures of proteins and other macromolecules often provide a starting point for designing new approaches to solving problems in a wide range of applications from bioenergy to medicine. The high-resolution structure of a specific protein can be used to identify small molecules that would bind to the protein and increase or decrease its activity to achieve a desired change in a biological system. A new study has determined the structures of an enzyme found in the malaria parasite (Plasmodium falciparum). The enzyme is not found in humans but is required by the parasite for the formation of its outer membrane. Several high-resolution structures were obtained for the enzyme in several stages of its functioning as well as with a small molecule that inhibits it. The structural information helped identify the enzyme’s active site and will be used as a starting point to seek drugs to treat infections by the malaria parasite. The results, published in the Journal of Biological Chemistry, were obtained by scientists from Washington University at the highly productive beamline 19ID of the DOE Structural Biology Center at Argonne National Laboratory’s Advanced Photon Source.


Infections by Plasmodium falciparum are the most severe with the highest rates of mortality and morbidity. In the malarial parasite Plasmodium falciparum, a multifunctional phosphoethanolamine methyltransferase (PfPMT) catalyzes the methylation of phosphoethanolamine (pEA) to phosphocholine for membrane biogenesis. This pathway is also found in plant and nematodes, but PMT from these organisms use multiple methyltransferase domains for the S-adenosylmethionine (AdoMet) reactions. This study provides the first insight on this antiparasitic target enzyme essential for survival of the malaria parasite. The PfPMT structure provides the first three-dimensional view of this enzyme from any species, yields new insight on catalysis and ligand binding in this group of methyltransferases, and may be useful for the development of inhibitors targeting this enzyme from P. falciparum, the major causative agent of malaria. The structural and mechanistic differences between the PMT and other methyltransferases suggest that the development of specific inhibitors is possible.

BER Program Manager

Amy Swain

U.S. Department of Energy, Biological and Environmental Research (SC-33)
Biological Systems Science Division
[email protected]


Lee, S. G., Y. Kim, T. D. Alpert, A. Nagata, and J. M. Jez. 2012. “Structure and Reaction Mechanism of Phosphoethanolamine Methyltransferase from the Malaria Parasite Plasmodium falciparum,” Journal of Biological Chemistry 287, 1426-1434, DOI: 10.1074/jbcM111.315267.