Each year, 300 million people are stricken by malaria and over 1 million people die from it. Plasmodium falciparum causes the most severe cases of the illness. As drug-resistant strains of the parasite emerge, there is an urgent need to identify new biochemical targets for developing antimalarial therapeutics. Phosphoethanolamine methyltransferase (PfPMT) catalyzes the methylation of phosphoethanolamine to form phosphocholine in P. falciparum. Because mammals don’t make phosphocholine, which the parasite needs to make phosphatidylcholine for membrane biogenesis, PfPMT is critical for the parasite’s survival. In a recent "Paper of the Week" in the Journal of Biological Chemistry, Joseph M. Jez at Washington University and colleagues described the structure of PfPMT. “This is the first molecular view of this enzyme,” explains Jez. The investigators obtained a series of 1.19–1.55 Å resolution crystal structures of the enzyme bound to substrates, products and other molecules, and identified Tyr19 and His132 as critical for enzymatic activity. The two amino acids carry out methylation of the phosphoethanolamine, lock ligands in the active site and arrange the site for catalysis. Jez says he was intrigued by how these two catalytic residues came from different parts of the enzyme and likely weren’t organized as a functional dyad until both of the enzyme’s substrates, phosphoethanolamine and S-adenosylmethionine, bound. Because PfPMT is found in parasites that attack humans, animals and plants, it “might be possible to develop compounds of medical, veterinary or agricultural value to hit various parasites,” Jez says.
Rajendrani Mukhopadhyay (firstname.lastname@example.org) is the senior science writer for ASBMB Today and the technical editor for the Journal of Biological Chemistry.