Two New Plant-Like Pathways Link Hemoglobin Degradation to Lipid Biogenesis in Falciparum Malaria: Novel Targets for Anti-Malarial Chemotherapy

摘要

Plasmodium falciparum is the causative agent of the most severe form of human malaria. The rapid multiplication of the parasite within human erythrocytes requires an active production of new membranes. Phosphatidylcholine (PtdCho) is the most abundant phospholipid in 'Plasmodium' membranes and the pathways leading to its synthesis are attractive targets for chemotherapy. In this report, the authors describe molecular and biochemical studies that provide evidence for the presence of a plant-like pathway in 'P. falciparum' for PtdCho biosynthesis. Serine, which is transported from human serum and is readily available in the parasite cytoplasm, is converted into ethanolamine and then phosphorylated into phosphoethanolamine. The authors show that 'P. falciparum' catalyzes a phosphoethanolamine methyltransferase (Pfpmt) reaction that converts phosphoethanolamine into phosphocholine, which is then incorporated into PtdCho. The authors also describe genetic studies seeking to disrupt the contiguity of the 'PfPMT' genomic locus and to solve the structure of the Pfpmt enzyme. During the first year of funding, the authors have focused their studies on the molecular, genetic, and biochemical characterization of Pfpmt. In this first progress report, they provide a detailed description of four important studies: (1) metabolic studies in 'P. falciparum' indicating that the parasite uses ethanolamine and serine as precursors for the synthesis of the major phospholipid, PtdCho; (2) biochemical evidence indicating that PfPMT encodes a methyltransferase with strong specificity for phosphoethanolamine and no preference for ethanolamine or phosphatidylethanolamine; (3) inhibition studies indicating that phosphocholine analogs inhibit Pfpmt activity and have antimalarial activity; and (4) genetic studies to knockout the 'PfPMT' gene.