Pathways for phosphatidylcholine biosynthesis: targets and strategies for antimalarial drugs

Phospholipids play an important role in the intra-erythrocytic life cycle of Plasmodium falciparum, the agent of the severe form of human malaria, both as essential structural components of parasite membranes and as regulatory molecules that modulate diverse essential enzymatic and cell biological functions. These molecules are therefore critical for parasite development and are required for their rapid multiplication inside human erythrocytes. Following invasion of erythrocytes, the relative levels of phospholipids increases up to sixfold, with phosphatidylcholine as the major constituent. Malaria parasites synthesize phosphatidylcholine de novo using choline as a precursor. The importance of this de novo pathway in parasite development and survival has been inferred by the fact that structural mimics of choline cause a strong inhibition of choline transport into the parasite, blockage of phosphatldylcholine biosynthesis from choline and inhibition of parasite growth, P falciparum uses a second pathway for biosynthesis of phosphatidylcholine from host serine. This pathway uses two plant-like enzymatic steps that seem to be lacking in mammalian cells. This alternative pathway initiates with the decarboxylation of serine into ethanolamine by a parasite serine decarboxylase, followed by a three-step methylation of phosphoethanolamine to form phosphocholine by a parasite phosphoethanolamine methyltransferase. The phosphocholine thus formed serves as the precursor for phosphatidylcholine biosynthesis. This review describes the current understanding of these two pathways of phosphatidylcholine biosynthesis and discusses strategies for the development of novel antimalarial drugs.