Phosphatidylcholine Biosynthesis as a Potential Target for Inhibition of Metabolism in Parasitic Nematodes

Joseph   M.   Jez

Abstract

Parasitic nematodes are major causes of human, animal, and plant diseases worldwide. Although a number of therapeutics are available as treatments, reported resistance to certain anthelmintics, severe side-effects, or limited efficacy resulting from differences in the life cycles of target organisms underscore the need for the continued development of nematicidal compounds. Identifying biochemical targets that differ between the parasite and host species is essential for finding effective new molecules. The free-living nematode Caenorhabditis elegans serves as a useful model system for studying nematode biology and for analyzing the biochemistry of enzymes in potential target pathways. Providing a major component of cellular membranes, the core metabolic pathways of phosphatidylcholine synthesis in eukaryotes are well conserved; however, recent studies suggest that nematodes (and Plasmodia) use a different metabolic route to this phospholipid than mammals. In addition, phosphatidylcholine is a precursor in the production of glycoconjugates secreted by parasitic nematodes to avoid host immune responses. RNA-mediated interference experiments in C. elegans suggest that the enzymes of phosphatidylcholine biosynthesis are essential for nematode normal growth and development. Therefore, small molecule inhibitors of these enzymes may be valuable as medical, veterinary, and agricultural nematicides. This review examines the current state of knowledge of phosphatidylcholine biosynthesis in the model organism C. elegans.

Keywords: Phosphatidylcholine, phosphocholine, parasite, nematode, Caenorhabditis elegans, kinase, methyltransferase, cytidylyltransferase