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Targeting Plasmodium falciparum Phosphethanolamine Methyltransferase for Malaria Therapy
Author(s) -
Ben Mamoun Choukri,
Kumar Vidya
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.885.25
Subject(s) - plasmodium falciparum , biology , malaria , choline , serine , metabolic pathway , biochemistry , enzyme , immunology
Plasmodium falciparum, the causative agent of the deadliest form of malaria, multiplies asexually within human erythrocytes to produce up to 36 new daughter parasites per red blood cell, and undergoes gametocytogenesis to produce sexual forms, which are essential for successful malaria transmission. Available data suggest an essential role of phosphatidylcholine (PC) metabolism in these processes. PC synthesis is fueled by precursors such as choline, serine, ethanolamine and fatty acids scavenged from the host. Metabolic analyses suggest the presence of two pathways for the synthesis of PC in P. falciparum: the CDP‐choline pathway from choline and the transmethylation (PMT) pathway from serine. Genetic and pharmacological studies demonstrated that the two pathways play distinct and essential functions in parasite development, survival and sexual differentiation. The limiting step in the PMT pathway is catalyzed by the phosphoethanolamine methyltransferase PfPMT. The PMT enzyme reaction does not occur in human cells, and no homologs of PfPMT are present in mammals, making it an ideal target for development of specific, selective and safe antimalarials. Equally important PMT orthologs are present primarily in Plasmodium species that infect humans thus making PMT activity a suitable target for drugs to kill different forms of human malaria.We have identified a set of highly active antimalarials using a yeast functional complementation assay. These compounds are potent inhibitors of P. falciparum development in vitro, show little to no toxicity in mammalian cells and display pharmacological properties suitable for further optimization. Biochemical, structural and functional analyses of these compounds and their mode of action will be presented.