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J. Biol. Chem., Vol. 280, Issue 13, 12461-12466, April 1, 2005

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In Vivo Evidence for the Specificity of Plasmodium falciparum Phosphoethanolamine Methyltransferase and Its Coupling to the Kennedy Pathway^*

Gabriella Pessi, Jae-Yeon Choi¶, Jennifer M. Reynolds, Dennis R. Voelker¶, and Choukri Ben Mamoun||

From the Center for Microbial Pathogenesis and Department of Genetics and Developmental Biology, University of Connecticut Health Center, Farmington, Connecticut 06030 and the ^¶Program in Cell Biology, Department of Medicine, National Jewish Medical Research Center, Denver, Colorado 80206

Unlike humans and yeast, Plasmodium falciparum, the agent of the most severe form of human malaria, utilizes host serine as a precursor for the synthesis of phosphatidylcholine via a plant-like pathway involving phosphoethanolamine methylation. The monopartite phosphoethanolamine methyltransferase, Pfpmt, plays an important role in the biosynthetic pathway of this major phospholipid by providing the precursor phosphocholine via a three-step S-adenosyl-L-methionine-dependent methylation of phosphoethanolamine. In vitro studies showed that Pfpmt has strong specificity for phosphoethanolamine. However, the in vivo substrate (phosphoethanolamine or phosphatidylethanolamine) is not yet known. We used yeast as a surrogate system to express Pfpmt and provide genetic and biochemical evidence demonstrating the specificity of Pfpmt for phosphoethanolamine in vivo. Wild-type yeast cells, which inherently lack phosphoethanolamine methylation, acquire this activity as a result of expression of Pfpmt. The Pfpmt restores the ability of a yeast mutant pem1pem2 lacking the phosphatidylethanolamine methyltransferase genes to grow in the absence of choline. Lipid analysis of the Pfpmt-complemented pem1pem2 strain demonstrates the synthesis of phosphatidylcholine but not the intermediates of phosphatidylethanolamine transmethylation. Complementation of the pem1pem2 mutant relies on specific methylation of phosphoethanolamine but not phosphatidylethanolamine. Interestingly, a mutation in the yeast choline-phosphate cytidylyltransferase gene abrogates the complementation by Pfpmt thus demonstrating that Pfpmt activity is directly coupled to the Kennedy pathway for the de novo synthesis of phosphatidylcholine.

Received for publication, December 28, 2004

^* This work was supported by Grants DAMD17-02-1-0211 and PR033005 from the United States Army Medical Research and Material Command (to C. B. M.) and Grants AI051507 and AI058962 (to C. B. M.) and 2R37-GM32453 and AI030060 (to D. R. V.) from the National Institute of Health. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| To whom correspondence should be addressed: Center for Microbial Pathogenesis, University of Connecticut Health Center, 263 Farmington Ave, Farmington, CT 06030. Tel.: 860-679-3544; Fax: 860-679-8130; E-mail: choukri{at}up.uchc.edu.

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