title: Plasmodium pyruvate dehydrogenase activity is only essential for the parasite's progression from liver infection to blood infection.
abstract: Plasmodium parasites possess a single pyruvate dehydrogenase (PDH) enzyme complex that is localized to the plastid-like organelle known as the apicoplast. Unlike most eukaryotes, Plasmodium parasites lack a mitochondrial PDH. The PDH complex catalyses the conversion of pyruvate to acetyl-CoA, an important precursor for the tricarboxylic acid cycle and type II fatty acid synthesis (FAS II). In this study, using a rodent malaria model, we show that the PDH E1 alpha and E3 subunits colocalize with the FAS II enzyme FabI in the apicoplast of liver stages but are not significantly expressed in blood stages. Deletion of the E1 alpha or E3 subunit genes of Plasmodium yoelii PDH caused no defect in blood stage development, mosquito stage development or early liver stage development. However, the gene deletions completely blocked the ability of the e1 alpha(-) and e3(-) parasites to form exo-erythrocytic merozoites during late liver stage development, thus preventing the initiation of a blood stage infection. This phenotype is similar to that observed for deletions of genes involved in FAS II elongation. The data strongly support the hypothesis that the sole role of PDH is to provide acetyl-CoA for FAS II.
authors.affiliation: Seattle Biomedical Research Institute, 307 Westlake Avenue North, Suite 500, Seattle, WA 98109, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Pei
authors.forename: Alice S
authors.initials: AS
authors.lastname: Tarun
authors.forename: Ashley M
authors.initials: AM
authors.lastname: Vaughan
authors.forename: Rob W
authors.initials: RW
authors.lastname: Herman
authors.forename: Joanne M B
authors.initials: JM
authors.lastname: Soliman
authors.forename: Alyssa
authors.initials: A
authors.lastname: Erickson-Wayman
authors.forename: Stefan H I
authors.initials: SH
authors.lastname: Kappe
mesh_terms: D000818:Animals; D008058:Dihydrolipoamide Dehydrogenase / Q000235:genetics / Q000378:metabolism*; D004912:Erythrocytes / Q000469:parasitology; D005260:Female; D008099:Liver / Q000469:parasitology; D008288:Malaria / Q000469:parasitology; D051379:Mice; D008807:Mice, Inbred BALB C; D030781:Organisms, Genetically Modified; D010967:Plasmodium yoelii / Q000201:enzymology* / Q000235:genetics / Q000254:growth & development / Q000378:metabolism; D018087:Plastids / Q000378:metabolism; D030481:Pyruvate Dehydrogenase (Lipoamide) / Q000235:genetics / Q000378:metabolism*
chemical_list: D030481:Pyruvate Dehydrogenase (Lipoamide); D008058:Dihydrolipoamide Dehydrogenase