title: Modeling metabolism and stage-specific growth of Plasmodium falciparum HB3 during the intraerythrocytic developmental cycle.
abstract: The human malaria parasite Plasmodium falciparum goes through a complex life cycle, including a roughly 48-hour-long intraerythrocytic developmental cycle (IDC) in human red blood cells. A better understanding of the metabolic processes required during the asexual blood-stage reproduction will enhance our basic knowledge of P. falciparum and help identify critical metabolic reactions and pathways associated with blood-stage malaria. We developed a metabolic network model that mechanistically links time-dependent gene expression, metabolism, and stage-specific growth, allowing us to predict the metabolic fluxes, the biomass production rates, and the timing of production of the different biomass components during the IDC. We predicted time- and stage-specific production of precursors and macromolecules for P. falciparum (strain HB3), allowing us to link specific metabolites to specific physiological functions. For example, we hypothesized that coenzyme A might be involved in late-IDC DNA replication and cell division. Moreover, the predicted ATP metabolism indicated that energy was mainly produced from glycolysis and utilized for non-metabolic processes. Finally, we used the model to classify the entire tricarboxylic acid cycle into segments, each with a distinct function, such as superoxide detoxification, glutamate/glutamine processing, and metabolism of fumarate as a byproduct of purine biosynthesis. By capturing the normal metabolic and growth progression in P. falciparum during the IDC, our model provides a starting point for further elucidation of strain-specific metabolic activity, host-parasite interactions, stress-induced metabolic responses, and metabolic responses to antimalarial drugs and drug candidates.
authors.affiliation: Department of Defense Biotechnology High Performance Computing Software Applications Institute, Telemedicine and Advanced Technology Research Center, U.S. Army Medical Research and Materiel Command, Ft. Detrick, MD 21702, USA. jaques.reifman.civ@mail.mil.
authors.forename: Xin
authors.initials: X
authors.lastname: Fang
authors.forename: Jaques
authors.initials: J
authors.lastname: Reifman
authors.forename: Anders
authors.initials: A
authors.lastname: Wallqvist
mesh_terms: D000818:Animals; D018533:Biomass; D004734:Energy Metabolism; D004912:Erythrocytes / Q000469:parasitology*; D006790:Host-Parasite Interactions; D006801:Humans; D008018:Life Cycle Stages; D016778:Malaria, Falciparum / Q000378:metabolism* / Q000469:parasitology*; D053858:Metabolic Networks and Pathways; D008954:Models, Biological; D010963:Plasmodium falciparum / Q000254:growth & development* / Q000378:metabolism*; D013997:Time Factors