Investigating the metabolic regulation capacity of the malaria parasite P. falciparum

© 2019 Dr. Laure DumontThe pathogenic stages of the malaria parasite Plasmodium falciparum develop within red blood cells, where they have access to an abundant supply of glucose. Unsurprisingly, these parasite stages are heavily reliant upon glucose for meeting their energy and biomass requirements, which is catabolized in the glycolytic and pentose phosphate pathways. While these pathways also exist in host cells, there is increasing evidence that P. falciparum has evolved novel ways for regulating glucose metabolism that could be targeted by the next generation of antimalarial drugs. During my PhD, I studied one such level of metabolic regulation, which occurs via metabolic repair enzymes regulation of central carbon metabolism, in blood stages of P. falciparum. The glyoxalase system is ubiquitous across organisms and facilitates the detoxification of methylglyoxal – generated via incorrect functioning of the glycolytic enzyme triose-phosphate isomerase – into D-lactate. I found the cytosolic glyoxalase enzymes to be responsible for the majority of detoxification of methylglyoxal, as disruption of the cytosolic glyoxalase I (GloI) impairs D-lactate production. In addition, I discovered a novel end-product to this pathway, the unusual metabolite phospho-D-lactate. In addition, I characterised a member of the haloacid dehalogenase family of metabolite phosphatases, the phospho-glycolate phosphatase (PGP), which regulates phospho-D-lactate levels. Parasite mutants lacking the PGP enzyme are viable but exhibit diminished growth rates in red blood cells. They accumulate phospho-D-lactate, as well as 4-phosphoerythronate – a putative side product of another glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase – suggesting PGP acts upon these two metabolites at minima. Metabolically, the accumulation of phospho-D-lactate and 4-phosphoerythronate was associated with changes in flux through the glycolytic and pentose phosphate pathways. Moreover, parasites with a non-functional PGP enzyme exhibited an increased sensitivity to the antimalarial fosmidomycin. Our findings suggest that metabolic end/side products of glycolysis directly regulate the metabolism of P. falciparum, and that the intracellular levels of these metabolites are tightly controlled by metabolic repair enzymes