The Metabolite Repair Enzyme Phosphoglycolate Phosphatase Regulates Central Carbon Metabolism and Fosmidomycin Sensitivity in Plasmodium falciparum

Abstract

The malaria parasite has a voracious appetite, requiring large amounts of glucose and nutrients for its rapid growth and proliferation inside human red blood cells. The host cell is resource rich, but this is a double-edged sword; nutrient excess can lead to undesirable metabolic reactions and harmful by-products. Here, we demonstrate that the parasite possesses a metabolite repair enzyme (PGP) that suppresses harmful metabolic by-products (via substrate dephosphorylation) and allows the parasite to maintain central carbon metabolism. Loss of PGP leads to the accumulation of two damaged metabolites and causes a domino effect of metabolic dysregulation. Accumulation of one damaged metabolite inhibits an essential enzyme in the pentose phosphate pathway, leading to substrate accumulation and secondary inhibition of glycolysis. This work highlights how the parasite coordinates metabolic flux by eliminating harmful metabolic by-products to ensure rapid proliferation in its resource-rich niche.

The Key Glycolytic Enzyme Phosphofructokinase Is Involved in Resistance to Antiplasmodial Glycosides

“…Given that fosmidomycin targets DXR, it is likely that the reduction in DXR’s substrate (DOXP) in PS-3-resistant parasites, coupled with a decrease in MEcPP and IPP, results in an increase in fosmidomycin activity. Increased sensitivity to fosmidomycin has also been reported in P. falciparum parasites lacking phosphoglycolate phosphatase (PGP) ( 40 ). PGP, a third member of the P. falciparum HAD family, has been shown to be involved in regulating glycolysis and PPP flux in asexual P. falciparum ( 40 ).…”

“…Increased sensitivity to fosmidomycin has also been reported in P. falciparum parasites lacking phosphoglycolate phosphatase (PGP) ( 40 ). PGP, a third member of the P. falciparum HAD family, has been shown to be involved in regulating glycolysis and PPP flux in asexual P. falciparum ( 40 ). In Δ pgp parasites, the loss of PGP leads to the inhibition of the PPP enzyme 6-phosphogluconate dehydrogenase (6-PGD), resulting in reduced glycolytic flux and causing reduced isoprenoid biosynthesis and increased sensitivity to fosmidomycin ( 40 ).…”

“…PGP, a third member of the P. falciparum HAD family, has been shown to be involved in regulating glycolysis and PPP flux in asexual P. falciparum ( 40 ). In Δ pgp parasites, the loss of PGP leads to the inhibition of the PPP enzyme 6-phosphogluconate dehydrogenase (6-PGD), resulting in reduced glycolytic flux and causing reduced isoprenoid biosynthesis and increased sensitivity to fosmidomycin ( 40 ). Interestingly, fosmidomycin-resistant parasites harboring mutations in Pf HAD2 display the opposite metabolomic profile to that of PS-3-resistant parasites.…”

Glutamine metabolism modulates azole susceptibility inTrypanosoma cruziamastigotes

“…Similarly, standard in vitro inhibitory activity of a candidate compound can be confounded by altered pathogen metabolism due to growth media composition (Hicks et al, 2018; Pethe et al, 2010) and conversely an understanding of these interactions can potentiate treatment (Vestergaard et al, 2017). These complex interactions are best understood in cases of bacterial pathogenesis, but recently, similar trends are apparent in eukaryotic pathogens (Dumont et al, 2019; McLean and Jacobs-Lorena, 2017; Murithi et al, 2020).…”

“…A third, less explored option, is the impact of metabolic and environmental heterogeneity on the efficacy of a given antimicrobial agent (Yang et al, 2017). Factors such as pathogen respiration (Lobritz et al, 2015), ATP levels (Conlon et al, 2016) and buildup of metabolic intermediates (Dumont et al, 2019) as well as environmental stressors such as the host immune response (Rowe et al, 2020) can modulate antibiotic efficacy. Recent work has shown that when the metabolic state and growth rate of microbes are disentangled, the factor that correlates with antibiotic efficacy is the microbial metabolic state (Lopatkin et al, 2019).…”