ORCID Profile
0000-0002-7292-788X
Current Organisations
Commonwealth Science and Industrial Research Organisation (CSIRO)
,
CSIRO
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Publications
The metabolic repair enzyme phosphoglycolate phosphatase regulates central carbon metabolism and fosmidomycin sensitivity inPlasmodium falciparum
Publisher: Cold Spring Harbor Laboratory
Date: 12-09-2018
DOI: 10.1101/415505
Abstract: The asexual blood stages of the malaria parasite, Plasmodium falciparum are highly dependent on glycolysis for ATP synthesis, redox balance and provision of essential anabolic precursors. Recent studies have suggested that members of the haloacid dehalogenase (HAD) family of metabolite phosphatases may play an important role in regulating multiple pathways in P. falciparum central carbon metabolism. Here, we show that the P. falciparum HAD protein, phosphoglycolate phosphatase ( Pf PGP), which is homologous to yeast Pho13 and mammalian PGP, regulates glycolysis in asexual blood stages by controlling intracellular levels of several intermediates and novel end-products of this pathway. Deletion of the P. falciparum pgp gene significantly attenuated asexual parasite growth in red blood cells, while comprehensive metabolomic analysis revealed the accumulation of two previously uncharacterized metabolites, as well as changes in a number of intermediates in glycolysis and the pentose phosphate pathway. The two unknown metabolites were assigned as 2-phospho-lactate and 4-phosphoerythronate by comparison of their mass spectra with synthetic standards. 2-Phospho-lactate was significantly elevated in wildtype and Δ Pf PGP parasites cultivated in the presence of methylglyoxal and D-lactate, but not L-lactate, indicating that it is a novel end-product of the methylglyoxal pathway. 4-Phosphoerythronate is a putative side product of the glycolytic enzyme, glyceraldehyde dehydrogenase and the accumulation of both 4-phosphoerythronate and 2-phospho-D-lactate were associated with changes in glycolytic and the pentose phosphate pathway fluxes as shown by 13 C-glucose labelling studies and increased sensitivity of the Δ Pf PGP parasites to the drug fosmidomycin. Our results suggest that Pf PGP contributes to a novel futile metabolic cycle involving the phosphorylation/dephosphorylation of D-lactate as well as detoxification of metabolites, such as 4-phosphoerythronate, and both may have important roles in regulating P. falciparum central carbon metabolism. The major pathogenic stages of the malaria parasite, Plasmodium falciparum , develop in red blood cells where they have access to an abundant supply of glucose. Unsurprisingly these parasite stages are addicted to using glucose, which is catabolized in the glycolytic and the 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 next-generation of anti-malarial drugs. In this study, we show the red blood cell stages of P. falciparum express an enzyme that is specifically involved in regulating the intracellular levels of two metabolites that are novel end-products or side products of glycolysis. Parasite mutants lacking this enzyme are viable but exhibit diminished growth rates in red blood cells. These mutant lines accumulate the two metabolites, and exhibit global changes in central carbon metabolism. Our findings suggest that metabolic end/side products of glycolysis directly regulate the metabolism of these parasites, and that the intracellular levels of these are tightly controlled by previously uncharacterized metabolite phosphatases.
Synthesis and Explosion Hazards of 4-Azido-l -phenylalanine
Publisher: American Chemical Society (ACS)
Date: 26-03-2018
Electrochemical Quantification of Glycated and Non-glycated Human Serum Albumin in Synthetic Urine
Publisher: American Chemical Society (ACS)
Date: 22-01-2019
Pyrocinchonimides Conjugate to Amine Groups on Proteins via Imide Transfer
Publisher: American Chemical Society (ACS)
Date: 17-04-2020
Total synthesis and mass spectrometric analysis of a Mycobacterium tuberculosis phosphatidylglycerol featuring a two-step synthesis of (R)-tuberculostearic acid
Publisher: Royal Society of Chemistry (RSC)
Date: 2017
DOI: 10.1039/C7OB01786C
Abstract: A two-step synthesis of ( R )-tuberculostearic acid enables the total synthesis of a Mycobacterium tuberculosis phosphatidylglycerol. Mass spectrometric fragmentation of synthetic PG regioisomers of acylation patterns.
Related Organisations
Commonwealth Science And Industrial Research Organisation (CSIRO)
Location: Australia
Related Funding Activities
No related grants have been discovered for Mark Bentley Richardson.