Metabolic proof-reading in Plasmodium berghei: essentiality of phosphoglycolate phosphatase
Plasmodium falciparum (Pf)4-nitrophenylphosphatase was earlier shown to be involved in vitamin B1 metabolism by Knockel et al., (Mol. Biochem. Parasitol. 2008, 157, 241-243). An independent BLASTp search showed that the protein had significant homology with phos-phoglycolate phosphatase from mouse, human and yeast, and prompted us to re-investigate the biochemical properties of the recombinant Plasmodium enzyme. Owing to the insoluble nature of the Pf enzyme, an extended substrate screen and biochemical characterization was performed on its P. berghei (Pb) homolog that led to the identification of 2-phosphoglycolate and 2-phospho L-lactate as the relevant physiological substrates. 2-phosphoglycolate is known to be generated during repair of damaged DNA ends whereas, 2-phospho L-lactate is a product of pyruvate kinase side reaction. These metabolites are potent inhibitors of the key glycolytic enzymes, triosephosphate isomerase and phosphofructokinase, and hence clearance of these toxic metabolites is vital for cell survival and functioning. Gene knockout studies conducted in P. berghei revealed the essential nature of this conserved metabolic proof-reading enzyme.