Parasite lactate dehydrogenase (pLDH) is a potential drug target for new antimalarials owing to parasite dependence on glycolysis for ATP production. The pLDH from all four species of human malarial parasites were cloned, expressed, and analyzed for structural and kinetic properties that might be exploited for drug development. pLDH from Plasmodium vivax, malariae, and ovale exhibit 90-92% identity to pLDH from Plasmodium falciparum. Catalytic residues are identical. Resides I250 and T246, conserved in most LDH, are replaced by proline in all pLDH. The pLDH contain the same five-amino acid insert (DKEWN) in the substrate specificity loops. Within the cofactor site, pLDH from P. falciparum and P. malariae are identical, while pLDH from P. vivax and P. ovale have one substitution. Homology modeling of pLDH from P. vivax, ovale, and malariae with the crystal structure of pLDH from P. falciparum gave nearly identical structures. Nevertheless, the kinetic properties and sensitivities to inhibitors targeted to the cofactor binding site differ significantly. Michaelis constants for pyruvate and lactate differ 8-9-fold; Michaelis constants for NADH, NAD(+), and the NAD(+) analogue 3-acetylpyridine adenine dinucleotide differ up to 4-fold. Dissociation constants for the inhibitors differ up to 21-fold. Molecular docking studies of the binding of the inhibitors to the cofactor sites of all four pLDH predict similar orientations, with the docked ligands positioned at the nicotinamide end of the cofactor site. pH studies indicate that inhibitor binding is independent of pH in the pH 6-8 range, suggesting that differences in dissociation constants for a specific inhibitor are not due to altered active site pK values among the four pLDH.
This research output has an Altmetric Attention Score of 12. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 05 December 2023.
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Altmetric has tracked 33,738,238 research outputs across all sources so far. Compared to these this one has done well and is in the 88th percentile: it's in the top 25% of all research outputs ever tracked by Altmetric.
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