Structure of Lactate Dehydrogenase from Plasmodium vivax:  Complexes with NADH and APADH

Abstract

Malaria caused by Plasmodium vivax is a major cause of global morbidity and, in rare cases, mortality. Lactate dehydrogenase is an essential Plasmodium protein and, therefore, a potential antimalarial drug target. Ideally, drugs directed against this target would be effective against both major species of Plasmodium, P. falciparum and P. vivax. In this study, the crystal structure of the lactate dehydrogenase protein from P. vivax has been solved and is compared to the equivalent structure from the P. falciparum enzyme. The active sites and cofactor binding pockets of both enzymes are found to be highly similar and differentiate these enzymes from their human counterparts. These structures suggest effective inhibition of both enzymes should be readily achievable with a common inhibitor. The crystal structures of both enzymes have also been solved in complex with the synthetic cofactor APADH. The unusual cofactor binding site in these Plasmodium enzymes is found to readily accommodate both NADH and APADH, explaining why the Plasmodium enzymes retain enzymatic activity in the presence of this synthetic cofactor.

Isolation, cloning and sequence analysis of lactate dehydrogenase gene from Theileria annulata may lead to design of new antitheilerial drugs

“…The crystal structure of P. falciparum LDH (Dunn et al 1996) indicated that this five amino acid insertion creates a distinctive cleft in the surface of the enzyme adjacent to the substrate binding site in contrast to the same region of the host LDH. Similar structures were also observed for P. vivax (Chaikuad et al 2005), P. berghei (Winter et al 2003) and T. gondii (Kavanagh et al 2004) LDHs. Several organic molecules have recently been designed and developed with the aim of blocking LDH from P. falciparum (Granchi et al 2010).…”

“…This enzyme catalyses the interconversion of pyruvate and l-lactate with a concomitant interconversion of NADH and NAD + (Holbrook et al 1975). On the basis of molecular cloning studies, kinetic characterisations and X-ray structure analysis, plasmodial LDH's have been studied in most detail (Dunn et al 1996;Turgut-Balik et al 2001a;Chaikuad et al 2005) among the apicomplexan parasites and have been identified as new enzyme targets for the development of novel antimalarial drugs. Determination of the key residues in the active site of this enzyme from Plasmodium showed that this site could be an attractive target for enzyme inhibitors (Dunn et al 1996;Turgut-Balik et al 2001b).…”

Isolation, Cloning and Sequence Analysis of Enolase Enzyme Encoding Gene from Theileria annulata for Assessment of Important Residues of This Enzyme

“…among apicomplexan parasites [16] . Because Plasmodium species do not have a functional Krebs cycle, as Thelieria species, they produce their energy via glycolysis [17,18] .…”

“…Because Plasmodium species do not have a functional Krebs cycle, as Thelieria species, they produce their energy via glycolysis [17,18] . Lactate dehydrogenase enzyme has a crucial role in this parasites life as it catalyzes the reduction of pyruvates to hydroxyls by oxidation of NADH to NAD + [16] . It is important to note that, Plasmodial LDH also has a pentapeptide insertion in the active site of the enzyme [19] .…”

“…From this point of view, in vitro studies showed that azole based inhibitors can bind to active site of PfLDH protein and stop both the enzyme activity and the parasite development in red blood cells. These compounds were selective against PfLDH than human LDH and crystallography studies showed that the binding regions were also maintained in P. berghei LDH forms [16] . Considering these studies on Plasmodium species, it is aimed to investigate if it is possible to open a route to design new antitheilerial drugs by the evaluation of the data from isolation and cloning of enolase encoding gene from T. annulata.…”