Plasmodium falciparum glutamate dehydrogenase a is dispensable and not a drug target during erythrocytic development

Background Plasmodium falciparum contains three genes encoding potential glutamate dehydrogenases. The protein encoded by gdha has previously been biochemically and structurally characterized. It was suggested that it is important for the supply of reducing equivalents during intra-erythrocytic deve...
Ausführliche Beschreibung

Background Plasmodium falciparum contains three genes encoding potential glutamate dehydrogenases. The protein encoded by gdha has previously been biochemically and structurally characterized. It was suggested that it is important for the supply of reducing equivalents during intra-erythrocytic development of Plasmodium and, therefore, a suitable drug target. Methods The gene encoding the NADP(H)-dependent GDHa has been disrupted by reverse genetics in P. falciparum and the effect on the antioxidant and metabolic capacities of the resulting mutant parasites was investigated. Results No growth defect under low and elevated oxygen tension, no up- or down-regulation of a number of antioxidant and NADP(H)-generating proteins or mRNAs and no increased levels of GSH were detected in the $ D10^{Δgdha} $parasite lines. Further, the fate of the carbon skeleton of [13C] labelled glutamine was assessed by metabolomic studies, revealing no differences in the labelling of α-ketoglutarate and other TCA pathway intermediates between wild type and mutant parasites. Conclusions First, the data support the conclusion that $ D10^{Δgdha} $parasites are not experiencing enhanced oxidative stress and that GDHa function may not be the provision of NADP(H) for reductive reactions. Second, the results imply that the cytosolic, NADP(H)-dependent GDHa protein is not involved in the oxidative deamination of glutamate but that the protein may play a role in ammonia assimilation as has been described for other NADP(H)-dependent GDH from plants and fungi. The lack of an obvious phenotype in the absence of GDHa may point to a regulatory role of the protein providing glutamate (as nitrogen storage molecule) in situations where the parasites experience a limiting supply of carbon sources and, therefore, under in vitro conditions the enzyme is unlikely to be of significant importance. The data imply that the protein is not a suitable target for future drug development against intra-erythrocytic parasite development. Ausführliche Beschreibung

Autor*in:	Storm, Janet [verfasserIn] Perner, Jan Aparicio, Isabela Patzewitz, Eva-Maria Olszewski, Kellen Llinas, Manuel Engel, Paul C Müller, Sylke

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2011

Schlagwörter:	Oxidative Deamination Mutant Parasite Parasite Extract Wild Type Parasite Parasite Lysate

Anmerkung:	© Storm et al; licensee BioMed Central Ltd. 2011. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (

Übergeordnetes Werk:	Enthalten in: Malaria journal - London : BioMed Central, 2002, 10(2011), 1 vom: 14. Juli
Übergeordnetes Werk:	volume:10 ; year:2011 ; number:1 ; day:14 ; month:07

Links:	Volltext

DOI / URN:	10.1186/1475-2875-10-193

Katalog-ID:	SPR028616022