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

Storm, J., Perner, J., Aparicio, I., Patzewitz, E.-M., Olszewski, K., Llinas, M., Engel, P.C. and Muller, S. (2011) Plasmodium falciparum glutamate dehydrogenase a is dispensable and not a drug target during erythrocytic development. Malaria Journal, 10(193), (doi: 10.1186/1475-2875-10-193)

Abstract

<p>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.</p> <p>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.</p> <p>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(Delta gdha) parasite lines. Further, the fate of the carbon skeleton of [(13)C] labelled glutamine was assessed by metabolomic studies, revealing no differences in the labelling of a-ketoglutarate and other TCA pathway intermediates between wild type and mutant parasites.</p> <p>Conclusions: First, the data support the conclusion that D10(Delta gdha) 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.</p>

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Muller, Professor Sylke and Patzewitz, Ms Eva-Maria and Storm, Dr Janet and Perner, Mr Jan
• Authors: Storm, J., Perner, J., Aparicio, I., Patzewitz, E.-M., Olszewski, K., Llinas, M., Engel, P.C., and Muller, S.
• College/School: College of Medical Veterinary and Life Sciences > School of Life Sciences; College of Medical Veterinary and Life Sciences > School of Infection & Immunity
• Journal Name: Malaria Journal
• Publisher: BioMed Central
• ISSN: 1475-2875
• Published Online: 14 July 2011
• Copyright Holders: Copyright © 2011 The Authors
• First Published: First published in Malaria Journal 10:193
• Publisher Policy: Reproduced in accordance with the copyright policy of the publisher

Project Code	Award No	Project Name	Principal Investigator	Funder's Name	Funder Ref	Lead Dept
50641					UNSPECIFIED