Biochemical and structural characterisation of the apicoplast dihydrolipoamide dehydrogenase of Plasmodium falciparum

Laine, L. M., Biddau, M. , Byron, O. and Müller, S. (2014) Biochemical and structural characterisation of the apicoplast dihydrolipoamide dehydrogenase of Plasmodium falciparum. Bioscience Reports, 35(1), e00171. (doi:10.1042/BSR20140150) (PMID:25387830) (PMCID:PMC4293902)

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Abstract

Pyruvate dehydrogenase complex (PDC) is a multi-enzyme complex comprising a decarboxylase (E1), a dihydrolipomide acetyltransferase (E2) and a dihydrolipoamide dehydrogenase (E3). PDC catalyses the decarboxylation of pyruvate and forms acetyl-CoA and NADH. In the human malaria parasite Plasmodium falciparum the single PDC is located exclusively in the apicoplast. Plasmodium PDC is essential for parasite survival in the mosquito vector and for late liver stage development in the human host, suggesting its suitability as a target for intervention strategies against malaria. Here, P. falciparum apicoplast E3 (PfaE3) was recombinantly expressed and characterised. Biochemical parameters were comparable with those determined for E3 from other organisms. A homology model for PfaE3 reveals an extra anti-parallel β-strand at the position where human E3 binding protein interacts with E3; a parasite-specific feature that may be exploitable for drug discovery against PDC. To assess the biological role of Pfae3,it was deleted from P. falciparum and although the mutants are viable, they displayed a highly synchronous growth phenotype during intra-erythrocytic development. The mutants also showed changes in the expression of some mitochondrial and antioxidant proteins suggesting that deletion of Pfae3 impacts on the parasite’s metabolic function with downstream effects on the parasite’s redox homeostasis and cell cycle.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Biddau, Marco and Muller, Professor Sylke and Byron, Professor Olwyn
Authors: Laine, L. M., Biddau, M., Byron, O., and Müller, S.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Bioscience Reports
Publisher:Portland Press Ltd.
ISSN:0144-8463
ISSN (Online):1573-4935
Copyright Holders:Copyright © 2015 The Authors
First Published:First published in Bioscience Reports 35(1):e00171
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
498481Functional, biochemical and structural analyses of Plasmodium falciparum pyruvate dehydrogenase complex and glycine cleavage systemsSylke MullerWellcome Trust (WELLCOME)086411/Z/08/ZIII - PARASITOLOGY
498483Functional, biochemical and structural analyses of Plasmodium falciparum pyruvate dehydrogenase complex and glycine cleavage systemsSylke MullerWellcome Trust (WELLCOME)086411/Z/08/ZIII - PARASITOLOGY
391203Redox mechanisms of the human malaria parasite plasmodium falciparumSylke MullerWellcome Trust (WELLCOME)061173III - PARASITOLOGY