Exploring inhibition of Pdx1, a component of the PLP synthase complex of the human malaria parasite Plasmodium falciparum

Author:

Reeksting Shaun B.12,Müller Ingrid B.2,Burger Pieter B.1,Burgos Emmanuel S.3,Salmon Laurent4,Louw Abraham I.1,Birkholtz Lyn-Marie1,Wrenger Carsten25

Affiliation:

1. Department of Biochemistry, Faculty of Natural and Agricultural Sciences, University of Pretoria, Private Bag X20, Hatfield 0028, South Africa

2. Bernhard Nocht Institute for Tropical Medicine, Department of Biochemistry, Bernhard Nocht-Strasse 74, D-20359 Hamburg, Germany

3. Biochemistry Department, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York, NY 10461, U.S.A.

4. Laboratoire de Chimie Bioorganique et Bioinorganique, CNRS-UMR 8182, Institut de Chimie Moléculaire et des Matériaux d’Orsay, Bâtiment 420, Université Paris Sud XI, F-91405 Orsay, France

5. Department of Parasitology, Institute of Biomedical Science, University of São Paulo, Av. Professor Lineu Prestes 1374, 05508-000 São Paulo-SP, Brazil

Abstract

Malaria tropica is a devastating infectious disease caused by Plasmodium falciparum. This parasite synthesizes vitamin B6de novo via the PLP (pyridoxal 5′-phosphate) synthase enzymatic complex consisting of PfPdx1 and PfPdx2 proteins. Biosynthesis of PLP is largely performed by PfPdx1, ammonia provided by PfPdx2 subunits is condensed together with R5P (D-ribose 5-phosphate) and G3P (DL-glyceraldehyde 3-phosphate). PfPdx1 accommodates both the R5P and G3P substrates and intricately co-ordinates the reaction mechanism, which is composed of a series of imine bond formations, leading to the production of PLP. We demonstrate that E4P (D-erythrose 4-phosphate) inhibits PfPdx1 in a dose-dependent manner. We propose that the acyclic phospho-sugar E4P, with a C1 aldehyde group similar to acyclic R5P, could interfere with R5P imine bond formations in the PfPdx1 reaction mechanism. Molecular docking and subsequent screening identified the E4P hydrazide analogue 4PEHz (4-phospho-D-erythronhydrazide), which selectively inhibited PfPdx1 with an IC50 of 43 μM. PfPdx1 contained in the heteromeric PLP synthase complex was shown to be more sensitive to 4PEHz and was inhibited with an IC50 of 16 μM. Moreover, the compound had an IC50 value of 10 μM against cultured P. falciparum intraerythrocytic parasites. To analyse further the selectivity of 4PEHz, transgenic cell lines overexpressing PfPdx1 and PfPdx2 showed that additional copies of the protein complex conferred protection against 4PEHz, indicating that the PLP synthase is directly affected by 4PEHz in vivo. These PfPdx1 inhibitors represent novel lead scaffolds which are capable of targeting PLP biosynthesis, and we propose this as a viable strategy for the development of new therapeutics against malaria.

Publisher

Portland Press Ltd.

Subject

Cell Biology,Molecular Biology,Biochemistry

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