Kinetic modelling of phospholipid synthesis in Plasmodium knowlesi unravels crucial steps and relative importance of multiple pathwaysReport as inadecuate




Kinetic modelling of phospholipid synthesis in Plasmodium knowlesi unravels crucial steps and relative importance of multiple pathways - Download this document for free, or read online. Document in PDF available to download.

BMC Systems Biology

, 7:123

First Online: 09 November 2013Received: 26 June 2013Accepted: 01 November 2013

Abstract

BackgroundPlasmodium is the causal parasite of malaria, infectious disease responsible for the death of up to one million people each year. Glycerophospholipid and consequently membrane biosynthesis are essential for the survival of the parasite and are targeted by a new class of antimalarial drugs developed in our lab. In order to understand the highly redundant phospholipid synthethic pathways and eventual mechanism of resistance to various drugs, an organism specific kinetic model of these metabolic pathways need to be developed in Plasmodium species.

ResultsFluxomic data were used to build a quantitative kinetic model of glycerophospholipid pathways in Plasmodium knowlesi. In vitro incorporation dynamics of phospholipids unravels multiple synthetic pathways. A detailed metabolic network with values of the kinetic parameters maximum rates and Michaelis constants has been built. In order to obtain a global search in the parameter space, we have designed a hybrid, discrete and continuous, optimization method. Discrete parameters were used to sample the cone of admissible fluxes, whereas the continuous Michaelis and maximum rates constants were obtained by local minimization of an objective function.The model was used to predict the distribution of fluxes within the network of various metabolic precursors.

The quantitative analysis was used to understand eventual links between different pathways. The major source of phosphatidylcholine PC is the CDP-choline Kennedy pathway.

In silico knock-out experiments showed comparable importance of phosphoethanolamine-N-methyltransferase PMT and phosphatidylethanolamine-N-methyltransferase PEMT for PC synthesis.

The flux values indicate that, major part of serine derived phosphatidylethanolamine PE is formed via serine decarboxylation, whereas major part of phosphatidylserine PS is formed by base-exchange reactions.

Sensitivity analysis of CDP-choline pathway shows that the carrier-mediated choline entry into the parasite and the phosphocholine cytidylyltransferase reaction have the largest sensitivity coefficients in this pathway, but does not distinguish a reaction as an unique rate-limiting step.

ConclusionWe provide a fully parametrized kinetic model for the multiple phospholipid synthetic pathways in P. knowlesi. This model has been used to clarify the relative importance of the various reactions in these metabolic pathways. Future work extensions of this modelling strategy will serve to elucidate the regulatory mechanisms governing the development of Plasmodium during its blood stages, as well as the mechanisms of action of drugs on membrane biosynthetic pathways and eventual mechanisms of resistance.

KeywordsMalaria Phospholipid metabolism Plasmodium knowlesi Mathematical model Fluxomics Hybrid optimization Electronic supplementary materialThe online version of this article doi:10.1186-1752-0509-7-123 contains supplementary material, which is available to authorized users.

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Author: Partho Sen - Henri J Vial - Ovidiu Radulescu

Source: https://link.springer.com/



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