Abstract
BackgroundControl effective flux (CEF) of a reaction is the weighted sum of all fluxes through that reaction, derived from elementary flux modes (EFM) of a metabolic network. Change in CEFs under different environmental conditions has earlier been proven to be correlated with the corresponding changes in the transcriptome. Here we use this to investigate the degree of transcriptional regulation of fluxes in the metabolism of Saccharomyces cerevisiae. We do this by quantifying correlations between changes in CEFs and changes in transcript levels for shifts in carbon source, i.e. between the fermentative carbon source glucose and nonfermentative carbon sources like ethanol, acetate, and lactate. The CEF analysis is based on a simple stoichiometric model that includes reactions of the central carbon metabolism and the amino acid metabolism.ResultsThe effect of the carbon shift on the metabolic fluxes was investigated for both batch and chemostat cultures. For growth on glucose in batch (respiro-fermentative) cultures, EFMs with no by-product formation were removed from the analysis of the CEFs, whereas those including any by-products (ethanol, glycerol, acetate, succinate) were omitted in the analysis of growth on glucose in chemostat (respiratory) cultures. This resulted in improved correlations between CEF changes and transcript levels. A regression correlation coefficient of 0.60 was obtained between CEF changes and gene expression changes in the central carbon metabolism for the analysis of 5 different perturbations. Out of 45 data points there were no more than 6 data points deviating from the correlation. Additionally, up- or down-regulation of at least 75% of the genes were in qualitative agreement with the CEF changes for all perturbations studied.ConclusionThe analysis indicates that changes in carbon source are associated with a high degree of hierarchical regulation of metabolic fluxes in the central carbon metabolism as the change in fluxes are correlating directly with the change in transcript levels of genes encoding their corresponding enzymes. For amino acid biosynthesis there was, however, not found to exist a similar correlation, and this may point to either post-transcriptional and/or metabolic regulation, or be due to the absence of a direct perturbation on the amino acid pathways in these experiments.
Highlights
Control effective flux (CEF) of a reaction is the weighted sum of all fluxes through that reaction, derived from elementary flux modes (EFM) of a metabolic network
In the field of functional genomics, there has been several studies on whether flux regulation is through the expression levels of metabolic genes [3,4,5], and a common approach is to compare flux levels calculated by flux balance analysis (FBA) or metabolic flux analysis (MFA) with mRNA levels [5,6,7]
The metabolic model consists of central carbon metabolism reactions as described by [13], and was improved by the addition of reactions involved in the synthesis of several amino acids (Additional File 1)
Summary
Control effective flux (CEF) of a reaction is the weighted sum of all fluxes through that reaction, derived from elementary flux modes (EFM) of a metabolic network. Change in CEFs under different environmental conditions has earlier been proven to be correlated with the corresponding changes in the transcriptome We use this to investigate the degree of transcriptional regulation of fluxes in the metabolism of Saccharomyces cerevisiae. Metabolic fluxes are functions of metabolite levels, enzyme properties (affinities and specific activities), and the concentrations of enzymes The latter are controlled at transcriptional, translational and/or post-translational levels, and is referred to as hierarchical regulation [1,2]. Weighted sum of fluxes through these elementary modes for each reaction, called control-effective fluxes (CEF), lead to the implicit incorporation of functionality and regulation into metabolic network structures [11,13,14]. Application to erythrocyte enzymopathies was demonstrated [15]
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