From genomes to systems: the path with yeast.

Metabolic Control Analysis (MCA) is a conceptual and mathematical formalism that models the relative contributions of individual effectors in a pathway to both the flux through the pathway and the concentrations of individual intermediates within it. To exploit MCA in an initial Systems Biology analysis of the eukaryotic cell, two categories of experiments are required. In category 1 experiments, flux is changed and the impact on the levels of the direct and indirect products of gene action is measured. We have measured the impact of changing the flux on the transcriptome, proteome and metabolome of Saccharomyces cerevisiae. In this whole-cell analysis, flux equates to growth rate. In category 2 experiments, the levels of individual gene products are altered, and the impact on the flux is measured. We have used competition analyses between the complete set of heterozygous yeast deletion mutants to reveal genes encoding proteins with high flux control coefficients. These genes may be exploited, in a top-down analysis, to build a coarse-grained model of the eukaryotic cell, as exemplified by yeast. More detailed modelling requires that 'natural' biological systems be identified. The combination of flux balance analysis with both genetics and metabolomics in the definition of metabolic systems is discussed.