Uncovering metabolic objectives pursued by changes of enzyme levels

Expression profiling and proteomic techniques reveal significant variations in the levels of thousands of mRNAs and proteins in response to environmental changes such as substrate depletion, oxidative stress, and hormonal stimulation. However, in most cases the functional implications of these variations remain elusive. One crucial problem complicating the functional interpretation of high-throughput data is that changes of protein levels do not simply translate into equivalent changes in the rate of the associated chemical processes due to various modes of enzyme regulation and the instantaneous effect of changed metabolite concentrations on adjacent flux rates. Here, we outline a theoretical concept to exploit information on (relative) changes in the level of metabolic enzymes for the prediction of (relative) flux changes in the underlying metabolic network. Our approach rests on the assumption that size and direction of fluxes (flux distribution) in the network are determined by an optimization principle in that the production of the physiologically relevant output metabolites is accomplished with minimal total flux. The prediction method comprises two main steps. First, we approximate (unknown) flux changes by a linear combination of so-called minimal flux modes, each representing a specific flux distribution minimally required to accomplish the production of only one of the numerous functionally relevant output metabolites. Second, the unknown coefficients of this decomposition are chosen such that a maximal correlation with observed differential expression data is obtained. Based on simulated enzyme expression scenarios in a metabolic model of the human red blood cell, we demonstrate the predictive capacity of our method.