Cellular networks are subject to extensive regulation, which modifies the availability and efficiency of connections between components in response to external conditions. Thus far, studies of large-scale networks have focused on their connectivity, but have not considered how the modulation of this connectivity might also determine network properties. To address this issue, we analyzed how the coordinated expression of enzymes shapes the metabolic network of Saccharomyces cerevisiae. By integrating large-scale expression data with the structural description of the metabolic network, we systematically characterized the transcriptional regulation of metabolic pathways. The analysis revealed recurrent patterns, which may represent design principles of metabolic gene regulation. First, we find that transcription regulation biases metabolic flow toward linearity by coexpressing only distinct branches at metabolic branchpoints. Second, individual isozymes were often separately coregulated with distinct processes, providing a means of reducing crosstalk between pathways using a common reaction. Finally, transcriptional regulation defined a hierarchical organization of metabolic pathways into groups of varying expression coherence. These results emphasize the utility of incorporating regulatory information when analyzing properties of large-scale cellular networks.
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