Influence of metabolic network structure and function on enzyme evolution

Our results, based on the yeast metabolic network, demonstrate that important evolutionary processes, such as the fixation of single nucleotide mutations, gene duplications, and gene deletions, are influenced by the structure and function of the network. Specifically, central and highly connected enzymes evolve more slowly than less connected enzymes. Also, enzymes carrying high metabolic fluxes under natural biological conditions experience higher evolutionary constraints. Genes encoding enzymes with high connectivity and high metabolic flux have higher chances to retain duplicates in evolution. In contrast to protein interaction networks, highly connected enzymes are no more likely to be essential compared to less connected enzymes.The presented analysis of evolutionary constraints, gene duplication, and essentiality demonstrates that the structure and function of a metabolic network shapes the evolution of its enzymes. Our results underscore the need for systems-based approaches in studies of molecular evolution.Molecular networks and the genes encoding their building blocks represent two different levels of biological organization that interact in evolution. On the one hand, genetic changes such as point mutations, gene deletions, and gene duplications influence the structure and evolution of these networks. Conversely, network function may constrain the kinds of mutations that can be tolerated, and thus how genes evolve. Existing work on the structure and evolution of molecular networks has mainly focused on protein interaction networks [1-6]. Such networks are very heterogeneous: they contain large macromolecular complexes, regulatory interactions, signaling interactions, and interactions of proteins that provide structural support for a cell. As a result, it is difficult to ascertain how network structure reflects network function. A large fraction of false positives and false negatives in protein interaction networks [7,8] further complicates the structure t