Influence of Metabolic Network Structure and Function on Enzyme Evolution
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CitationVitkup, Dennis, Peter Kharchenko, and Andreas Wagner. 2006. Influence of metabolic network structure and function on enzyme evolution. Genome Biology 7(5): R39.
AbstractBackground: Most studies of molecular evolution are focused on individual genes and proteins.
However, understanding the design principles and evolutionary properties of molecular networks
requires a system-wide perspective. In the present work we connect molecular evolution on the
gene level with system properties of a cellular metabolic network. In contrast to protein interaction
networks, where several previous studies investigated the molecular evolution of proteins,
metabolic networks have a relatively well-defined global function. The ability to consider fluxes in
a metabolic network allows us to relate the functional role of each enzyme in a network to its rate
Results: 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.
Conclusion: 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
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