Insights to metabolic network evolution by fusion proteins

Human fusion proteins consisting of two or more fusion partners of prokaryotic origin exhibit accreted function. Recent studies have elucidated the importance of fusion proteins in complex regulatory networks. The significance of fusion proteins in cellular networks and their evolutionary mechanism is largely unknown. Here, we discuss the association of six fusion proteins with the citric acid cycle. We define possible gene fusion scenarios and show that they produce metabolites with high connectivity for complex networking. Complex networking of metabolites requires proteins with incremental structural architectures and functional capabilities. Such higher order functionality is frequently provided by fusion proteins. Therefore, evolution of fusion proteins capable of producing metabolites with greater connectivity for enhanced cross-talk between pathways is critical for the selection of multiple trajectories in maintaining a stoichiometric balance during regulation. The association of six fusion proteins with the citric acid cycle and their capability to produce metabolites with high connectivity index is intriguing. This suggests that fusion gene products and their evolution have had a key role in the selection of complex multifaceted networks. In addition, we propose that fusion proteins have gained additive biochemical function for a balanced regulation of metabolic networks.