Abstract
The emergence of functional novelties during protein evolution has puzzled scientists for many years. Most proposed models focus on repeated duplication‐divergence cycles, but the entanglement of selection pressures acting on the control of transcriptional and enzymatic activity, for example, by metabolites, has not been addressed so far. In this issue of EMBO Reports, Noda‐Garcia et al 1 describe two glutamate dehydrogenase paralogs from Bacillus subtilis with very similar sequences and under two distinct modes of activity control. The functional divergence of these two enzymes during evolution is driven by an interlinked combination of differences between their enzymatic properties and their transcriptional regulation. This article thus illuminates another level of complexity in molecular evolution that may help understand the hitherto unexplained co‐existence of paralogous genes that at first sight appear to be functionally redundant.