“…Intuitively, the evolution of a new protein function is bound to necessitate a certain degree of active site reconfiguration to accommodate a novel substrate or ligand, particularly if an enzyme evolves a new chemical reaction such as the cleavage of a different chemical bond . Compared to substitutions, indels may offer greater potential for such a task, by facilitating the swift acquisition of novel structural features that enable ligand recognition, novel catalysis, or new protein–protein interactions. ,, For instance, Toledo-Patiño et al recently demonstrated how indels could have triggered a switch in coenzyme specificity (NAD(P)- vs SAM-binding) during the evolutionary divergence of two Rossmann lineages …”