The fold has been linked to three different functions in bacteria: oxidoreductase, copper chaperone, or cell division factor. PcoA and CueO perform a particular case of oxidation activity of cuprous ions [35]. CueO is mainly found in Enterobacteria whereas PcoA is characteristic of Pseudomonadales and Xanthomonadales, being the presence of both proteins mutually exclusive. Evolution of copper homeostasis in gamma Pevonedistat chemical structure proteobacteria Diverse biochemical, genetic and crystallographic studies have been performed to characterize the different proteins involved in copper tolerance in gamma proteobacteria [11, 13, 15, 25, 33, 36]. In this paper we analyzed the

current copper homeostasis model, where systems are the evolutionary and functional unit, from a phylogenomic perspective. It can be observed from our results that copper homeostatic systems do not behave as evolutionary units but particular species assemble different combinations of basic functions. To PD0332991 explain this behavior we propose that the process

by which bacteria handle copper can be compared to a metabolic pathway since organisms avoid free copper ions within the cell by developing copper translocation routes based in precise sequences of specific protein-protein interactions [16–18]. There are currently different models aimed at explaining the evolution of metabolic pathways. The patchwork hypothesis postulates that duplication of genes encoding primitive and promiscuous enzymes (capable of P-gp inhibitor catalyzing various reactions) allows each descendant enzyme to specialize in one of the ancestral reactions, this model considers the chemical mechanism as dominant [37]. Alternatively, the retrograde hypothesis suggests that, in the case where a substrate tends to be depleted, gene duplication can provide an enzyme capable of supplying the exhausted substrate, Isotretinoin giving rise to homologous enzymes catalyzing consecutive reactions

with the implicit assumption that substrate specificity is dominant [38]. Assuming that the selectable phenotype would be the control of copper concentration in the cellular space in response to its availability, the fitness value would rely first on the ability of proteins for copper binding (a trait previously and independently acquired) and then on the affinity and specificity of protein-protein interactions. Following these considerations, we propose two alternative hypotheses for the evolution of copper homeostasis in gamma proteobacteria: 1) Function is dominant. 2) Protein-protein interaction is dominant. In the first case and assuming each protein fulfills a specific function among the three known for copper homeostasis proteins in bacteria, its occurrence in a repertoire will be determined by functional complementation and not by stringent protein-protein interactions.