Going Forward and Back: The Complex Evolutionary History of the GPx

SIMPLE SUMMARY: Glutathione peroxidases (GPxs) are considered as one of the main antioxidant enzymes, which reduce peroxides into less toxic compounds. This family of enzymes is found in most eukaryotic organisms, but it is highly divergent regarding its structure, catalytic mechanism, and substrate usage. Furthermore, it is still unclear how these enzymes are dispersed in the animal kingdom. Through robust phylogenetic and sequence analyses, we show that all GPx genes originated from a common ancestor and evolved independently across different kingdoms. In Metazoa, GPx genes expanded into three main groups before the rise of bilaterian animals, and they were further expanded in vertebrates. These expansions allowed GPx enzymes to diversify, not only structurally, but also functionally. Our study contributes to the understanding of how this abundant class of antioxidant enzymes evolved. The evolution of GPxs appears to be a continuous process, leading to the diversification of their functions. ABSTRACT: There is large diversity among glutathione peroxidase (GPx) enzymes regarding their function, structure, presence of the highly reactive selenocysteine (SeCys) residue, substrate usage, and reducing agent preference. Moreover, most vertebrate GPxs are very distinct from non-animal GPxs, and it is still unclear if they came from a common GPx ancestor. In this study, we aimed to unveil how GPx evolved throughout different phyla. Based on our phylogenetic trees and sequence analyses, we propose that all GPx encoding genes share a monomeric common ancestor and that the SeCys amino acid was incorporated early in the evolution of the metazoan kingdom. In addition, classical GPx and the cysteine-exclusive GPx07 have been present since non-bilaterian animals, but they seem to have been lost throughout evolution in different phyla. Therefore, the birth-and-death of GPx family members (like in other oxidoreductase families) seems to be an ongoing process, occurring independently across different kingdoms and phyla.