title: Evolutionary and structural insights into the multifaceted glutathione peroxidase (Gpx) superfamily.
abstract: Glutathione peroxidase (GPx) is a widespread protein superfamily found in many organisms throughout all kingdoms of life. Although it was initially thought to use only glutathione as reductant, recent evidence suggests that the majority of GPxs have specificity for thioredoxin. We present a thorough in silico analysis performed on 724 sequences and 12 structures aimed to clarify the evolutionary, structural, and sequence determinants of GPx specificity. Structural variability was found to be limited to only two regions, termed oligomerization loop and functional helix, which modulate both reduced substrate specificity and oligomerization state. We show that mammalian GPx-1, the canonic selenocysteine-based tetrameric glutathione peroxidase, is a recent "invention" during evolution. Contrary to common belief, cysteine-based thioredoxin-specific GPx, which we propose the TGPx, are both more common and more ancient. This raises interesting evolutionary considerations regarding oligomerization and the use of active-site selenocysteine residue. In addition, phylogenetic analysis has revealed the presence of a novel member belonging to the GPx superfamily in Mammalia and Amphibia, for which we propose the name GPx-8, following the present numeric order of the mammalian GPxs.
authors.affiliation: Department of Biological Chemistry, University of Padova, Italy. stefano.toppo@unipd.it
authors.forename: Stefano
authors.initials: S
authors.lastname: Toppo
authors.forename: Stefano
authors.initials: S
authors.lastname: Vanin
authors.forename: Valentina
authors.initials: V
authors.lastname: Bosello
authors.forename: Silvio C E
authors.initials: SC
authors.lastname: Tosatto
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D018360:Crystallography, X-Ray; D030562:Databases, Protein; D019281:Dimerization; D019143:Evolution, Molecular; D005979:Glutathione Peroxidase / Q000737:chemistry* / Q000145:classification / Q000235:genetics*; D006801:Humans; D007527:Isoenzymes / Q000737:chemistry / Q000145:classification / Q000235:genetics; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010802:Phylogeny; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid
chemical_list: D007527:Isoenzymes; D005979:Glutathione Peroxidase