The evolutionary origins of peroxynitrite signalling

Peroxynitrite is a reactive intermediate formed in vivo through uncatalysed reaction of superoxide and nitric oxide radicals. Despite significant interest in detecting peroxynitrite in vivo and understanding its production, little attention has been given to the evolutionary origins of peroxynitrite signalling. Herein we focus on two enzymes that are key to the biosynthesis of superoxide and nitric oxide, NADPH oxidase 5 (NOX5) and endothelial nitric oxide synthase (eNOS), respectively. Multiple sequence alignments of both enzymes including homologues from all domains of life, coupled with a phylogenetic analysis of NOX5, suggest eNOS and NOX5 are present in animals as the result of horizontal gene transfer from ancestral cyanobacteria to ancestral eukaryotes. Therefore, biochemical studies from other laboratories on a NOX5 homologue in Cylindrospermum stagnale and an eNOS homologue in Synechococcus sp. PCC 7335 are likely to be of relevance to human NOX5 and eNOS and to the production of superoxide, nitric oxide and peroxynitrite in humans. Enzymes that catalyse biosynthesis of nitric oxide & superoxide, and hence peroxynitrite, likely entered the animal kingdom from ancestral cyanobacteria. [Display omitted] •This bioinformatics study suggests that NADPH oxidase 5 (NOX5) and nitric oxide synthase (NOS) both evolved in cyanobacteria.•Cyanobacteria may be useful organisms in which to study NOX5 and NOS homologues, validating literature experiments.•Our understanding of peroxynitrite biosynthesis in humans may advance, since NOS and NOX5 are involved in its production.•The results add to an emerging picture of cyanobacterial contributions to animal as well as plant genomes.