Metabolic Origin, Role and Fate of the Denaturant Guanidine

Despite its unusual structure and detrimental role as a chaotropic guanidinium ion, guanidine [HNC(NH₂)₂] exists as a genuine metabolite in many microbes, and its negative effects are mitigated by specific exporters. The metabolic origin of this molecule remains unknown, except in a few cases. We propose here that it results from the deep oxidation of guanine-containing nucleotides derived from 8-oxoguanine in the presence of molecular oxygen. Analysis of the co-evolutionary patterns of guanidine exporters in distant bacteria, together with the analysis of operons involved in purine catabolism, revealed that although purines are generally broken down to urea, guanidine can be produced instead in the presence of molecular oxygen. We investigated how this process could enable guanidine to play a distinct regulatory role in directing metabolism in the presence of molecular oxygen. We propose that it is used as a signal meant to control the generation of reactive oxygen species at an optimal level for the cell.