| Thorough study of cellular metabolism reveals that evolution has favored the advent of useful enzymologies despite deleterious consequences they may pose. Molecular oxygen biochemistry exemplifies this paradigm and proves indispensable and unavoidable for much of life despite the toxic products intrinsic to its utilization. Enzymes evolved to neutralize the reactive oxygen species inherent in aerobic environments; superoxide dismutase and catalase are nearly ubiquitous enzymes amongst aerobic organisms. Subsequently, it can be said that the evolution of efficient metabolism requires the balance of useful catalysis with the development of means to neutralize any inherent toxic products and byproducts.;Much effort has been put toward understanding pathways used to utilize substrates for carbon or nitrogen and pathways used to synthesize compounds needed for cellular life. These efforts have generated an exquisite map of canonical metabolic reactions. However subtle, low-flux connections between these pathways have gone unnoticed. In the same way, toxic metabolites inherent to certain reactions may have never been uncovered in the laboratory due to their subtle effects. These subtle effects, however, have a profound impact in the evolutionary pressures of the real world.;The story presented here is one such paradigm of a toxic metabolite, 2-aminoacrylate (2-AA), and the enzyme responsible for its neutralization, RidA. The endogenous production of 2-AA and the role of RidA to neutralize it have been overlooked and misunderstood until recently. The current model is that 2-AA is generated by some metabolic enzymes and can, in the absence of RidA, accumulate and inactivate a different set of metabolic enzymes.;The story of RidA is complicated and nuanced, drawing together far-reaching areas of the metabolic network, and has uncovered more details about the complex cellular milieu. This work used Salmonella enterica to show the intimate connection of the highly conserved RidA family to pyridoxal 5'-phosphate (PLP) enzymology. RidA protects the PLP-containing enzymes alanine racemase and serine hydroxymethyltransferase from damage via 2-AA generated from the PLP-enzyme threonine dehydratase, preserving alanine and one-carbon metabolisms. |
