Features and regulation of non-enzymatic post-translational modifications

Non-enzymatic post-translational modifications of proteins can occur when a nucleophilic or redox-sensitive amino acid side chain encounters a reactive metabolite. In many cases, the biological function of these modifications is limited by their irreversibility, and consequently these non-enzymatic modifications are often considered as indicators of stress and disease. Certain non-enzymatic post-translational modifications, however, can be reversed, which provides an additional layer of regulation and renders these modifications suitable for controlling a diverse set of cellular processes ranging from signaling to metabolism. Here we summarize recent examples of irreversible and reversible non-enzymatic modifications, with an emphasis on the latter category. We use two examples, lysine glutarylation and pyrophosphorylation, to highlight principles of the regulation of reversible non-enzymatic post-translational modifications in more detail. Overall, a picture emerges that goes well beyond nonspecific chemical reactions and cellular damage, and instead portrays multifaceted functions of non-enzymatic post-translational modifications.