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Features and regulation of non-enzymatic post-translational modifications

Abstract

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.

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Figure 1: Post-translational modifications of proteins occur via a number of different mechanisms.
Figure 2: Summary of selected non-enzymatic PTMs.
Figure 3: Reversible cysteine oxidation in PTP-1B.
Figure 4: Lysine glutarylation of proteins.
Figure 5: Protein pyrophosphorylation.

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Acknowledgements

R.H. gratefully acknowledges funding from the Leibniz-Gemeinschaft (SAW-2017-FMP-1).

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Harmel, R., Fiedler, D. Features and regulation of non-enzymatic post-translational modifications. Nat Chem Biol 14, 244–252 (2018). https://doi.org/10.1038/nchembio.2575

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