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Mechanisms of metabolism-coupled protein modifications

Nature Chemical Biology volume 21, pages 819–830 (2025)Cite this article

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Abstract

Intricate coupling between metabolism and protein post-translational modifications (PTMs) has emerged as a fundamental aspect of cellular regulation. Recent studies demonstrate that protein modifications can originate from diverse metabolites, and that their regulation is closely tied to the cellular metabolic state. Here we explore recently uncovered PTMs, including the concept of ‘modification of a modification’, as well as associated feedback and feedforward regulatory mechanisms, in which modified proteins impact not only related metabolic pathways but also other signaling cascades affecting physiology and diseases. The recently uncovered role of nucleus-localized metabolic enzymes for histone modifications additionally highlights the importance of cell-compartment-specific metabolic states. We further comment on the utility of untargeted metabolomics and proteomics for previously unrecognized PTMs and associated metabolic patterns. Together, these advances have uncovered a dynamic interplay between metabolism and PTMs, offering new perspectives for understanding metabolic regulation and developing targeted therapeutic strategies.

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Fig. 1: Schematic overview of the mechanisms coupling protein modifications and metabolism.
Fig. 2: Biochemical diversity of metabolite-derived protein modifications.
Fig. 3: Metabolite sensing by reactive metabolite-derived non-enzymatic PTMs.
Fig. 4: Metabolic states interact with enzymatic protein modification dynamics.
Fig. 5: Untargeted metabolomics and proteomics reveal PTM signatures.

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Acknowledgements

We thank E. N. Garner for comments and proofreading the manuscript. This work was supported, in part, by the National Institutes of Health (R35GM131877).

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  1. Boyce Thompson Institute, Cornell University, Ithaca, NY, USA

    Bingsen Zhang & Frank C. Schroeder

  2. Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY, USA

    Bingsen Zhang & Frank C. Schroeder

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  1. Bingsen Zhang
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  2. Frank C. Schroeder
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B.Z. conceived the idea and outline for this Perspective. B.Z. and F.C.S. wrote the text and prepared figures.

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Correspondence to Frank C. Schroeder.

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Nature Chemical Biology thanks Shi-Min Zhao and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Zhang, B., Schroeder, F.C. Mechanisms of metabolism-coupled protein modifications. Nat Chem Biol 21, 819–830 (2025). https://doi.org/10.1038/s41589-024-01805-z

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