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bioRxiv · 10.1101/2020.01.11.902973

An Oncometabolite Isomer Rapidly Induces A Pathophysiological Protein Modification

Bergholtz, S. E.·Briney, C. A.·Najera, S. S.·Perez, M.·Linehan, M.·Meier, J. L.
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Abstract

Metabolites regulate protein function via covalent and non-covalent interactions. However, manipulating these interactions in living cells remains a major challenge. Here we report a chemical strategy for inducing cysteine S-succination, a non-enzymatic posttranslational modification derived from the oncometabolite fumarate. Using a combination of antibody-based detection and kinetic assays we benchmark the in vitro and cellular reactivity of two novel S-succination "agonists," maleate and 2-bromosuccinate. Cellular assays reveal maleate to be a more potent and less toxic inducer of S-succination which can activate KEAP1-NRF2 signaling in living cells. By enabling the cellular reconstitution of an oncometabolite-protein interaction with physiochemical accuracy and minimal toxicity, this study provides a methodological basis for better understanding the signaling role of metabolites in disease.

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Bergholtz, S. E., Briney, C. A., Najera, S. S., Perez, M., Linehan, M., Meier, J. L.. 2020-01-14. An Oncometabolite Isomer Rapidly Induces A Pathophysiological Protein Modification. https://doi.org/10.1101/2020.01.11.902973

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