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The redox-based modifications of cysteine residues in proteins regulate their function in many biological processes. The gas molecule H2S has been shown to persulfidate redox sensitive cysteine residues resulting in an H2S-modified proteome known as the sulfhydrome. Tandem Mass Tags (TMT) multiplexing strategies for large-scale proteomic analyses have become increasingly prevalent in detecting cysteine modifications. Here we developed a TMT-based proteomics approach for selectively trapping and tagging cysteine persulfides in the cellular proteomes. We revealed the natural protein sulfhydrome of two human cell lines, and identified insulin as a novel substrate in pancreatic beta cells. Moreover, we showed that under oxidative stress conditions, increased H2S can target enzymes involved in energy metabolism by switching specific cysteine modifications to persulfides. Specifically, we discovered a Redox Thiol Switch, from protein S-glutathioinylation to S-persulfidation (RTSGS). We propose that the RTSGS from S-glutathioinylation to S-persulfidation is a potential mechanism to fine tune cellular energy metabolism in response to different levels of oxidative stress.


post-translational modifications, thiol redox chemistry, energy metabolism, tandem mass spectrometry, quantification, chemoproteomics, diabetes, cysteine modifications, glutathionylation, H2S, persulfidation, protein sulfhydrome

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Molecular and Cellular Proteomics





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R37-DK060596; R01-DK053307; DK48280; 1-16-PDF-018; 2018/30/E/NZ1/00605; 1S10RR031537-01; 1S10OD023436-01


National Institutes of Health (NIH); American Diabetes Association Postdoctoral Fellowship; Poland National Science Centre

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Creative Commons Attribution 4.0 International License
This work is licensed under a Creative Commons Attribution 4.0 International License.



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