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Leveraging an enzyme/artificial substrate system to enhance cellular persulfides and mitigate neuroinflammation

Bora, P and Manna, S and Nair, MA and Sathe, RRM and Singh, S and Sreyas Adury, VS and Gupta, K and Mukherjee, A and Saini, DK and Kamat, SS and Hazra, AB and Chakrapani, H (2021) Leveraging an enzyme/artificial substrate system to enhance cellular persulfides and mitigate neuroinflammation. In: Chemical Science, 12 (39). pp. 12939-12949.

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Official URL: https://doi.org/10.1039/d1sc03828a


Persulfides and polysulfides, collectively known as the sulfane sulfur pool along with hydrogen sulfide (H2S), play a central role in cellular physiology and disease. Exogenously enhancing these species in cells is an emerging therapeutic paradigm for mitigating oxidative stress and inflammation that are associated with several diseases. In this study, we present a unique approach of using the cell's own enzyme machinery coupled with an array of artificial substrates to enhance the cellular sulfane sulfur pool. We report the synthesis and validation of artificial/unnatural substrates specific for 3-mercaptopyruvate sulfurtransferase (3-MST), an important enzyme that contributes to sulfur trafficking in cells. We demonstrate that these artificial substrates generate persulfidesin vitroas well as mediate sulfur transfer to low molecular weight thiols and to cysteine-containing proteins. A nearly 100-fold difference in the rates of H2S production for the various substrates is observed supporting the tunability of persulfide generation by the 3-MST enzyme/artificial substrate system. Next, we show that the substrate1apermeates cells and is selectively turned over by 3-MST to generate 3-MST-persulfide, which protects against reactive oxygen species-induced lethality. Lastly, in a mouse model,1ais found to significantly mitigate neuroinflammation in the brain tissue. Together, the approach that we have developed allows for the on-demand generation of persulfidesin vitroandin vivousing a range of shelf-stable, artificial substrates of 3-MST, while opening up possibilities of harnessing these molecules for therapeutic applications. © The Royal Society of Chemistry 2021.

Item Type: Journal Article
Publication: Chemical Science
Publisher: Royal Society of Chemistry
Additional Information: The copyright for this article belongs to Royal Society of Chemistry
Keywords: Amino acids; Cells; Cytology; Machinery; Substrates; Sulfur compounds, Artificial substrates; Cell-be; Cell/B.E; Cell/BE; Cellular physiology; Cellulars; Neuroinflammation; Polysulphides; Substrate system; Therapeutic paradigms, Enzymes
Department/Centre: Division of Biological Sciences > Molecular Reproduction, Development & Genetics
Date Deposited: 28 Nov 2021 07:24
Last Modified: 28 Nov 2021 07:24
URI: http://eprints.iisc.ac.in/id/eprint/70416

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