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

Abstract

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 persulfides in vitro as 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 substrate 1a permeates 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, 1a is found to significantly mitigate neuroinflammation in the brain tissue. Together, the approach that we have developed allows for the on-demand generation of persulfides in vitro and in vivo using a range of shelf-stable, artificial substrates of 3-MST, while opening up possibilities of harnessing these molecules for therapeutic applications.

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

Supplementary files

Article information

Article type
Edge Article
Submitted
13 Jul 2021
Accepted
24 Aug 2021
First published
24 Aug 2021
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY-NC license

Chem. Sci., 2021, Advance Article

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

P. Bora, S. Manna, M. A. Nair, R. R. M. Sathe, S. Singh, V. S. Sreyas Adury, K. Gupta, A. Mukherjee, D. K. Saini, S. S. Kamat, A. B. Hazra and H. Chakrapani, Chem. Sci., 2021, Advance Article , DOI: 10.1039/D1SC03828A

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