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

Autor: Bora P; Department of Chemistry, Indian Institute of Science Education and Research Pune Dr. Homi Bhabha Road, Pashan Pune 411 008 Maharashtra India amrita@iiserpune.ac.in harinath@iiserpune.ac.in., Manna S; Department of Chemistry, Indian Institute of Science Education and Research Pune Dr. Homi Bhabha Road, Pashan Pune 411 008 Maharashtra India amrita@iiserpune.ac.in harinath@iiserpune.ac.in., Nair MA; Department of Chemistry, Indian Institute of Science Education and Research Pune Dr. Homi Bhabha Road, Pashan Pune 411 008 Maharashtra India amrita@iiserpune.ac.in harinath@iiserpune.ac.in., Sathe RRM; Department of Biology, Indian Institute of Science Education and Research Pune Dr. Homi Bhabha Road, Pashan Pune 411 008 Maharashtra India., Singh S; Department of Biology, Indian Institute of Science Education and Research Pune Dr. Homi Bhabha Road, Pashan Pune 411 008 Maharashtra India., Sreyas Adury VS; Department of Chemistry, Indian Institute of Science Education and Research Pune Dr. Homi Bhabha Road, Pashan Pune 411 008 Maharashtra India amrita@iiserpune.ac.in harinath@iiserpune.ac.in., Gupta K; Department of Molecular Reproduction, Development and Genetics, Indian Institute of Science Bangalore 560012 Karnataka India., Mukherjee A; Department of Chemistry, Indian Institute of Science Education and Research Pune Dr. Homi Bhabha Road, Pashan Pune 411 008 Maharashtra India amrita@iiserpune.ac.in harinath@iiserpune.ac.in., Saini DK; Department of Molecular Reproduction, Development and Genetics, Indian Institute of Science Bangalore 560012 Karnataka India., Kamat SS; Department of Biology, Indian Institute of Science Education and Research Pune Dr. Homi Bhabha Road, Pashan Pune 411 008 Maharashtra India., Hazra AB; Department of Chemistry, Indian Institute of Science Education and Research Pune Dr. Homi Bhabha Road, Pashan Pune 411 008 Maharashtra India amrita@iiserpune.ac.in harinath@iiserpune.ac.in.; Department of Biology, Indian Institute of Science Education and Research Pune Dr. Homi Bhabha Road, Pashan Pune 411 008 Maharashtra India., Chakrapani H; Department of Chemistry, Indian Institute of Science Education and Research Pune Dr. Homi Bhabha Road, Pashan Pune 411 008 Maharashtra India amrita@iiserpune.ac.in harinath@iiserpune.ac.in.
Jazyk: angličtina
Zdroj: Chemical science [Chem Sci] 2021 Aug 24; Vol. 12 (39), pp. 12939-12949. Date of Electronic Publication: 2021 Aug 24 (Print Publication: 2021).
DOI: 10.1039/d1sc03828a
Abstrakt: Persulfides and polysulfides, collectively known as the sulfane sulfur pool along with hydrogen sulfide (H 2 S), 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 H 2 S 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.
Competing Interests: There are no conflicts to declare.
(This journal is © The Royal Society of Chemistry.)
Databáze: MEDLINE
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