biostudies-literatureBora PScience and Engineering Research BoardUniversity Grants CommissionIndian Institute of Science Education and Research PuneDepartment of Science and Technology, Ministry of Science and Technology, IndiaCouncil of Scientific and Industrial Research, IndiaDBT/Wellcome Trust India AllianceWellcome TrustDepartment of Biotechnology, Ministry of Science and Technology, India12939-12949https://www.ebi.ac.uk/biostudies/studies/S-EPMC8513928biostudies-literatureUnknown12(39)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 <Chemical scienceLeveraging an enzyme/artificial substrate system to enhance cellular persulfides and mitigate neuroinflammation.PMC8513928IA/I/15/2/502058CRG/2019/002900BT/RLF/Re-entry/12/2014Nair MAHazra ABChakrapani HKamat SSManna SSaini DKSathe RRMGupta KMukherjee ASingh SSreyas Adury VSBora PfalseLeveraging an enzyme/artificial substrate system to enhance cellular persulfides and mitigate neuroinflammation.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 <2021-01-01T00:00:00Z2021 Oct2026-05-08T15:34:44.668Z2022-02-11T12:42:28.278ZS-EPMC85139283474552410.1039/d1sc03828a