Endogenous hydrogen sulfide (H₂S) renders bacteria highly resistant to oxidative stress, but its mechanism remains poorly understood. Here, we report that 3-mercaptopyruvate sulfurtransferase (3MST) is the major source of endogenous H₂S in Escherichia coli Cellular resistance to H₂O₂ strongly depends on the activity of mstA, a gene that encodes 3MST. Deletion of the ferric uptake regulator (Fur) renders ∆mstA cells hypersensitive to H₂O₂ Conversely, induction of chromosomal mstA from a strong pLtetO-1 promoter (P _tet -mstA) renders ∆fur cells fully resistant to H₂O₂ Furthermore, the endogenous level of H₂S is reduced in ∆fur or ∆sodA ∆sodB cells but restored after the addition of an iron chelator dipyridyl. Using a highly sensitive reporter of the global response to DNA damage (SOS) and the TUNEL assay, we show that 3MST-derived H₂S protects chromosomal DNA from oxidative damage. We also show that the induction of the CysB regulon in response to oxidative stress depends on 3MST, whereas the CysB-regulated l-cystine transporter, TcyP, plays the principle role in the 3MST-mediated generation of H₂S. These findings led us to propose a model to explain the interplay between l-cysteine metabolism, H₂S production, and oxidative stress, in which 3MST protects E. coli against oxidative stress via l-cysteine utilization and H₂S-mediated sequestration of free iron necessary for the genotoxic Fenton reaction.

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