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      Mechanism of H 2S-mediated protection against oxidative stress in Escherichia coli

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          Significance

          Hydrogen sulfide (H 2S) is a highly toxic gas that interferes with cellular respiration; however, at low physiological amounts, it plays an important role in cell signaling. Remarkably, in bacteria, endogenously produced H 2S has been recently recognized as a general protective molecule, which renders multiple bacterial species highly resistant to oxidative stress and various classes of antibiotics. The mechanism of this phenomenon remains poorly understood. In this paper, we use Escherichia coli as a model system to elucidate its major enzymatic source of H 2S and establish the principle biochemical pathways that account for H 2S-mediated protection against reactive oxygen species. Understanding those mechanisms has far-reaching implications in preventing bacterial resistance and designing effective antimicrobial therapies.

          Abstract

          Endogenous hydrogen sulfide (H 2S) 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 H 2S in Escherichia coli. Cellular resistance to H 2O 2 strongly depends on the activity of mstA, a gene that encodes 3MST. Deletion of the ferric uptake regulator (Fur) renders ∆ mstA cells hypersensitive to H 2O 2. Conversely, induction of chromosomal mstA from a strong pLtetO-1 promoter (P tet - mstA) renders ∆ fur cells fully resistant to H 2O 2. Furthermore, the endogenous level of H 2S is reduced in ∆ fur or ∆ sodAsodB 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 H 2S 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 H 2S. These findings led us to propose a model to explain the interplay between l-cysteine metabolism, H 2S production, and oxidative stress, in which 3MST protects E. coli against oxidative stress via l-cysteine utilization and H 2S-mediated sequestration of free iron necessary for the genotoxic Fenton reaction.

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          Author and article information

          Journal
          Proc Natl Acad Sci U S A
          Proc. Natl. Acad. Sci. U.S.A
          pnas
          pnas
          PNAS
          Proceedings of the National Academy of Sciences of the United States of America
          National Academy of Sciences
          0027-8424
          1091-6490
          6 June 2017
          22 May 2017
          : 114
          : 23
          : 6022-6027
          Affiliations
          a Department of Genetics, State Research Institute of Genetics and Selection of Industrial Microorganisms , Moscow 117545, Russia;
          bDepartment of Molecular Biology, Engelhardt Institute of Molecular Biology, Russian Academy of Science , Moscow 119991, Russia;
          cDepartment of Biochemistry and Molecular Pharmacology, New York University School of Medicine , New York, NY 10016;
          d Howard Hughes Medical Institute , New York University School of Medicine , New York, NY 10016
          Author notes
          1To whom correspondence should be addressed. Email: evgeny.nudler@ 123456nyumc.org .

          Edited by James J. Collins, Massachusetts Institute of Technology, Boston, MA, and approved April 27, 2017 (received for review March 3, 2017)

          Author contributions: A.M. and E.N. designed research; A.M., T.S., M.N., L.G.L., N.K., L.E.L., V.K., and K.S. performed research; G.Z. and R.S. contributed new reagents/analytic tools; A.M., T.S., M.N., L.G.L., G.Z., R.S., and K.S. analyzed data; and A.M. and E.N. wrote the paper.

          Article
          PMC5468659 PMC5468659 5468659 201703576
          10.1073/pnas.1703576114
          5468659
          28533366
          Page count
          Pages: 6
          Funding
          Funded by: Russian Foundation for Basic Research (RFBR) 501100002261
          Award ID: 14-14-00524
          Funded by: Howard Hughes Medical Institute (HHMI) 100000011
          Award ID: NA
          Categories
          Biological Sciences
          Biochemistry

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