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  1. Article ; Online: Mycobacterium tuberculosis DosS binds H2S through its Fe3+ heme iron to regulate the DosR dormancy regulon

    Ritesh R. Sevalkar / Joel N. Glasgow / Martín Pettinati / Marcelo A. Marti / Vineel P. Reddy / Swati Basu / Elmira Alipour / Daniel B. Kim-Shapiro / Dario A. Estrin / Jack R. Lancaster, Jr. / Adrie J.C. Steyn

    Redox Biology, Vol 52, Iss , Pp 102316- (2022)

    2022  

    Abstract: Mycobacterium tuberculosis (Mtb) senses and responds to host-derived gasotransmitters NO and CO via heme-containing sensor kinases DosS and DosT and the response regulator DosR. Hydrogen sulfide (H2S) is an important signaling molecule in mammals, but ... ...

    Abstract Mycobacterium tuberculosis (Mtb) senses and responds to host-derived gasotransmitters NO and CO via heme-containing sensor kinases DosS and DosT and the response regulator DosR. Hydrogen sulfide (H2S) is an important signaling molecule in mammals, but its role in Mtb physiology is unclear. We have previously shown that exogenous H2S can modulate expression of genes in the Dos dormancy regulon via an unknown mechanism(s). Here, we test the hypothesis that Mtb senses and responds to H2S via the DosS/T/R system. Using UV–Vis and EPR spectroscopy, we show that H2S binds directly to the ferric (Fe3+) heme of DosS (KDapp = 5.30 μM) but not the ferrous (Fe2+) form. No interaction with DosT(Fe2+-O2) was detected. We found that the binding of sulfide can slowly reduce the DosS heme iron to the ferrous form. Steered Molecular Dynamics simulations show that H2S, and not the charged HS− species, can enter the DosS heme pocket. We also show that H2S increases DosS autokinase activity and subsequent phosphorylation of DosR, and H2S-mediated increases in Dos regulon gene expression is lost in Mtb lacking DosS. Finally, we demonstrate that physiological levels of H2S in macrophages can induce DosR regulon genes via DosS. Overall, these data reveal a novel mechanism whereby Mtb senses and responds to a third host gasotransmitter, H2S, via DosS(Fe3+). These findings highlight the remarkable plasticity of DosS and establish a new paradigm for how bacteria can sense multiple gasotransmitters through a single heme sensor kinase.
    Keywords Hydrogen sulfide ; Tuberculosis ; Dormancy regulon ; Two-component system ; DosS ; Medicine (General) ; R5-920 ; Biology (General) ; QH301-705.5
    Subject code 572
    Language English
    Publishing date 2022-06-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: Mitochondria-meditated pathways of organ failure upon inflammation

    Andrey V. Kozlov / Jack R. Lancaster, Jr. / Andras T. Meszaros / Adelheid Weidinger

    Redox Biology, Vol 13, Iss C, Pp 170-

    2017  Volume 181

    Abstract: Liver failure induced by systemic inflammatory response (SIRS) is often associated with mitochondrial dysfunction but the mechanism linking SIRS and mitochondria-mediated liver failure is still a matter of discussion. Current hypotheses suggest that ... ...

    Abstract Liver failure induced by systemic inflammatory response (SIRS) is often associated with mitochondrial dysfunction but the mechanism linking SIRS and mitochondria-mediated liver failure is still a matter of discussion. Current hypotheses suggest that causative events could be a drop in ATP synthesis, opening of mitochondrial permeability transition pore, specific changes in mitochondrial morphology, impaired Ca2+ uptake, generation of mitochondrial reactive oxygen species (mtROS), turnover of mitochondria and imbalance in electron supply to the respiratory chain. The aim of this review is to critically analyze existing hypotheses, in order to highlight the most promising research lines helping to prevent liver failure induced by SIRS. Evaluation of the literature shows that there is no consistent support that impaired Ca++ metabolism, electron transport chain function and ultrastructure of mitochondria substantially contribute to liver failure. Moreover, our analysis suggests that the drop in ATP levels has protective rather than a deleterious character. Recent data suggest that the most critical mitochondrial event occurring upon SIRS is the release of mtROS in cytoplasm, which can activate two specific intracellular signaling cascades. The first is the mtROS-mediated activation of NADPH-oxidase in liver macrophages and endothelial cells; the second is the acceleration of the expression of inflammatory genes in hepatocytes. The signaling action of mtROS is strictly controlled in mitochondria at three points, (i) at the site of ROS generation at complex I, (ii) the site of mtROS release in cytoplasm via permeability transition pore, and (iii) interaction with specific kinases in cytoplasm. The systems controlling mtROS-signaling include pro- and anti-inflammatory mediators, nitric oxide, Ca2+ and NADPH-oxidase. Analysis of the literature suggests that further research should be focused on the impact of mtROS on organ failure induced by inflammation and simultaneously providing a new theoretical basis for a targeted therapy of overwhelmed inflammatory response.
    Keywords Liver failure ; Mitochondria ; Reactive oxygen species ; Signaling ; Inflammation ; Medicine (General) ; R5-920 ; Biology (General) ; QH301-705.5
    Subject code 610
    Language English
    Publishing date 2017-10-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: Endogenous generation of nitro-fatty acid hybrids having dual nitrate ester (RONO2) and nitroalkene (RNO2) substituents

    Marco Fazzari / Steven R. Woodcock / Pascal Rowart / Karina Ricart / Jack R. Lancaster, Jr. / Rakesh Patel / Dario A. Vitturi / Bruce A. Freeman / Francisco J. Schopfer

    Redox Biology, Vol 41, Iss , Pp 101913- (2021)

    2021  

    Abstract: Organic nitrate esters, long-recognized therapies for cardiovascular disorders, have not been detected biologically. We characterize in rat stomach unsaturated fatty acid nitration reactions that proceed by generation of nitro-nitrate intermediates (NO2– ... ...

    Abstract Organic nitrate esters, long-recognized therapies for cardiovascular disorders, have not been detected biologically. We characterize in rat stomach unsaturated fatty acid nitration reactions that proceed by generation of nitro-nitrate intermediates (NO2–ONO2-FA) via oxygen and nitrite dependent reactions. NO2–ONO2-lipids represent ∼70% of all nitrated lipids in the stomach and they decay in vitro at neutral or basic pH by the loss of the nitrate ester group (-ONO2) from the carbon backbone upon deprotonation of the α-carbon (pKa ∼7), yielding nitrate, nitrite, nitrosative species, and an electrophilic fatty acid nitroalkene product (NO2-FA). Of note, NO2-FA are anti-inflammatory and tissue-protective signaling mediators, which are undergoing Phase II trials for the treatment of kidney and pulmonary diseases. The decay of NO2–ONO2-FA occurs during intestinal transit and absorption, leading to the formation of NO2-FA that were subsequently detected in circulating plasma triglycerides. These observations provide new insight into unsaturated fatty acid nitration mechanisms, identify nitro-nitrate ester-containing lipids as intermediates in the formation of both secondary nitrogen oxides and electrophilic fatty acid nitroalkenes, and expand the scope of endogenous products stemming from metabolic reactions of nitrogen oxides.
    Keywords Nitro-nitrate-fatty acid ; Nitro-conjugated linoleic acid ; Conjugated linoleic acid ; Fatty acid nitroalkene ; Nitrate ester ; Medicine (General) ; R5-920 ; Biology (General) ; QH301-705.5
    Subject code 540 ; 571
    Language English
    Publishing date 2021-05-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: Electrophiles modulate glutathione reductase activity via alkylation and upregulation of glutathione biosynthesis

    Soma Jobbagy / Dario A. Vitturi / Sonia R. Salvatore / Lucía Turell / Maria F. Pires / Emilia Kansanen / Carlos Batthyany / Jack R. Lancaster, Jr. / Bruce A. Freeman / Francisco J. Schopfer

    Redox Biology, Vol 21, Iss , Pp - (2019)

    2019  

    Abstract: Cells evolved robust homeostatic mechanisms to protect against oxidation or alkylation by electrophilic species. Glutathione (GSH) is the most abundant intracellular thiol, protects cellular components from oxidation and is maintained in a reduced state ... ...

    Abstract Cells evolved robust homeostatic mechanisms to protect against oxidation or alkylation by electrophilic species. Glutathione (GSH) is the most abundant intracellular thiol, protects cellular components from oxidation and is maintained in a reduced state by glutathione reductase (GR). Nitro oleic acid (NO2-OA) is an electrophilic fatty acid formed under digestive and inflammatory conditions that both reacts with GSH and induces its synthesis upon activation of Nrf2 signaling. The effects of NO2-OA on intracellular GSH homeostasis were evaluated. In addition to upregulation of GSH biosynthesis, we observed that NO2-OA increased intracellular GSSG in an oxidative stress-independent manner. NO2-OA directly inhibited GR in vitro by covalent modification of the catalytic Cys61, with kon of (3.45 ± 0.04) × 103 M−1 s−1, koff of (4.4 ± 0.4) × 10−4 s−1, and Keq of (1.3 ± 0.1) × 10−7 M. Akin to NO2-OA, the electrophilic Nrf2 activators bardoxolone-imidazole (CDDO-Im), bardoxolone-methyl (CDDO-Me) and dimethyl fumarate (DMF) also upregulated GSH biosynthesis while promoting GSSG accumulation, but without directly inhibiting GR activity. In vitro assays in which GR was treated with increasing GSH concentrations and GSH depletion experiments in cells revealed that GR activity is finely regulated via product inhibition, an observation further supported by theoretical (kinetic modeling of cellular GSSG:GSH levels) approaches. Together, these results describe two independent mechanisms by which electrophiles modulate the GSH/GSSG couple, and provide a novel conceptual framework to interpret experimentally determined values of GSH and GSSG. Keywords: Glutathione, Glutathione reductase, Electrophile, Nitrated fatty acid, Disulfide, Nrf2, Thiol, Oxidation-reduction (redox)
    Keywords Medicine (General) ; R5-920 ; Biology (General) ; QH301-705.5
    Subject code 580
    Language English
    Publishing date 2019-02-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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