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      Identification of H 2S 3 and H 2S produced by 3-mercaptopyruvate sulfurtransferase in the brain

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          Abstract

          Hydrogen polysulfides (H 2S n) have a higher number of sulfane sulfur atoms than hydrogen sulfide (H 2S), which has various physiological roles. We recently found H 2S n in the brain. H 2S n induced some responses previously attributed to H 2S but with much greater potency than H 2S. However, the number of sulfur atoms in H 2S n and its producing enzyme were unknown. Here, we detected H 2S 3 and H 2S, which were produced from 3-mercaptopyruvate (3 MP) by 3-mercaptopyruvate sulfurtransferase (3MST), in the brain. High performance liquid chromatography with fluorescence detection (LC-FL) and tandem mass spectrometry (LC-MS/MS) analyses showed that H 2S 3 and H 2S were produced from 3 MP in the brain cells of wild-type mice but not 3MST knockout (3MST-KO) mice. Purified recombinant 3MST and lysates of COS cells expressing 3MST produced H 2S 3 from 3 MP, while those expressing defective 3MST mutants did not. H 2S 3 was localized in the cytosol of cells. H 2S 3 was also produced from H 2S by 3MST and rhodanese. H 2S 2 was identified as a minor H 2S n, and 3 MP did not affect the H 2S 5 level. The present study provides new insights into the physiology of H 2S 3 and H 2S, as well as novel therapeutic targets for diseases in which these molecules are involved.

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          Most cited references 27

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          The vasorelaxant effect of H(2)S as a novel endogenous gaseous K(ATP) channel opener.

          Hydrogen sulfide (H(2)S) has been traditionally viewed as a toxic gas. It is also, however, endogenously generated from cysteine metabolism. We attempted to assess the physiological role of H(2)S in the regulation of vascular contractility, the modulation of H(2)S production in vascular tissues, and the underlying mechanisms. Intravenous bolus injection of H(2)S transiently decreased blood pressure of rats by 12- 30 mmHg, which was antagonized by prior blockade of K(ATP) channels. H(2)S relaxed rat aortic tissues in vitro in a K(ATP) channel-dependent manner. In isolated vascular smooth muscle cells (SMCs), H(2)S directly increased K(ATP) channel currents and hyperpolarized membrane. The expression of H(2)S-generating enzyme was identified in vascular SMCs, but not in endothelium. The endogenous production of H(2)S from different vascular tissues was also directly measured with the abundant level in the order of tail artery, aorta and mesenteric artery. Most importantly, H(2)S production from vascular tissues was enhanced by nitric oxide. Our results demonstrate that H(2)S is an important endogenous vasoactive factor and the first identified gaseous opener of K(ATP) channels in vascular SMCs.
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            H2S signals through protein S-sulfhydration.

             R. Barrow,  W Mu,  Sadia Gazi (2008)
            Hydrogen sulfide (H2S), a messenger molecule generated by cystathionine gamma-lyase, acts as a physiologic vasorelaxant. Mechanisms whereby H2S signals have been elusive. We now show that H2S physiologically modifies cysteines in a large number of proteins by S-sulfhydration. About 10 to 25% of many liver proteins, including actin, tubulin, and glyceraldehyde-3-phosphate dehydrogenase (GAPDH), are sulfhydrated under physiological conditions. Sulfhydration augments GAPDH activity and enhances actin polymerization. Sulfhydration thus appears to be a physiologic posttranslational modification for proteins.
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              The possible role of hydrogen sulfide as an endogenous smooth muscle relaxant in synergy with nitric oxide.

              Hydrogen sulfide (H2S), which is well known as a toxic gas, is produced endogenously in mammalian tissues from L-cysteine mainly by two pyridoxal-5'-phosphate-dependent enzymes, cystathionine beta-synthetase and cystathionine gamma-lyase. Recently, we showed that cystathionine beta-synthetase in the brain produces H2S, and that H2S facilitates the induction of hippocampal long-term potentiation by enhancing NMDA receptor activity. Here we show that mRNA for another H2S producing enzyme, cystathionine gamma-lyase, is expressed in the ileum, portal vein, and thoracic aorta. The ileum also expresses cystathionine beta-synthetase mRNA. These tissues produce H2S, and this production is blocked by cystathionine beta-synthetase and cystathionine gamma-lyase specific inhibitors. Although exogenously applied H2S alone relaxed these smooth muscles, much lower concentrations of H2S greatly enhanced the smooth muscle relaxation induced by NO in the thoracic aorta. These observations suggest that the endogenous H2S may regulate smooth muscle tone in synergy with NO.
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                Author and article information

                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group
                2045-2322
                06 October 2015
                2015
                : 5
                Affiliations
                [1 ]Department of Molecular Pharmacology, National Institute of Neuroscience, National Center of Neurology and Psychiatry , 4-1-1 Ogawahigashi, Kodaira, Tokyo 187-8502, Japan
                [2 ]Department of Analytical Biochemistry, Meiji Pharmaceutical University , 2-522-1 Noshio, Kiyose, Tokyo 204-8588, Japan.
                [3 ]Radioisotope Center, Nippon Medical School , 1-1-5 Sendagi, Bunkyo, Tokyo 113-8602, Japan.
                [4 ]Department of Pharmacology and Experimental Therapeutics and Cardiovascular Center of Excellence, LSU Health Science Center , New Orleans, LA 70112, USA
                Author notes
                Article
                srep14774
                10.1038/srep14774
                4594004
                26437775
                Copyright © 2015, Macmillan Publishers Limited

                This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

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