title: Polysulfides link H2S to protein thiol oxidation.
abstract: OBJECTIVE
  Hydrogen sulfide (H2S) is suggested to act as a gaseous signaling molecule in a variety of physiological processes. Its molecular mechanism of action was proposed to involve protein S-sulfhydration, that is, conversion of cysteinyl thiolates (Cys-S(-)) to persulfides (Cys-S-S(-)). A central and unresolved question is how H2S-that is, a molecule with sulfur in its lowest possible oxidation state (-2)-can lead to oxidative thiol modifications.
  
  
  RESULTS
  Using the lipid phosphatase PTEN as a model protein, we find that the "H2S donor" sodium hydrosulfide (NaHS) leads to very rapid reversible oxidation of the enzyme in vitro. We identify polysulfides formed in NaHS solutions as the oxidizing species, and present evidence that sulfane sulfur is added to the active site cysteine. Polysulfide-mediated oxidation of PTEN was induced by all "H2S donors" tested, including sodium sulfide (Na2S), gaseous H2S, and morpholin-4-ium 4-methoxyphenyl(morpholino) phosphinodithioate (GYY4137). Moreover, we show that polysulfides formed in H2S solutions readily modify PTEN inside intact cells.
  
  
  METHODS
  Our results shed light on the previously unresolved question of how H2S leads to protein thiol oxidation, and suggest that polysulfides formed in solutions of H2S mediate this process.
  
  
  CONCLUSIONS
  This study suggests that the effects that have been attributed to H2S in previous reports may in fact have been mediated by polysulfides. It also supports the notion that sulfane sulfur rather than sulfide is the actual in vivo agent of H2S signaling.
authors: 1 Division of Redox Regulation, German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance , Heidelberg, Germany .
authors: Romy
authors: R
authors: Greiner
authors: Zoltán
authors: Z
authors: Pálinkás
authors: Katrin
authors: K
authors: Bäsell
authors: Dörte
authors: D
authors: Becher
authors: Haike
authors: H
authors: Antelmann
authors: Péter
authors: P
authors: Nagy
authors: Tobias P
authors: TP
authors: Dick
mesh_terms: D020134:Catalytic Domain; D002460:Cell Line; D003545:Cysteine / Q000737:chemistry; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D006862:Hydrogen Sulfide / Q000737:chemistry*; D007700:Kinetics; D009025:Morpholines / Q000737:chemistry; D009946:Organothiophosphorus Compounds / Q000737:chemistry; D010084:Oxidation-Reduction; D051059:PTEN Phosphohydrolase / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism*; D012996:Solutions; D013438:Sulfhydryl Compounds / Q000737:chemistry*; D013440:Sulfides / Q000737:chemistry* / Q000494:pharmacology
chemical_list: C529376:GYY 4137; D009025:Morpholines; D009946:Organothiophosphorus Compounds; D011506:Proteins; D012996:Solutions; D013438:Sulfhydryl Compounds; D013440:Sulfides; C032915:polysulfide; D051059:PTEN Phosphohydrolase; C025451:sodium bisulfide; D003545:Cysteine; C033479:sodium sulfide; D006862:Hydrogen Sulfide
references: Mol Cell. 2012 Jan 13;45(1):13-24
references: 22244329
references: Proc Natl Acad Sci U S A. 2012 Jun 5;109(23):9161-6
references: 22570497
references: Free Radic Biol Med. 2012 Jun 1-15;52(11-12):2276-83
references: 22561703
references: J Biol Chem. 2002 Jun 7;277(23):20336-42
references: 11916965
references: Amino Acids. 2011 Jun;41(1):113-21
references: 20191298
references: Proc Natl Acad Sci U S A. 2009 Dec 29;106(52):22090-5
references: 20007376
references: Anal Biochem. 2011 Jun 1;413(1):1-7
references: 21303647
references: Antioxid Redox Signal. 2009 Feb;11(2):205-14
references: 18754702
references: Biochem J. 2011 Nov 1;439(3):479-85
references: 21732914
references: EMBO J. 2003 Oct 15;22(20):5501-10
references: 14532122
references: J Biol Chem. 1959 Aug;234(8):2141-4
references: 13673028
references: Chem Res Toxicol. 2010 Oct 18;23(10):1541-3
references: 20845929
references: Antioxid Redox Signal. 2012 Jul 1;17(1):119-40
references: 22432697
references: Sci Signal. 2009 Nov 10;2(96):ra72
references: 19903941
references: Sci Signal. 2011 Dec 13;4(203):ra86
references: 22169477
references: Am J Public Health. 2001 Sep;91(9):1380-2
references: 11527762
references: Methods Enzymol. 1987;143:25-9
references: 3657542
references: Biochem J. 1989 Dec 15;264(3):625-32
references: 2695062
references: Free Radic Biol Med. 2009 Nov 15;47(10):1346-53
references: 19770036
references: Environ Sci Technol. 2004 Dec 15;38(24):6633-44
references: 15669322
references: Nat Methods. 2008 Jun;5(6):553-9
references: 18469822
references: Cell Signal. 2007 Jul;19(7):1434-45
references: 17324556
references: Antioxid Redox Signal. 2013 May 20;18(15):1906-19
references: 23176571
references: Antioxid Redox Signal. 2013 Aug 10;19(5):465-81
references: 23145493
references: Nat Chem Biol. 2006 Apr;2(4):185-94
references: 16547481
references: Physiol Rev. 2012 Apr;92(2):791-896
references: 22535897
references: Antioxid Redox Signal. 2010 Sep 1;13(5):621-50
references: 20088706
references: Nat Rev Mol Cell Biol. 2012 Jul 11;13(8):499-507
references: 22781905
references: Proc Natl Acad Sci U S A. 2009 Dec 22;106(51):21972-7
references: 19955410
references: J Biol Chem. 2004 Mar 26;279(13):13044-53
references: 14722062
references: Free Radic Biol Med. 2011 May 1;50(9):1021-31
references: 21276849
references: Anal Biochem. 1996 Feb 1;234(1):107-9
references: 8742092
references: Pflugers Arch. 2008 Jan;455(4):607-16
references: 17674030
references: Antioxid Redox Signal. 2009 Apr;11(4):703-14
references: 18855522
references: Antioxid Redox Signal. 2012 Apr 15;16(8):747-53
references: 22149235
references: Mol Cell Proteomics. 2011 Nov;10(11):M111.009506
references: 21749987
references: Curr Opin Chem Biol. 1998 Oct;2(5):633-41
references: 9818190
references: Proc Natl Acad Sci U S A. 2004 Nov 23;101(47):16419-24
references: 15534200
references: Nat Methods. 2012 Jul;9(7):671-5
references: 22930834
references: Cardiovasc Res. 2007 Oct 1;76(1):29-40
references: 17631873
references: J Biol Chem. 2010 Jul 16;285(29):21903-7
references: 20448039
references: Circ Res. 2011 Nov 11;109(11):1259-68
references: 21980127
references: Circulation. 2008 May 6;117(18):2351-60
references: 18443240
references: FASEB J. 2013 Jun;27(6):2451-7
references: 23413359
references: Antioxid Redox Signal. 2012 Jul 1;17(1):32-44
references: 22074253