NEBRASKA REDOX BIOLOGY CENTER EDUCATIONAL PORTAL

Nebraska Redox Biology Center Educational Portal


Sulfiredoxins

Sulfiredoxin (Srx) was discovered in 2003 by Toledano's group as hydrogen peroxide induced protein. Sulfiredoxin gene deletion causes decreased yeast tolerance to hydroperoxides and this observation suggested its involvement in hydroperoxides stress response. Analysis of the redox state of sulfiredoxin in lysates of H2O2-treated cells showed that a significant fraction of the protein exist as 55KDa disulphide-linked multimer. H2O2 inducible 2-cysteine peroxiredoxins Tsa1, Tsa2 and Ahp1 were identified as sulfiredoxin interacting partners. The redox association of sulfiredoxin and 2-Cys peroxiredoxins suggested that these proteins have linked functions [ 1 ].

2-Cys peroxiredoxins are homodimers with two redox-active cysteines per subunit. They reduce hydroperoxides with the N-terminal cysteine that oxidizes to a sulphenic acid (Cys-SOH). The Cys-SOH at the catalytic site is then attacked by the carboxy-terminal cysteine of the other subunit to form a disulphide bond. High H2O2 concentration ressulting in inactivation of peroxiredoxins by oxidation of the Cys-SOH to sulphinic acid (Cys-SO2H) instead of its condensation to a disulphide bond with the C-terminal cysteine. Sulfiredoxins are responsable for reparing of such overoxidized catalytic cysteines by Mg2+ and ATP-dependent reduction of the sulfinic acid back to sulfenic acid, thus, returning peroxiredoxins back to normal catalytic cycle [ 2, 3, 4, 5 ].

Sulfinic acid reduction by sulfiredoxin [ 6 ].

There are 7 solved sulfiredoxin structures in Protein Data Bank at this time (January 2016).


Crystal structure of Human sulfiredoxin in complex with ATP and magnesium. Mg atom is shown as pink sphere and ATP is shown in blue color.

Crystal structure of Human sulfiredoxin in complex with peroxiredoxin I, ATP and magnesium. Mg atom is shown as pink sphere and ATP is shown in blue color.

Sulfiredoxins are broadly distributed among lower and higher eukaryotes, and were not found in prokaryotes. All sulfiredoxis sharing concerved active site cysteine and a high identity of such Cys surrounding areas [ 1, 5, 7, 8 ].


ATP bound sulfiredoxin catalyzes the phosphorylation of Prx sulfinic acid forming a sulfinic phosphoryl ester intermediate. This enables the sulfhydryl group of the catalytic cysteine of Srx to attack the peroxidatic cysteine phosphoryl ester forming a thiosulfinate intermediate that is reduced by thiols such as thioredoxin or glutaredoxin to Prx sulfenic acid and Srx mixed disulfide. [ 5, 7, 8, 9, 10, 11, 11 ].

The 2 Cys Prx catalytic cycle and reaction scheme for the reduction of sulfinic 2-Cys Prx by sulfiredoxin. In the 2 Cys Prx catalytic cycle, the peroxidatic cysteine (SP) is oxidized by peroxide (ROOH) forming a sulfenic acid (SPOH). The peroxidatic cysteine sulfenic acid condenses with the resolving cysteine (SR) to form an intermolecular disulfide. Reduced 2 Cys Prx is reconstituted by thioredoxin (Trx). The peroxidatic cysteine sulfenic acid can be hyperoxidized by a second peroxide molecule to form a peroxidatic cysteine sulfinic acid. Srx with ATP bound catalyzes the formation of the sulfinic phosphoryl ester intermediate in the first step of the retroreduction reaction. In the second step, the catalytic cysteine of Srx attacks the Prx phosphoryl ester forming a thiosulfinate intermediate. Subsequent reduction occurs by glutathione (GSH) thiol disulfide exchange reactions or is catalyzed by Trx. [ 5 ].


In addition cysteine sulfinic acid reductase activity specific to 2-Cys Prxs sulfiredoxin may be involved in protein deglutathionylation [ 13, 14 ]. Sulfiredoxin expression is indusable by variety of signaling pathways in mammals. For example, mammalian Srx is regulated by activator protein-1 (AP-1) complex. The AP-1 complex is formed by transcription factors of the Jun and Fos families that bind as homo and hetero dimers to AP-1 response elements in promoters of target genes to activate transcription [ 15 ]. In addition, sulfiredoxin expression is regulated by Nuclear factor erythroid 2 related factor (Nrf2). Nrf2 is a transcription factor that binds as hetero-dimers with members of the Maf protein family to Antioxidant Response Elements (AREs) in target genes whose products are involved in protecting cells from oxidative stress [ 16 ].


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