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Review
. 2011 Mar 15;14(6):1065-77.
doi: 10.1089/ars.2010.3376. Epub 2010 Sep 17.

Cysteine-based redox switches in enzymes

Chananat Klomsiri  1 , P Andrew Karplus, Leslie B Poole
Affiliations
Review

Cysteine-based redox switches in enzymes

Chananat Klomsiri et al. Antioxid Redox Signal. .

Abstract

The enzymes involved in metabolism and signaling are regulated by posttranslational modifications that influence their catalytic activity, rates of turnover, and targeting to subcellular locations. Most prominent among these has been phosphorylation/dephosphorylation, but now a distinct class of modification coming to the fore is a set of versatile redox modifications of key cysteine residues. Here we review the chemical, structural, and regulatory aspects of such redox regulation of enzymes and discuss examples of how these regulatory modifications often work in concert with phosphorylation/dephosphorylation events, making redox dependence an integral part of many cell signaling processes. Included are the emerging roles played by peroxiredoxins, a family of cysteine-based peroxidases that now appear to be major players in both antioxidant defense and cell signaling.

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Figures

FIG. 1.
FIG. 1.
Biological modifications of cysteine thiols. Reactive cysteine thiols (R-SH), typically in their ionized, thiolate form (R-S−), are oxidized by hydrogen peroxide, organic hydroperoxides, hypohalous acids (HOX), and peroxynitrite to form sulfenic acids, which may be stabilized or go on to form other reversible (disulfides [R-SS-R′] or sulfenamides [R-SN-R′]) or irreversible oxidation products (sufinic acids [R-SO2H], sulfonic acids [R-SO3H], sulfinamides [R-SON-R′], and sulfonamides [R-SO2N-R′]). Reversible S-nitrosocysteine modifications are also observed in cells exposed to RNS. Both ROS and RNS promote these oxidations. Modifications within the blue box are considered reversible (by cellular reductants like thioredoxin and glutathione), whereas the species in the orange box are not. Although sulfinic and sulfonic acids are shown here as irreversible modifications, recent discoveries show that sulfinic acid forms of some Prxs can be recovered through action of specialized sulfinic acid reductases (sulfiredoxins). Prx, peroxiredoxin; RNS, reactive nitrogen species; ROS, reactive oxygen species. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article at www.liebertonline.com/ars).
FIG. 2.
FIG. 2.
Two potential loops of oxidative regulation (A) and the chemical steps of thiol–disulfide interchange reactions (B). (A) Oxidants and particularly H2O2 modify specific reactive cysteine residues within proteins to sulfenic acids (R-SOH), with a corresponding alteration in protein function. The sulfenic acid is also susceptible to further modification by oxidants to form sulfinic acid (R-SO2−), a modification that could have distinct effects on functional properties of enzymes. This species in some Prxs may be repaired by sulfiredoxins to recover the unmodified protein, but typically the sulfinic acid is an irreversible oxidation state in the cell. (B) Reversible thiol-disulfide interchange reactions among proteins proceed via mixed disulfide intermediates and can lead to migration of disulfide bonds to other locations in the same or separate protein(s).
FIG. 3.
FIG. 3.
Mechanisms of catalysis by Prxs. The three main reactions universal to the catalytic cycle of Prxs are [1] peroxidation, [2] resolution, and [3] recycling. During reaction 2, a local unfolding event occurs to facilitate the formation of disulfide bonds, with SP and SR designating the sulfur atoms of the peroxidatic and resolving cysteines, respectively. For the typical 2-Cys Prxs, the resolving cysteine, CR, is located in the C-terminus of the protein and the CR from one subunit forms a disulfide bond with the peroxidatic cysteine, CP, on its partner subunit. For atypical 2-Cys Prxs, the CR is found in an alternate location, frequently in the same subunit as the corresponding CP. 1-Cys Prxs do not contain a CR and are presumably recycled by a low-molecular-weight thiol or are directly reduced by thioredoxin. 2 R′SH in reaction 3 represents a thioredoxin-like protein or domain. Overoxidation of CP (reaction 4) and ATP-dependent reduction of Cys-SPO2H by sulfiredoxin (reaction 5) depict redox regulation and repair occurring in some eukaryotic typical 2-Cys Prxs.
FIG. 4.
FIG. 4.
The mechanism of Saccharomyces cerevisiae Gpx3–Yap1 redox interaction. Gpx3 reacts with H2O2 at its peroxidatic cysteine (Cys36), which becomes oxidized to a sulfenic acid. The Cys36 sulfenic acid then reacts either with its own resolving cysteine, Cys82, or with Cys598 in the C-terminal region of Yap1 to form an intermolecular disulfide bond. Subsequent thiol–disulfide interchange with Cys303 in Yap1 completes the transfer of the oxidation state from Gpx3 to Yap1. A second disulfide bond (Cys310–Cys629) of Yap1 may be introduced by thiol–disulfide interchange with the first and/or reaction with another oxidized Gpx3. Yap1 binding protein, Ybp1, may be involved in bringing oxidized Gpx3 Cys36 close to Yap1 Cys598 and/or preventing its condensation with Gpx3 Cys82. The intramolecular disulfide bond of Gpx3 (Cys36 and Cys82) can be reduced by Trx. Gpx, glutathione peroxidase; Trx, thioredoxin; Yap1, yeast activator protein-1; Ybp1, Yap1 binding protein.
FIG. 5.
FIG. 5.
Model of two interconnected Schizosaccharomyces pombe H2O2-responsive pathways. (A) Mechanism for the redox relay between Tpx1 and Pap1. Partitioning of the sulfenic acid of Tpx1 between condensation with the normal resolving cysteine of the catalytic cycle or a thiol group from Pap1 proceeds in a similar way as the Gpx3–Yap1 pathway shown in Figure 4. Activation of Pap1 regulates expression of a thioredoxin (from trx2) and cytosolic catalase-1 (from ctt1). At high concentrations of H2O2, Tpx1 is hyperoxdized to sulfinic acid, which can be reversed by sulfiredoxin. (B) The Sty1 pathway. Sty1 (also known as Spc1), a relative of the c-Jun N-terminal kinase/p38 stress-activated protein kinases in higher organisms, is activated independently by a phosphorelay system that is promoted by formation of a mixed disulfide between Cys35 on Sty1 and the peroxidatic Cys of Tpx1. Activated Sty1 activates the bZIP-type transcription factor Atf1, leading to upregulation of antioxidant gene expression (including Gpx from gpx1 and sulfiredoxin from srx1). An alternative mode of activating Sty1 may be formation of an internal disulfide bond that is induced by high H2O2 concentrations. Pap1, Schizosaccharomyces pombe activator protein-1; Sty1, stress-activated protein kinase in fission yeast.
FIG. 6.
FIG. 6.
Three proposed roles for Prxs in peroxide signaling. (A) Thiol–disulfide interchange between Prxs and other proteins resulting in the transfer of the Prx disulfide to an acceptor protein or complex (depicted by the disulfide bond between pink and green proteins or other molecules). The reactivation of the Prx occurs by thiol–disulfide interchange with the reductant (green). (B) The chaperone model, represented by the formation of higher order oligomers of overoxidized Prxs. This is involved in stress-related signaling and requires sensitivity of Prxs toward hyperoxidation. In A and B, the Prxs are represented as purple and blue decamers under normal cellular conditions. (C). The floodgate model is an unproven mechanism. Prxs are represented as tall barriers made up of gray rectangles—vertical for active, horizontal for overoxidized and inactive. The multiple barriers on the right reflect the cell-wide Prx distribution; Prxs that are close to the peroxide generation site (marked by an arrow) are overwhelmed and inactivated, whereas those at increasing distances away are not. This creates a steep peroxide gradient and allows for localized peroxide build-up after endogenous peroxide generation. The level of hydrogen peroxide is represented by both color gradient and height. This proposed role may be involved in both stress- and nonstress-related signaling and requires that the Prxs be sensitive to hyperoxidation. Reprinted by permission from Hall et al. (28). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article at www.liebertonline.com/ars).
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