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Review
. 2013 Sep 13;288(37):26480-8.
doi: 10.1074/jbc.R113.467738. Epub 2013 Jul 16.

The redox biochemistry of protein sulfenylation and sulfinylation

Mauro Lo Conte  1 , Kate S Carroll
Affiliations
Review

The redox biochemistry of protein sulfenylation and sulfinylation

Mauro Lo Conte et al. J Biol Chem. .

Abstract

Controlled generation of reactive oxygen species orchestrates numerous physiological signaling events (Finkel, T. (2011) Signal transduction by reactive oxygen species. J. Cell Biol. 194, 7-15). A major cellular target of reactive oxygen species is the thiol side chain (RSH) of Cys, which may assume a wide range of oxidation states (i.e. -2 to +4). Within this context, Cys sulfenic (Cys-SOH) and sulfinic (Cys-SO2H) acids have emerged as important mechanisms for regulation of protein function. Although this area has been under investigation for over a decade, the scope and biological role of sulfenic/sulfinic acid modifications have been recently expanded with the introduction of new tools for monitoring cysteine oxidation in vitro and directly in cells. This minireview discusses selected recent examples of protein sulfenylation and sulfinylation from the literature, highlighting the role of these post-translational modifications in cell signaling.

Keywords: Cysteine Oxidation; Hydrogen Peroxide; Post-translational Modification; Redox Regulation; Redox Signaling; Thiol.

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Figures

FIGURE 1.
FIGURE 1.
Main oxidative modifications of protein cysteine residues. A, the diagram shows the main oxidative modifications of protein cysteine residues. The initial reaction of cysteine with oxidants ([O] = ROS/RNS) yields a sulfenic acid (SOH). Once formed, the SOH can be reduced to thiol or further oxidized to generate Cys-SO2H and Cys-SO3H. B, thiolate anion is much more nucleophilic than the corresponding protonated form and can be readily oxidized to sulfenic acid. The protein microenvironment can help to stabilize the poor hydroxide leaving group and thus accelerate the reaction rate. C, two possible mechanisms have been proposed for the H2O2-mediated oxidation of RSOH to RSO2H: the first pathway, which involves the direct participation of a sulfenate anion, or the second concerted mechanism, which is mediated by a hydrogen bond.
FIGURE 2.
FIGURE 2.
Sulfenic and sulfinic acid redox cycles. A, RSOH can be directly reduced to free thiol by Trx, although the importance of this pathway in cells is still debated (Cycle 1). RSOH can also react with GSH to generate a mixed disulfide (although not all protein-SOHs are accessible to GSH), which is subsequently reduced by glutaredoxin (Grx; Cycle 2). B, in the presence of a neighboring Cys residue, RSOH forms an internal disulfide that is later reduced by Trx (Cycle 3). C, typical eukaryotic 2-Cys Prxs are inactivated by overoxidation to sulfinic acid (Step 1). Srx restores the sulfenic acid group using an ATP-dependent mechanism in which an activated sulfinic phosphoryl ester is generated (Step 2). This intermediate collapses to form a thiosulfinate moiety with Cys-99 of Srx (Step 3). It has been proposed that this intramolecular thiosulfinate is finally resolved by a common cellular reductant, such as GSH or Trx, with consequent release of Prx-SOH (Step 4).
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