Thiol–Disulfide Exchange in Signaling: Disulfide Bonds As a Switch

Matching a Reversible Sulfur Tipped-Reaction

I n this Forum, we brought together articles that highlight the current up-to-date knowledge on various thiol–disulfide exchange reactions accomplished either by low-molecular-weight (LMW) thiols or by enzymes operating along several pathways in the cell. The amino acid cysteine, embedded in a protein structural environment or in LMW compounds, is at the central core of the reactions discussed in this Forum.

In guerilla warfare, it is not easy to recognize your enemy from your friend, and how to combat. Oxygen has several faces: oxygen can be your friend or your foe, but in both cases, it plays an important role in supplying the oxidative equivalents or in receiving the electrons. Oxygen damage might occur directly on the sulfur or selenium element when targeted by reactive oxygen species (ROS), resulting in increased electrophilicity of the respective S or Se. On the other hand, oxygen is also the final molecule receiving the electrons from a cascade of thiol–disulfide exchange reactions involving proteins taking part in oxidative protein folding. The electron transfer process needs to work in good shape, as defects might lead to increased production of hydrogen peroxide with an impact on the fitness of the cell. The favorability of this electron transfer is given by the difference in redox potentials along the pathway, but the final reaction is driven and controlled by the kinetic forces of the oxidoreductases involved. These oxidoreductases are important cellular weapons against damaging ROS. It is crucial to understand how they operate. Peter Nagy (6) guides us through the subtle details of the kinetics, thiol–disulfide substitution, and redox mechanisms applied by these oxidoreductases.

War Troupes Against ROS in the Thiol World

To win a war in a Thiol World, the cellular military headquarters need to recruit enough resources and guide them to the correct compartment. Toledano et al. (7) describe the latest insights on glutathione fluxes between compartments and how each compartment has its own redox defense mechanism and redox state for optimal defense and function. Glutathione is not only drafted for redox duty, but also traffics iron to the iron–sulfur clusters, which is discussed by Lillig and Berndt (5). With the help of some glutaredoxins, the iron atom is properly coordinated in the iron–sulfur clusters, but glutaredoxins are multifunctional, and they also protect and regulate proteins via reversible S-glutathionylation (Fig. 1).

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FIG. 1.

An oxygen radical tries to damage a disulfide, for instance, between a protein thiol and glutathione, but does not succeed. As such, the sulfur is protected against overoxidation. When the stress is over, a protein such as a glutaredoxin can reduce the disulfide, via a thiol–disulfide exchange mechanism. This thiol on-and-off mechanism is tightly controlled to survive oxidative stress conditions.

Next to glutaredoxins, one of the most general oxidoreductase weapons is thioredoxin. Cho and Collet (2) review the several faces of the thioredoxin family members in the reducing pathways of the bacterial periplasm. These thioredoxin-fold enzymes correct the protein disulfide bonds and kinetically prevent overoxidation of lonesome cysteines. Ester Zito reports on peroxiredoxin 4 (9), a redox enzyme present in the endoplasmic reticulum. This efficient judoka-fighting protein captures the attacking damaging hydrogen peroxide and utilizes the oxidative equivalents to provide disulfide bonds to the oxidative protein-folding pathway. By combining hydrogen peroxide catabolism with oxidative folding, Prx4 double protects. Peroxiredoxins are also the main soldiers in the article by Couturier et al. (3). In Thermotoga maritima, a bacterium that lives under hot conditions and in the absence of oxygen as the final electron acceptor, peroxiredoxins uniquely remove peroxide with electrons shuttled from NADH-dependent thioredoxin reductase via glutaredoxin-like proteins.

For fast operations under exotic conditions, the cell benefits from the evolutionary expansion of the more-established cysteine containing defense arsenal with selenocysteine-containing enzymes. Hondal et al. (4) look at the benefits of this new weapon and how it accelerates reactions toward the diffusion-controlled limits.

Next to the battalions of oxidoreductases, the cell applies an additional defense line against oxidative stress to maintain redox homeostasis. Van Laer et al. (8) highlight the diverse and highly concentrated infantry of nonprotein thiol compounds, the LMW thiols. We have already mentioned glutathione, but certain cells evolved to not-so-well-known sulfur compounds, such as bacillithiol, mycothiol, trypanothione, ovothiol, and ergothioneine. These LMW thiols operate on their own or together with oxidoreductases to rescue single-oxidized sulfurs, also known as sulfenic acids, or to defeat the peroxide enemy even before the fatal attack (Fig. 1).

Operation S-Thiolation To Be Continued

Nature has decided to use an arsenal of weapons to fight ROS, to protect, to regulate, and to signal. Nevertheless, battles can be lost. However, when crucial cellular functions are jeopardized, there is always the survival act. Bode et al. (1) show that an increased hydrogen peroxide level due to a defect in the mitochondrial respiratory chain slows down the cellular proliferation of the damaged cells. Only the fittest will survive.

The Thiol World is an extremely interesting and challenging world from which many mysteries are still to be discovered. For instance, researchers still have to understand the code of the ROS language used by the cell. As the ROS wave travels through the cell, the thiol–disulfide exchange switches keep the wave on the signaling track away from fatal damage. We still need to get a clearer view on how the cell senses ROS above the metabolic ROS noise, allowing signaling, regulation, and finally protection via S-thiolation. The S-thiolated sulfurs need to be reactivated, and also here, catalyzed thiol–disulfide exchange comes into action.