Thiol-disulfide exchange

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Thiol-disulfide exchange is a chemical reaction in which a thiolate group S ⁻ attacks a sulfur atom of a disulfide bond -S-S-. The original disulfide bond is broken, and its other sulfur atom (green atom in Figure 1) is released as a new thiolate, carrying away the negative charge. Meanwhile, a new disulfide bond forms between the attacking thiolate (red atom in Figure 1) and the original sulfur atom (blue atom in Figure 1).

Figure 1: Thiol-disulfide exchange showing the linear intermediate in which the charge is shared among the three sulfur atoms. The thiolate group (shown in red) attacks a sulfur atom (shown in blue) of the disulfide bond, displacing the other sulfur atom (shown in green) and forming a new disulfide bond.

The transition state of the reaction is a linear arrangement of the three sulfur atoms, in which the charge of the attacking thiolate is shared equally. The protonated thiol form -SH is unreactive, i.e., thiols cannot attack disulfide bonds, only thiolates. Hence, thiol-disulfide exchange is inhibited at low pH (typically, below 8) where the protonated thiol form is favored relative to the deprotonated thiolate form. (The pKa of a typical thiol group is roughly 8.3, but can vary due to its environment.)

Thiol-disulfide exchange is the principal reaction by which disulfide bonds are formed and rearranged in a protein. The rearrangement of disulfide bonds within a protein generally occurs via intra-protein thiol-disulfide exchange reactions; a thiolate group of a cysteine residue attacks one of the protein's own disulfide bonds. This process of disulfide rearrangement (known as disulfide shuffling) does not change the number of disulfide bonds within a protein, merely their location (i.e., which cysteines are bonded). Disulfide reshuffling is generally much faster than oxidation/reduction reactions, which change the number of disulfide bonds within a protein. The oxidation and reduction of protein disulfide bonds in vitro also generally occurs via thiol-disulfide exchange reactions. Typically, the thiolate of a redox reagent such as glutathione or dithiothreitol attacks the disulfide bond on a protein forming a mixed disulfide bond between the protein and the reagent. This mixed disulfide bond when attacked by another thiolate from the reagent, leaves the cysteine oxidised. In effect, the disulfide bond is transferred from the protein to the reagent in two steps, both thiol-disulfide exchange reactions.

The in vivo oxidation and reduction of protein disulfide bonds by thiol-disulfide exchange is facilitated by a protein called thioredoxin.

Increasing evidence suggests that many G protein-coupled receptors GPCR are thiol sensitive proteins (see Ref: Rubenstein, LA & Lanzara, RG. (1998)).

[edit] References

Gilbert HF. (1990) "Molecular and Cellular Aspects of Thiol-Disulfide Exchange", Advances in Enzymology, 63, 69-172.

Gilbert HF. (1995) "Thiol/disulfide exchange equilibria and disulfide bond stability", Methods in Enzymology, 251, 8-28.

Rubenstein, LA & Lanzara, RG. (1998) "Activation of G Protein-Coupled Receptors Entails Cysteine Modulation of Agonist Binding", J. Molecular Structure (Theochem), 430/1-3: 57-71 Links - [1] and [2].

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