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 vivo also generally occurs via thiol-disulfide exchange reactions. Typically, the thiolate of a cysteine residue attacks the disulfide bond of a redox reagent such as glutathione or DTT, forming a mixed disulfide bond between the protein and the reagent; if this mixed disulfide bond is attacked by another protein thiolate, an intra-protein disulfide bond is formed, leaving the reagent reduced. In effect, the disulfide bond is transferred from the reagent to the protein in two steps, both thiol-disulfide exchange reactions.

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

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