GSTA1-2, A2-2, and P1-1 display selenium-independent glutathione peroxidase activity, a property also characterizing the selenium-containing enzyme glutathione peroxidase (EC 18.104.22.168). The GST A1-1 and A1-2 are also known as ligandin when they act as binding or carrier proteins, a property also displayed by mu class GSTs. In the latter function, these enzymes bind and transport a number of active endogenous compounds (e.g., bilirubin, cholic acid, steroid and thyroid hormones, and hematin), as well as some exogenous dyes and carcinogens.
The conjugating reactivity of glutathione is due to its thiol group (pKa 9.0), which makes it a highly effective nucleophile. The nucleophilic character of the thiol group is greatly enhanced by deprotonation to a thiolate. In fact, an essential component of the catalytic mechanism of glutathione transferases is the marked increase in acidity (pKa decreased by 2-3 units) experienced by the thiol group upon binding of glutathione to the active site of the enzyme.118 As a result, GSTs transfer glutathione to a very large variety of electrophilic groups; depending on the nature of the substrate, the reactions can be categorized as nucleophilic substitutions or nucleophilic additions. And with compounds of sufficient reactivity, these reactions can also occur nonenzymatically.118'124'125
Once formed, glutathione conjugates (65, Figure 22; R-SG) are seldom excreted as such (they are best characterized in vitro or in the bile of laboratory animals), but usually undergo further biotransformation prior to urinary or fecal excretion. Cleavage of the glutamyl moiety by glutamyl transpeptidase (EC 22.214.171.124) and of the glycyl moiety by cysteinylglycine dipeptidase (EC 126.96.36.199; aminopeptidase M) leaves a cysteine conjugate (66; R-S-Cys), which is further N-acetylated by cysteine-S-conjugate N-acetyltransferase (EC 188.8.131.52) to yield an N-acetylcysteine conjugate (67; R-S-CysAc). The latter type of conjugates are known as mercapturic acids, a name which clearly indicates that they were first characterized in urine. This, however, does not imply that the degradation of unexcreted glutathione conjugates must stop at this stage, since cysteine conjugates can be substrates of cysteine-S-conjugate b-lyase (EC 184.108.40.206) to yield thiols (R-SH). These in turn can rearrange, be oxidized, or be S-methylated and then S-oxygenated to yield thiomethyl conjugates (R-S-Me), sulfoxides (R-SO-Me), and sulfones (R-SO2-Me).
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