Stability to Conjugation Processes

Of key importance is a hydrogen bond between a conserved G-site tyrosine residue and the glutathione thiol group. This hydrogen bond stabilizes the thiolate anion of the active site-bound glutathione. Estimated pfC, values for the bound glutathione are at least two pfC, units below the pfC, value for glutathione free in aqueous solution. 

The H-site is formed of clusters ofnon-polar amino acid side chains which provide a highly hydrophobic surface, which, in the absence of a drug substrate is open to bulk solvent Binding of substrates to this site has been shown to relate to increased lipophilicity for substrates (4-hydroxyalkenes). The actual conjugation reaction, with the thiolate anion acting as a nucleophile proceeds via an SN2-type mechanism yielding the deactivated product 

Conjugation with glucuronic acid or sulphate requires a nucleophilic substituent to be present in the molecule, normally an hydroxyl function. In the case of the glu- 

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