Significance of an unusually low Km for glutathione in glutathione transferases of the alpha, mu and pi classes.
1. Interactions of glutathione transferases (GST) of the alpha, mu and pi classes with glutathione (GSH) and glutathione conjugates (GS-X) are in contrast with those of a GST of the theta class (GST5-5). 2. GST 5-5 has a Km for GSH of approx. 5 mM. Thus Km/ambient [GSH] is approx. 1, within the range of Km/ambient [s] of glycolytic enzymes. GSTs of the alpha, mu and pi classes yield much lower values of Km for GSH (approx. 0.1 mM) hence Km/ambient [s] is significantly lower than those of most (non-GST) enzymes (p < 0.025). 3. GSTs of the alpha, mu and pi classes are sensitive to inhibition by GS-X (i.e. product) and GS-X analogues. GST 5-5 is not. 4. Rate enhancements up to 10(10), similar to an average enzyme (10(8)-10(12)), are seen in catalysis by GST 5-5, but not in catalysis by GSTs of alpha, mu and pi classes (> 10(7)). 5. Comparisons of primary structure indicate that theta class GSTs may have a decreased binding of the glu-alpha-amino- and gly-COO(-)-groups of GSH compared with GSTs of the other classes. 6. It is concluded that GSTs of alpha, mu and pi classes have evolved towards increased product binding at the expense of catalytic efficiency. Thus GSH is uniquely utilized both as a nucleophile and a 'tag' which can be used to bind and sequester product particularly during GSH-depletion. This interpretation unifies the catalytic and binding properties of these GSTs and alters their perceived role in detoxication.
Meyer
D J
DJ
Department of Biochemistry and Molecular Biology, University College London, UK.
D000222:Adaptation, Physiological; D000595:Amino Acid Sequence; D002384:Catalysis; D005978:Glutathione / Q000378:metabolism*; D005982:Glutathione Transferase / Q000096:biosynthesis / Q000378:metabolism*; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism*; D007700:Kinetics; D008969:Molecular Sequence Data; D015394:Molecular Structure; D017386:Sequence Homology, Amino Acid
D007527:Isoenzymes; D005982:Glutathione Transferase; D005978:Glutathione