Structural basis for 4-hydroxyalkenal activity in human glutathione transferase A4-4

The Alpha class glutathione transferase A4-4 (GST A4-4) detoxifies products of lipid peroxidation, e.g.4-hydroxynonenal, by a Michael-addition to glut athione. Another Alpha class enzyme, GST A1-1, is not as efficient although the structures of the enzymes are superimposable and their amino acid sequ ences show 53% identity. In an attempt to identify the residues that are es sential for 4-hydroxyalkenal activity, active-site residues of GST A1-1 wer e mutated to the corresponding residues in GST A4-4. The residues were chos en by structure comparisons of the two different enzymes. The resulting mut ant displayed a catalytic efficiency with 4-hydroxynonenal, that was 20-fol d higher than the GST A1-1 value and only three times lower than the value for wild-type GST A4-4. (C) 2001 Elsevier Science Ireland Ltd. All rights r eserved.