HUMAN GLUTATHIONE TRANSFERASE A4-4 - AN ALPHA-CLASS ENZYME WITH HIGH CATALYTIC EFFICIENCY IN THE CONJUGATION OF 4-HYDROXYNONENAL AND OTHER GENOTOXIC PRODUCTS OF LIPID-PEROXIDATION

A sequence encoding a novel glutathione transferase, GST A4-4, has bee n identified in a human fetal brain cDNA library. The protein has been produced in Escherichia coli after optimization of the codon usage fo r high-level heterologous expression. The dimeric protein has a subuni t molecular mass of 25704 Da based on the deduced amino acid compositi on. Human GST A4-4 is a member of the Alpha class but shows only 53 % amino acid sequence identity with the major liver enzyme GST A1-1. Hig h catalytic efficiency with 4-hydroxyalkenals and other cytotoxic and mutagenic products of radical reactions and lipid peroxidation is a si gnificant feature of GST A4-4. The k(cat)/K-m values for 4-hydroxynone nal and 4-hydroxydecenal are > 3 x 10(6) M-1.s(-1), several orders of magnitude higher than the values for conventional GST substrates. 4-Hy droxynonenal and other reactive electrophiles produced by oxidative me tabolism have been linked to aging, atherosclerosis, cataract formatio n, Parkinson's disease and Alzheimer's disease, as well as other degen erative human conditions, suggesting that human GST A4-4 fulfills an i mportant protective role and that variations in its expression may hav e significant pathophysiological consequences.