Reduction of derived aldehydes by a fibro blast growth factor-induced enyzme, FR-I

Free radicals-catalyzed peroxidation of polyunsaturated fatty acids yields alkanals, alkenals, 4-hydroxyalkenals and alkadienals, which can act as toxic second messengers and lead to spatial and temporal extension of the injurious potential of the initial free radical events. We show that murine fibroblast growth factor-regulated enzyme (FR-I) catalyses the reduction the lipid derived aldehydes. K", aldehydes decreased as a function of chain length. The aldehydes with nine carbons viz. nonanal, nonenal, 4-hydroxynonenal (HNE) and nonadienal have a K" of 8-10 uM as compared to K m j,rolmi| and K(tm) cioionaiddiydc. 3-5 mM. The catalytic efficiency of C-9 compounds increased by more than 500 fold as compared to C-3 and C-4 compounds. Incubation of the apoenzyme with 'H-HNE led to an irrversible loss of activity. Sequence analysis of the radiolabeled peptides revealed the modification of Cys-299. The Cys-299 mutant was insensitive to HNE-induced modification of the enzyme and Km of 4-hydroxyalkenals increased by 5 to 10 fold for the mutant enzyme. These studies indicate that FR-I which has - 70% homology with mammalian aldose reductase and comparable active site, could play a pivotal role in the detoxification of lipid derived aldehydes.