Characterization of WY 14,643 and its complex with Aldose reductase

Abstract

The peroxisome proliferator, WY 14,643 exhibits a pure non-competitive inhibition pattern in the aldehyde reduction and in alcohol oxidation activities of human Aldose reductase (hAR). Fluorescence emission measurements of the equilibrium dissociation constants, Kd, of oxidized (hAR• NADP+) and reduced (hAR• NADPH) holoenzyme complexes display a 2-fold difference between them. Kd values for the dissociation of WY 14,643 from the oxidized (hAR• NADP+ • WY 14,643) and reduced (hAR• NADPH• WY 14,643) ternary complexes are comparable to each other. The ternary complex structure of hAR• NADP+ • WY 14,643 reveals the first structural evidence of a fibrate class drug binding to hAR. These observations demonstrate how fibrate molecules such as WY 14,643, besides being valued as agonists for PPAR, also inhibit hAR.