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

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Date
20162016
Author
Sawaya, M.R.
Verma, M.
Balendiran, V.
Rath, N.P.
Cascio, D.
Balendiran, G.K.
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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. ? The Author(s) 2016.
Journal
Scientific Reports