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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.

SUBMITTER: Sawaya MR 

PROVIDER: S-EPMC5056380 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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Characterization of WY 14,643 and its Complex with Aldose Reductase.

Sawaya Michael R MR   Verma Malkhey M   Balendiran Vaishnavi V   Rath Nigam P NP   Cascio Duilio D   Balendiran Ganesaratnam K GK  

Scientific reports 20161010


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, K<sub>d</sub>, of oxidized (hAR•NADP<sup>+</sup>) and reduced (hAR•NADPH) holoenzyme complexes display a 2-fold difference between them. K<sub>d</sub> values for the dissociation of WY 14,643 from the oxidized (hAR•NADP<sup>+</sup>•WY 14  ...[more]

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