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

Sawaya, Michael R.; Verma, Malkhey; Balendiran, Vaishnavi; Rath, Nigam P.; Cascio, Duilio; Balendiran, Ganesaratnam K.

doi:10.1038/srep34394

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

Journal Article · Mon Oct 10 00:00:00 EDT 2016 · Scientific Reports

DOI:https://doi.org/10.1038/srep34394· OSTI ID:1378554

Sawaya, Michael R. ^[1]; Verma, Malkhey ^[2]; Balendiran, Vaishnavi ^[3]; Rath, Nigam P. ^[4]; Cascio, Duilio ^[1]; Balendiran, Ganesaratnam K. ^[3]

UCLA-DOE, Los Angeles, CA (United States)
Univ. of Manchester (United Kingdom)
Youngstown State Univ., OH (United States)
Univ. of Missouri, St. Louis, MO (United States)

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.

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Research Organization:: Stanford Synchrotron Radiation Lab., (SSRL), CA (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Biological and Environmental Research (BER)

OSTI ID:: 1378554

Journal Information:: Scientific Reports, Vol. 6, Issue 1; ISSN 2045-2322

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

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Cited by: 1 work

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