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

Journal Article · · Scientific Reports
DOI:https://doi.org/10.1038/srep34394· OSTI ID:1378554
 [1];  [2];  [3];  [4];  [1];  [3]
  1. UCLA-DOE, Los Angeles, CA (United States)
  2. Univ. of Manchester (United Kingdom)
  3. Youngstown State Univ., OH (United States)
  4. Univ. of Missouri, St. Louis, MO (United States)
+ Show Author Affiliations
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.
Research Organization:
Stanford Synchrotron Radiation Lab., (SSRL), CA (United States)
Sponsoring Organization:
USDOE Office of Science (SC), Biological and Environmental Research (BER) (SC-23)
OSTI ID:
1378554
Journal Information:
Scientific Reports, Journal Name: Scientific Reports Journal Issue: 1 Vol. 6; ISSN 2045-2322
Publisher:
Nature Publishing GroupCopyright Statement
Country of Publication:
United States
Language:
English

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37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY