skip to main content
DOE PAGES title logo U.S. Department of Energy
Office of Scientific and Technical Information

Title: 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.

Authors:
 [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)
Publication Date:
Research Org.:
Stanford Synchrotron Radiation Lab., (SSRL), CA (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Biological and Environmental Research (BER) (SC-23)
OSTI Identifier:
1378554
Resource Type:
Accepted Manuscript
Journal Name:
Scientific Reports
Additional Journal Information:
Journal Volume: 6; Journal Issue: 1; Journal ID: ISSN 2045-2322
Publisher:
Nature Publishing Group
Country of Publication:
United States
Language:
English
Subject:
37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY

Citation Formats

Sawaya, Michael R., Verma, Malkhey, Balendiran, Vaishnavi, Rath, Nigam P., Cascio, Duilio, and Balendiran, Ganesaratnam K. Characterization of WY 14,643 and its Complex with Aldose Reductase. United States: N. p., 2016. Web. doi:10.1038/srep34394.
Sawaya, Michael R., Verma, Malkhey, Balendiran, Vaishnavi, Rath, Nigam P., Cascio, Duilio, & Balendiran, Ganesaratnam K. Characterization of WY 14,643 and its Complex with Aldose Reductase. United States. doi:10.1038/srep34394.
Sawaya, Michael R., Verma, Malkhey, Balendiran, Vaishnavi, Rath, Nigam P., Cascio, Duilio, and Balendiran, Ganesaratnam K. Mon . "Characterization of WY 14,643 and its Complex with Aldose Reductase". United States. doi:10.1038/srep34394. https://www.osti.gov/servlets/purl/1378554.
@article{osti_1378554,
title = {Characterization of WY 14,643 and its Complex with Aldose Reductase},
author = {Sawaya, Michael R. and Verma, Malkhey and Balendiran, Vaishnavi and Rath, Nigam P. and Cascio, Duilio and Balendiran, Ganesaratnam K.},
abstractNote = {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.},
doi = {10.1038/srep34394},
journal = {Scientific Reports},
number = 1,
volume = 6,
place = {United States},
year = {2016},
month = {10}
}

Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record

Citation Metrics:
Cited by: 1 work
Citation information provided by
Web of Science

Save / Share:

Works referenced in this record:

A short history of SHELX
journal, December 2007

  • Sheldrick, George M.
  • Acta Crystallographica Section A Foundations of Crystallography, Vol. 64, Issue 1, p. 112-122
  • DOI: 10.1107/S0108767307043930

Coot model-building tools for molecular graphics
journal, November 2004

  • Emsley, Paul; Cowtan, Kevin
  • Acta Crystallographica Section D Biological Crystallography, Vol. 60, Issue 12, p. 2126-2132
  • DOI: 10.1107/S0907444904019158

    Works referencing / citing this record:

    CCDC 1476501: Experimental Crystal Structure Determination: IXIJOQ : ((4-chloro-6-((2,3-dimethylphenyl)amino)pyrimidin-2-yl)sulfanyl)acetic acid
    dataset, April 2016