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. Kdvalues 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.affiliation: UCLA-DOE, 611 Charles E. Young Drive East, 220 Boyer Hall, Los Angeles, CA 90095, USA.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Sawaya
authors.affiliation: Manchester Interdisciplinary Biocentre, 131 Princess Street, The University of Manchester, Manchester, M1 7DN, UK.
authors.forename: Malkhey
authors.initials: M
authors.lastname: Verma
authors.affiliation: Department of Chemistry, WBSH 6017, Youngstown State University, One University Plaza, Youngstown, OH 44555, USA.
authors.forename: Vaishnavi
authors.initials: V
authors.lastname: Balendiran
authors.affiliation: Department of Chemistry and Biochemistry, University of Missouri-St. Louis, St. Louis, MO 63121, USA.
authors.forename: Nigam P
authors.initials: NP
authors.lastname: Rath
authors.affiliation: UCLA-DOE, 611 Charles E. Young Drive East, 220 Boyer Hall, Los Angeles, CA 90095, USA.
authors.forename: Duilio
authors.initials: D
authors.lastname: Cascio
authors.affiliation: Department of Chemistry, WBSH 6017, Youngstown State University, One University Plaza, Youngstown, OH 44555, USA.
authors.forename: Ganesaratnam K
authors.initials: GK
authors.lastname: Balendiran
mesh_terms: D000449:Aldehyde Reductase / Q000737:chemistry*; D020035:Holoenzymes / Q000737:chemistry; D006801:Humans; D009249:NADP / Q000737:chemistry*; D000072417:Protein Domains; D011743:Pyrimidines / Q000737:chemistry*
chemical_list: D020035:Holoenzymes; D011743:Pyrimidines; D009249:NADP; C006253:pirinixic acid; D000449:Aldehyde Reductase