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

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

doi:10.1038/srep34394

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

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

University of Missouri-St. Louis

Research output: Contribution to journal › Article › peer-review

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, K d , of oxidized (hAR•NADP + ) and reduced (hAR•NADPH) holoenzyme complexes display a 2-fold difference between them. K d 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.

Original language	American English
Journal	Scientific Reports
Volume	6
DOIs	https://doi.org/10.1038/srep34394
State	Published - Oct 10 2016

Disciplines

Biochemistry, Biophysics, and Structural Biology
Biochemistry
Chemistry

Access to Document

10.1038/srep34394License: CC BY

Characterization of WY 14,643 and its complex with.pdfFinal published version, 3.64 MBLicense: CC BY
srep34394.pdfFinal published version, 1.44 MBLicense: CC BY

Cite this

@article{8293d3771302438b905a61e7190c8e14,

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, K d , of oxidized (hAR•NADP + ) and reduced (hAR•NADPH) holoenzyme complexes display a 2-fold difference between them. K d 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. ",

author = "Sawaya, {Michael R.} and Malkhey Verma and Vaishnavi Balendiran and Nigam Rath and Duilio Cascio and Balendiran, {Ganesaratnam K.}",

year = "2016",

month = oct,

day = "10",

doi = "10.1038/srep34394",

language = "American English",

volume = "6",

journal = "Scientific Reports",

}

TY - JOUR

T1 - Characterization of WY 14,643 and its Complex with Aldose Reductase

AU - Sawaya, Michael R.

AU - Verma, Malkhey

AU - Balendiran, Vaishnavi

AU - Rath, Nigam

AU - Cascio, Duilio

AU - Balendiran, Ganesaratnam K.

PY - 2016/10/10

Y1 - 2016/10/10

N2 - 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 d , of oxidized (hAR•NADP + ) and reduced (hAR•NADPH) holoenzyme complexes display a 2-fold difference between them. K d 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.

AB - 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 d , of oxidized (hAR•NADP + ) and reduced (hAR•NADPH) holoenzyme complexes display a 2-fold difference between them. K d 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.

U2 - 10.1038/srep34394

DO - 10.1038/srep34394

M3 - Article

VL - 6

JO - Scientific Reports

JF - Scientific Reports

ER -