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.
Highlights
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
Clofibrate amphipathic carboxylic acids of a class known as fibrates, or peroxisome proliferators, are drugs once widely used in the clinical management of hyperlipidemia[1]
Clofibric acid glucuronide has been shown to mediate the formation of covalently bound clofibric acid-albumin adducts in vitro[2] and clofibric acid-plasma protein adducts are identified in man and rat[3]
Summary
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). Hyperlipidemia is a medical condition involving elevated levels of lipids in the blood, such as cholesterol and triglycerides It causes blood vessels occlusion and increases the risk of developing atherosclerosis, coronary heart disease, strokes, hypertension or diabetes. A synthetic derivative of clofibrate, [4-Chloro-6-(2,3-xylidino)-2-pyrimidinylthio]acetic Acid (WY 14,643) (Fig. 1), is a potent anti hypercholesterolemic agent[8] It is currently under investigation for prevention of heart failure resulting from hyperlipidemia. Overall WY 14,643 is considered a potent murine (PPAR)αagonist and a weak PPARγagonist[13] Through this agonistic behavior, WY 14,643 increases PPAR transcriptional activity, thereby increasing levels of fatty acid oxidation, cell division, and cancer. AR has been linked in increased cardiovascular mortality rate with diabetic autonomic neuropathy patients[24] These observations form the foundation to develop specific effective AR inhibitors
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