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Originally published In Press as doi:10.1074/jbc.M909235199 on April 10, 2000

J. Biol. Chem., Vol. 275, Issue 28, 21587-21595, July 14, 2000
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Kinetic and Structural Characterization of the Glutathione-binding Site of Aldose Reductase*

Bharat L. DixitDagger , Ganesaratnam K. Balendiran§, Stanley J. WatowichDagger , Sanjay Srivastava, Kota V. RamanaDagger , J. Mark Petrash||, Aruni Bhatnagar, and Satish K. SrivastavaDagger **

From the Dagger  Department of Human Biological Chemistry and Genetics, University of Texas Medical Branch, Galveston, Texas 77555-0647, the || Departments of Ophthalmology and Visual Sciences and of Genetics, Washington University School of Medicine, St. Louis, Missouri 63110, the § Department of Biochemistry/Biophysics, Texas A&M University, College Station, Texas 77843, and the  Division of Cardiology, Department of Medicine, University of Louisville, Louisville, Kentucky 40202

Aldose reductase (AR), a member of the aldo-keto reductase superfamily, has been implicated in the etiology of secondary diabetic complications. However, the physiological functions of AR under euglycemic conditions remain unclear. We have recently demonstrated that, in intact heart, AR catalyzes the reduction of the glutathione conjugate of the lipid peroxidation product 4-hydroxy-trans-2-nonenal (Srivastava, S., Chandra, A., Wang, L., Seifert, W. E., Jr., DaGue, B. B., Ansari, N. H., Srivastava, S. K., and Bhatnagar, A. (1998) J. Biol. Chem. 273, 10893-10900), consistent with a possible role of AR in the metabolism of glutathione conjugates of aldehydes. Herein, we present several lines of evidence suggesting that the active site of AR forms a specific glutathione-binding domain. The catalytic efficiency of AR in the reduction of the glutathione conjugates of acrolein, trans-2-hexenal, trans-2-nonenal, and trans,trans-2,4-decadienal was 4-1000-fold higher than for the corresponding free alkanal. Alterations in the structure of glutathione diminished the catalytic efficiency in the reduction of the acrolein adduct, consistent with the presence of specific interactions between the amino acid residues of glutathione and the AR active site. In addition, non-aldehydic conjugates of glutathione or glutathione analogs displayed active-site inhibition. Molecular dynamics calculations suggest that the conjugate adopts a specific low energy configuration at the active site, indicating selective binding. These observations support an important role of AR in the metabolism of glutathione conjugates of endogenous and xenobiotic aldehydes and demonstrate, for the first time, efficient binding of glutathione conjugates to an aldo-keto reductase.

* This work was supported in part by National Institutes of Health Grants DK36118 (to S. K. S.) and Grants HL55477 and HL59378 (to A. B.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

** To whom correspondence should be addressed: Dept. of Human Biological Chemistry and Genetics, Rm. 6.644, Basic Science Bldg., University of Texas Medical Branch, Galveston, TX 77555-0647. Tel.: 409-772-3926; Fax: 409-772-9679; E-mail: ssrivast@utmb.edu.

Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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