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Title: Aldose and aldehyde reductases : structure-function studies on the coenzyme and inhibitor-binding sites.

Abstract

PURPOSE: To identify the structural features responsible for the differences in coenzyme and inhibitor specificities of aldose and aldehyde reductases. METHODS: The crystal structure of porcine aldehyde reductase in complex with NADPH and the aldose reductase inhibitor sorbinil was determined. The contribution of each amino acid lining the coenzyme-binding site to the binding of NADPH was calculated using the Discover package. In human aldose reductase, the role of the non-conserved Pro 216 (Ser in aldehyde reductase) in the binding of coenzyme was examined by site-directed mutagenesis. RESULTS: Sorbinil binds to the active site of aldehyde reductase and is hydrogen-bonded to Trp 22, Tyr 50, His 113, and the non-conserved Arg 312. Unlike tolrestat, the binding of sorbinil does not induce a change in the side chain conformation of Arg 312. Mutation of Pro 216 to Ser in aldose reductase makes the binding of coenzyme more similar to that of aldehyde reductase. CONCLUSIONS: The participation of non-conserved active site residues in the binding of inhibitors and the differences in the structural changes required for the binding to occur are responsible for the differences in the potency of inhibition of aldose and aldehyde reductases. We report that the non-conserved Pro 216 inmore » aldose reductase contributes to the tight binding of NADPH.« less

Authors:
; ; ; ; ; ;
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States)
Sponsoring Org.:
USDOE Office of Science (SC)
OSTI Identifier:
942680
Report Number(s):
ANL/BIO/JA-33698
Journal ID: ISSN 1090-0535; TRN: US200920%%123
DOE Contract Number:  
DE-AC02-06CH11357
Resource Type:
Journal Article
Journal Name:
Mol. Vision
Additional Journal Information:
Journal Volume: 5; Journal Issue: 20 ; Sep. 3, 1999; Journal ID: ISSN 1090-0535
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; ALDEHYDES; AMINO ACIDS; CHAINS; COENZYMES; CRYSTAL STRUCTURE; MUTAGENESIS; MUTATIONS; OXIDOREDUCTASES; RESIDUES

Citation Formats

El-Kabbani, O., Old, S. E., Ginell, S. L., Carper, D. A., Biosciences Division, Monash Univ., and NIH. Aldose and aldehyde reductases : structure-function studies on the coenzyme and inhibitor-binding sites.. United States: N. p., 1999. Web.
El-Kabbani, O., Old, S. E., Ginell, S. L., Carper, D. A., Biosciences Division, Monash Univ., & NIH. Aldose and aldehyde reductases : structure-function studies on the coenzyme and inhibitor-binding sites.. United States.
El-Kabbani, O., Old, S. E., Ginell, S. L., Carper, D. A., Biosciences Division, Monash Univ., and NIH. Fri . "Aldose and aldehyde reductases : structure-function studies on the coenzyme and inhibitor-binding sites.". United States.
@article{osti_942680,
title = {Aldose and aldehyde reductases : structure-function studies on the coenzyme and inhibitor-binding sites.},
author = {El-Kabbani, O. and Old, S. E. and Ginell, S. L. and Carper, D. A. and Biosciences Division and Monash Univ. and NIH},
abstractNote = {PURPOSE: To identify the structural features responsible for the differences in coenzyme and inhibitor specificities of aldose and aldehyde reductases. METHODS: The crystal structure of porcine aldehyde reductase in complex with NADPH and the aldose reductase inhibitor sorbinil was determined. The contribution of each amino acid lining the coenzyme-binding site to the binding of NADPH was calculated using the Discover package. In human aldose reductase, the role of the non-conserved Pro 216 (Ser in aldehyde reductase) in the binding of coenzyme was examined by site-directed mutagenesis. RESULTS: Sorbinil binds to the active site of aldehyde reductase and is hydrogen-bonded to Trp 22, Tyr 50, His 113, and the non-conserved Arg 312. Unlike tolrestat, the binding of sorbinil does not induce a change in the side chain conformation of Arg 312. Mutation of Pro 216 to Ser in aldose reductase makes the binding of coenzyme more similar to that of aldehyde reductase. CONCLUSIONS: The participation of non-conserved active site residues in the binding of inhibitors and the differences in the structural changes required for the binding to occur are responsible for the differences in the potency of inhibition of aldose and aldehyde reductases. We report that the non-conserved Pro 216 in aldose reductase contributes to the tight binding of NADPH.},
doi = {},
journal = {Mol. Vision},
issn = {1090-0535},
number = 20 ; Sep. 3, 1999,
volume = 5,
place = {United States},
year = {1999},
month = {9}
}