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Aldose and aldehyde reductases: structure-function studies on the coenzyme and inhibitor-binding sites
O El-Kabbani1, S E Old, S L Ginell
1Department of Medicinal Chemistry, Victorian College of Pharmacy, Monash University, Parkville, Australia. ossama.el-kabbani@vcp.monash.edu.au
Molecular Vision
|September 24, 1999
Summary
Structural differences in aldose and aldehyde reductases explain varying inhibitor specificities. Non-conserved residues, like Pro 216 in aldose reductase, are key to coenzyme binding and inhibitor interactions.
Area of Science:
- Biochemistry
- Enzymology
- Structural Biology
Background:
- Aldose and aldehyde reductases are crucial enzymes with distinct substrate specificities.
- Understanding their structural differences is key to developing targeted inhibitors.
Purpose of the Study:
- To elucidate the structural basis for differing coenzyme and inhibitor specificities between aldose and aldehyde reductases.
- To identify specific amino acid residues and structural features responsible for these differences.
Main Methods:
- Determined the crystal structure of porcine aldehyde reductase complexed with NADPH and sorbinil.
- Calculated amino acid contributions to NADPH binding in the coenzyme-binding site.
- Utilized site-directed mutagenesis in human aldose reductase to study Pro 216's role.
Main Results:
- Sorbinil binds aldehyde reductase, forming hydrogen bonds with key residues including non-conserved Arg 312.
- Sorbinil binding does not alter Arg 312 conformation, unlike other inhibitors.
- Mutating aldose reductase's Pro 216 to Ser enhances NADPH binding similarity to aldehyde reductase.
Conclusions:
- Non-conserved active site residues and differential structural changes dictate inhibitor binding and potency.
- The non-conserved Pro 216 in aldose reductase significantly contributes to tight NADPH binding.
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