X-Ray Crystallographic and Kinetic Studies of Human Sorbitol Dehydrogenase
| Autor: | Peter J. Oates, Virginia L. Rath, David Wasilko, Thomas A. Pauly, David A. Beebe, Ajith V. Kamath, Paul D. Adams, Boris A. Chrunyk, S. Edward Lee, Jennifer L Ekstrom, Banavara L. Mylari, Paul Colson Watts, Matthew C. Griffor, David Cunningham, Dewitt Mcguire, Rebecca Anne Madura, Timothy A. Subashi |
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| Jazyk: | angličtina |
| Předmět: |
chemistry.chemical_classification
Aldose reductase L-Iditol 2-Dehydrogenase Likelihood Functions Binding Sites biology Sorbitol dehydrogenase Protein Conformation Fructose macromolecular substances Crystallography X-Ray Cofactor chemistry.chemical_compound Kinetics Polyol pathway chemistry Biochemistry Oxidoreductase Structural Biology biology.protein Humans Sorbitol NAD+ kinase Molecular Biology Protein Binding |
| Zdroj: | Structure. (9):1071-1085 |
| ISSN: | 0969-2126 |
| DOI: | 10.1016/S0969-2126(03)00167-9 |
| Popis: | Sorbitol dehydrogenase (hSDH) and aldose reductase form the polyol pathway that interconverts glucose and fructose. Redox changes from overproduction of the coenzyme NADH by SDH may play a role in diabetes-induced dysfunction in sensitive tissues, making SDH a therapeutic target for diabetic complications. We have purified and determined the crystal structures of human SDH alone, SDH with NAD+, and SDH with NADH and an inhibitor that is competitive with fructose. hSDH is a tetramer of identical, catalytically active subunits. In the apo and NAD+ complex, the catalytic zinc is coordinated by His69, Cys44, Glu70, and a water molecule. The inhibitor coordinates the zinc through an oxygen and a nitrogen atom with the concomitant dissociation of Glu70. The inhibitor forms hydrophobic interactions to NADH and likely sterically occludes substrate binding. The structure of the inhibitor complex provides a framework for developing more potent inhibitors of hSDH. |
| Databáze: | OpenAIRE |
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