X-ray crystallographic and kinetic studies of human sorbitol dehydrogenase |
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Authors: | Pauly Thomas A Ekstrom Jennifer L Beebe David A Chrunyk Boris Cunningham David Griffor Matthew Kamath Ajith Lee S Edward Madura Rebecca Mcguire Dewitt Subashi Timothy Wasilko David Watts Paul Mylari Banavara L Oates Peter J Adams Paul D Rath Virginia L |
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Institution: | Exploratory Medicinal Sciences, Pfizer Global Research and Development, Eastern Point Road, Groton, CT 06340, USA. |
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Abstract: | 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. |
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